thromboxane-b2 and Hypertension

The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ascitic Fluid; Endometriosis; Epoprostenol; Estrogens; Female; Genital Diseases, Female; Genital Neoplasms, Female; Humans; Hypertension; Menorrhagia; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Progestins; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction; Vasoconstriction

It has been suggested that deficient formation of vasodilatory prostanoids may be involved in the pathogenesis of hypertension. PUFA can be a source of arachidonic acid, which is partly converted into prostanoids. Increasing the dietary amount of PUFA has been consistently shown to decrease blood pressure in animals and man. The mechanism of the blood pressure lowering action, however, is not clear. We have found that a diet rich in PUFA can lower blood pressure but at the same time reduce the formation of those vasodilatory prostanoids which nowadays are regarded as the most active ones in the circulatory regulation.

Topics: Adult; Blood Pressure; Dietary Fats; Fatty Acids, Essential; Humans; Hypertension; Kidney; Middle Aged; Prostaglandins; Thromboxane B2; Vasomotor System

There is an abundance of information suggesting that prostaglandins are involved in the development and clinical expression of atherosclerosis. Many studies demonstrate a relationship between prostaglandins and the risk factors for peripheral and coronary artery disease. Thus, part of the mechanism by which hyperlipidemia, diabetes mellitus, smoking, hypertension, sex hormones, age, heredity, emotional stress and diet contribute to the development and progression of atherosclerosis may be through an imbalance between thromboxane A2 and prostaglandin I2. Recent studies show a temporal relationship between acute ischemic events (specifically, unstable angina) and a transcardiac increase in thromboxane B2, while others demonstrate a salutary effect of disaggregatory and vasodilatory prostaglandins in such patients. If prostaglandins and thromboxane prove important in ischemic vascular disease, attention will be directed at the correction of their pathologic imbalance. This may be accomplished by dietary manipulation as well as by the development of prostaglandin receptor antagonists or inhibitors of specific prostaglandin pathways.

Topics: Age Factors; Arteriosclerosis; Coronary Disease; Diabetes Mellitus; Diet; Epoprostenol; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypertension; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Risk; Smoking; Stress, Physiological; Thromboxane A2; Thromboxane B2

Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.. Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).. PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).. AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Blood Platelets; Blotting, Western; Cell Line; Cyclooxygenase 2; Female; Humans; Hypertension; Male; Platelet Aggregation; Real-Time Polymerase Chain Reaction; Tetrazoles; Thrombosis; Thromboxane B2; Valine; Valsartan

To observe the effect of a integrative medical regimen (IMR), i.e. combined use of Jiangya Capsule (JYC) and Nimodipine (ND), on blood pressure, TCM clinical symptoms, and blood levels of vascular endothelial function and hypersensitive C-reactive protein (hs-CRP) in elderly patients with isolated systolic hypertension (EISH).. Adopting randomized, double-blinded and controlled principle, a trial was conducted on 135 patients with EISH by randomized them into three groups, they were administered IMR (Group A), JYC plus ND simulator (Group B) and ND plus JYC simulator (Group C) respectively, for 4 weeks. Changes of blood pressure and TCM symptoms, as well as the levels of serum nitric oxide (NO), plasma endothelin-1 (ET-1), 6-keto-prostaglandin 1alpha (6-keto-PGF(1alpha)), thromboxane B2 (TXB2) and hs-CRP were observed before and after treatment.. After treatment the systolic blood pressure reduced and clinical symptoms improved, with serum NO and 6-keto-PGF(1alpha) lelels elevated, plasma ET-1, TXB2 and serum hs-CRP decreased in all the three groups (P<0.05 or P<0.01). But the inter-group comparisons showed that the effect in Group A was superior to the other two groups in decreasing systolic pressure, and superior to Group C in improving clinical symptoms, elevating serum NO and decreasing plasma TXB2 (P <0.05).. The integrative medical regimen of combined use JYC and ND has markedly effect in lowering blood pressure, it could obviously improve the symptoms and vascular endothelial function, and inhibit the level of inflammatory factor in patients with EISH.

Topics: Aged; C-Reactive Protein; Double-Blind Method; Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Hypertension; Integrative Medicine; Male; Middle Aged; Nimodipine; Nitric Oxide; Phytotherapy; Thromboxane B2

Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system.. We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios.. Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Topics: Adolescent; Adult; Aged; Angioplasty; Angiotensin II; Antioxidants; Biomarkers; Blood Glucose; Cholesterol; Cross-Sectional Studies; Dinoprost; F2-Isoprostanes; Female; Homocysteine; Humans; Hypertension; Hypertension, Renovascular; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Platelet Activation; Reference Values; Renal Artery Obstruction; Renin; Renin-Angiotensin System; Thromboxane B2; Triglycerides; Vitamins

Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy.. In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF(1 alpha)and 2,3-dinor-6-keto-PGF(1 alpha)) and thromboxane A(2)(TxB(2)and 2,3-dinor-TxB(2)) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls.. In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF(1 alpha)/ TxB(2)-ratio as well as the 2, 3-dinor-6-keto-PGF(1 alpha)/ 2,3-dinor-TxB(2)-ratio did not significantly change in pregnancy. CONCLUISION Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Creatinine; Diet, Sodium-Restricted; Epoprostenol; Female; Humans; Hypertension; Longitudinal Studies; Postpartum Period; Pregnancy; Prostaglandins; Random Allocation; Sodium; Thromboxane A2; Thromboxane B2; Water-Electrolyte Balance

The ability of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors. This trial studied the interaction between aspirin (ASA) and enalapril, an ACE inhibitor, and ASA and losartan, an angiotensin subtype 1 receptor antagonist. Seventeen essential hypertensive patients were studied, maintained on a stable dose of either enalapril (n = 7) or losartan (n = 10) monotherapy for > or =12 weeks before and throughout the study. Each patient received a 2-week course of placebo, 81 mg/day ASA, and 325 mg/day ASA, each treatment separated by a 2-week washout period. Blood pressure (BP) and serum thromboxane B2 (TXB2) samples were obtained at the end of each treatment period. Placebo was compared with each dose of ASA for each group. In both the enalapril and losartan groups, mean, systolic, and diastolic BP were unchanged with the addition of ASA. Concentrations of TXB2 were suppressed to <10% in both groups with ASA. This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aspirin; Blood Pressure; Cross-Over Studies; Cyclooxygenase Inhibitors; Double-Blind Method; Drug Interactions; Enalapril; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Patient Compliance; Thromboxane B2

Nonsteroidal antiinflammatory drugs (NSAID) are frequently reported to interfere with the blood pressure lowering actions of various antihypertensive medications. We studied 17 women with arthritis and hypertension who were receiving fosinopril and HCTZ, and administered sequentially in random order ibuprofen, sulindac, and nabumetone for 1 month each, with an intervening 2-week washout period between each treatment period. During the washout period, subjects received acetaminophen. Blood pressure at the end of 2 weeks of acetaminophen was compared with blood pressure after 1 month of treatment with each of the NSAID. Mean blood pressure was unchanged before and after all NSAID: 108 +/- 7 v 107 +/- 9 for nabumetone, 108 +/-9 v 108 +/- 9 for sulindac, and 108 +/- 8 v 107 +/- 9 for ibuprofen. The 24-h urinary sodium excretion was not significantly different. We conclude that the three NSAID did not neutralize the antihypertensive effect of the combination of fosinopril and HCTZ, and hence the blood pressure lowering action of the combination may not be prostaglandin dependent.

Topics: Acetaminophen; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Blood Pressure; Butanones; Creatinine; Dinoprostone; Diuretics; Drug Interactions; Drug Therapy, Combination; Female; Fosinopril; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Ibuprofen; Middle Aged; Nabumetone; Renal Plasma Flow; Sodium; Sodium Chloride Symporter Inhibitors; Sulindac; Thromboxane B2

The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved.. Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods.. 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]).. A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Double-Blind Method; Enalapril; Humans; Hypertension; Middle Aged; Phthalic Acids; Platelet Aggregation Inhibitors; Thromboxane B2; Thromboxanes

Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function.. We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free.. The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Topics: Adult; Aged; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Prospective Studies; Reproducibility of Results; Risk Factors; Smoking; Thromboxane A2; Thromboxane B2; Vascular Diseases

Angiotensin II enhances platelet aggregation through activation of the G protein-linked pathway present in platelets. Studies of several angiotensin-converting enzyme (ACE) inhibitors have demonstrated marked differences on platelets. Therefore this prospective, randomized, double-blind, crossover study compared the ex vivo effects of equivalent antihypertensive doses of captopril, enalapril, and fosinopril on platelet aggregation and thromboxane B2 (TxB2) formation in subjects with stage I-II essential hypertension. Nineteen male subjects with a baseline mean seated blood pressure of 141 +/- 3/100 +/- 1 mm Hg were enrolled. The decline in mean arterial pressure after 4 weeks of stable dosing was 10 +/- 1, 12 +/- 1, and 11 +/- 1 mm Hg for captopril, enalapril, and fosinopril, respectively (p = NS). There was no significant change in adenosine diphosphate (ADP)-, epinephrine-, or thrombin-stimulated platelet aggregation from baseline or between ACE inhibitors. Compared with baseline, fosinopril decreased TxB2 concentrations 27.5-67.6% with all stimuli after 1 and 5 min. Captopril also decreased TxB2 formation, but this effect was stimulus and time dependent. Enalapril consistently increased TxB2 concentrations, independent of stimuli or time. We conclude that different ACE inhibitors have distinct effects on platelet TxB2 formation without significant effects on platelet aggregation. Fosinopril may be a direct antagonist ofTxA2 synthase, suggesting benefit in syndromes of platelet activation or vascular occlusion.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Area Under Curve; Blood Platelets; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

Forty-five patients of essential hypertension differentiated into two TCM types, i.e. Gan Yang Shang Kang Zheng (GYSK) and Yin Xu Yang Kang Zheng (YXYK) were randomly selected. Among them, the 31 patients received qi-gong therapy including 12 GYSK cases (group b) and 19 YXYK cases (group c) and 14 patients (group d) received nifedipine therapy. It was found that the plasma 6-K-PGF1 alpha was increased and TXB2 as well as TXB2/6-K-PGF1 alpha ratio were decreased after the therapy (P < 0.05) in group b, c and d. No statistical significant difference was found between group b and group c (P > 0.05). The results suggest that qi-gong is regulatory on TXB2 and 6-K-PGF1 alpha in patients with essential hypertension and is identical in the two different TCM Zheng types.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Breathing Exercises; Diagnosis, Differential; Female; Humans; Hypertension; Male; Medicine, Chinese Traditional; Middle Aged; Thromboxane B2; Yin Deficiency

Protacyclin biosynthesis was investigated in 133 untreated newly diagnosed patients with uncomplicated essential hypertension. Urinary excretion of 6-oxo-prostaglandin F1 alpha and of 2,3-dinor-6-oxo-prostaglandin F1 alpha, stable breakdown products of prostacyclin, was measured following a 1 month run-in period. To determine whether lowering blood pressure (BP) influenced prostacyclin biosynthesis, 106 consenting patients with diastolic pressure 90-120 mm Hg were allocated randomly to treatment with bendrofluazide, metoprolol, quinapril or amlodipine in an open parallel group design. Dose was increased to reduce diastolic arterial pressure to <90 mm Hg. Terazosin was added if this target BP was not achieved, and its dose increased if necessary. Urinary excretion rates of prostaglandins were measured after 1 year in patients in whom the target diastolic pressure was achieved. Mean arterial pressure varied from 106-168 mm Hg in untreated patients and excretion of both prostacyclin-derived products varied from <5 to >350 ng/g creatinine. Arterial pressure and prostaglandin excretion were not significantly correlated. In 57 patients in whom target pressure was achieved, BP before treatment was 166 +/- 2/100 +/- 1 at baseline and 144 +/- 2/86 +/- 1 mm Hg at 1 year. Excretion rates of each prostacyclin-derived product were similar before treatment and at 1 year, with no significant differences between the drugs. These findings do not support the hypothesis that deficient prostacyclin biosynthesis contributes to the pathogenesis of essential hypertension, or that increased prostacyclin biosynthesis plays a part in the response to treatment with antihypertensive medication.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Amlodipine; Antihypertensive Agents; Bendroflumethiazide; Epoprostenol; Female; Humans; Hypertension; Isoquinolines; Male; Metoprolol; Middle Aged; Quinapril; Tetrahydroisoquinolines; Thromboxane A2; Thromboxane B2

The use of cyclooxygenase inhibitors has been seen to reduce the efficacy of many antihypertensive drugs. However, cyclooxygenase inhibitors are normally non-selective because they affect both vascular tissue, where the endothelial prostanoids exert principally a vasodilatory action, and the kidneys, where they also play an important role in regulating hydroelectrolytic metabolism by redistribution of intraparenchymal flow. To evaluate the relative importance of vascular district in the hypertensive patient, we administered ibuprofen - a drug acting with only a minimal antagonist activity. A group of 20 male hypertensives were randomly allocated, according to a single-blind protocol, to treatment with amlodipine (A, 10 mg/day) or lisinopril (L, 20 mg/day). Blood pressure was significantly reduced after 30 days, with a mean difference of -21.75 mmHg for systolic blood pressure (SBP) (95% confidence interval (Cl): -27.46 to -16.04; P< 0.0001) and -14.15 mmHg for diastolic blood pressure (DBP) (95% Cl: -17.13 to -11.17; P< 0.0001). Brachial artery compliance showed a mean increase of 1.657 x 10(-7) dyn-1 cm(4) (95% Cl: 1.188 to 2.126; P<0.001), and forearm resistances showed a mean decrease of -41.973 mmHg ml(-1)s (95% Cl: -75.479 to -8.467; P = 0.017). Changes in compliance were significantly related to those in SBP (r= -0.546; P= 0.013). The administration of ibuprofen (400 mg, three times a day for 3 days) was accompanied by a slight but significant increase in SBP, but not in brachial artery compliance or forearm resistances. Only SBP was affected, showing a mean increase of 4.25 mmHg (95% Cl: 1.26 to 7.24; P = 0.008). There was also reduced urinary excretion of PGI(2) and TXA(2) metabolites. The mean change in 6-keto-PGF(1 alpha) and 2,3-dinor-6-keto-PGF(1 alpha) was 45.71 ng per g urinary creatinine (uCr) (95% Cl: -0.16 to-91.25; P= 0.049) and -73.17 ng (g uCr)(-1) (95% Cl: -38.81 to -107.53; P<0.001), respectively. The mean decrease in TXA(2) catabolites was highly significant: -39.2 ng (g uCr)(-1) (95% Cl: -18.17 to-60.22; P< 0.001) and -102.87 ng (g uCr)(-1) (95% Cl: -61.86 to -143.88; P< 0.001) for TXB(2) and 2,3-dinor-TXB(2), respectively. Our study highlighted an inverse correlation between changes in blood pressure and those in urinary 2,3-dinor-6-keto-PGF(1alpha) excretion, irrespective of antihypertensive regimen. This suggests that, in the hypertensive patient treated with NSAIDs, inhibition of vascular prostanoid synthesis may play an import

Topics: 6-Ketoprostaglandin F1 alpha; Amlodipine; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cyclooxygenase Inhibitors; Epoprostenol; Heart Function Tests; Heart Rate; Humans; Hypertension; Ibuprofen; Lisinopril; Male; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxane B2; Vasodilator Agents

Aspirin at low doses is used as an inhibitor of platelet aggregation and is frequently administered to essential hypertensive patients with arterial thrombotic complications. However, it is unknown whether aspirin can modify blood pressure values either in treated or untreated hypertensive patients, as described for other non steroidal anti-inflammatory drugs. Thus 30 patients. 10 with mild uncomplicated and untreated essential hypertension, 10 with essential hypertension under chronic treatment with captopril, 50 mg bid, and 10 with essential hypertension under chronic treatment with atenolol, 100 mg oid, received aspirin, 100 mg oid, and the corresponding placebo for one month, according to a double blind randomized cross-over design. At the end of each treatment, blood pressure, heart rate, generated serum thromboxane B2 and urinary excretion of thromboxane B2 and 6 keto prostaglandin F1 alpha and plasma renin activity were measured. Both in treated and untreated essential hypertensive patients, aspirin administration did not affect blood pressure, heart rate and urinary 6 keto prostaglandin F1 alpha, while it significantly reduced serum and urinary excretion of thromboxane B2 and plasma renin activity. In conclusion, while the present data confirm that low doses of aspirin selectively inhibit thromboxane B2 synthesis, they indicate that aspirin at 100 mg oid can be administered to treated and untreated essential hypertensive patients without any harmful effect on blood pressure values.

Topics: Adult; Aldosterone; Aspirin; Captopril; Cross-Over Studies; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renin; Thromboxane B2

The newly developed antihypertensive drugs, the long-acting beta-blocker propranolol and the sustained release calcium antagonist verapamil, are compared in their antihypertensive, platelet function, rheological properties and metabolic effects. The trial was a double-blind, randomised, placebo-controlled cross-over study. Thirty patients with mild to moderate hypertension received propranolol (40-120 mg) or verapamil (80-200 mg) once daily in two separate ten week courses. After ten weeks treatment both drugs had significantly reduced both SBP and DBP. Beta-thromboglobulin (beta-TG) concentration, reflecting the status of platelet activation in vivo, was significantly decreased after propranolol (129.6 +/- 13.5 vs. 77.9 +/- 8.6 ng/ml) and verapamil (129.6 +/- 13.5 vs. 90.7 +/- 10.1 ng/ml) treatments while platelet aggregation induced by ADP, collagen, arachidonic acid or adrenaline and the production of thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and platelet cyclic 3'-5' adenosine monophosphate (C-AMP) concentration were not affected. Significant alterations in rheological parameters such as plasma and whole blood viscosity, fibrinogen level and red cell deformability were not found. Higher cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels were observed after propranolol treatment but not in verapamil treatment. Side-effects were mild, tolerated and no patient had to be withdrawn from the study. In conclusion, propranolol and verapamil are generally effective antihypertensive as well as rheologically safe drugs. Compared with the metabolic effect on serum lipid, verapamil may be a better choice. Both drugs possess the tendency to inhibit platelet properties which is desirable in hypertension treatment.

Topics: Adult; Aged; beta-Thromboglobulin; Blood Flow Velocity; Blood Platelets; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Erythrocyte Deformability; Female; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Propranolol; Thromboxane B2; Time Factors; Verapamil

Concern has been expressed about possible neonatal side effects after the use of maternal anti-platelet agents in pregnancy, particularly low dose aspirin treatment. We have studied neonatal platelet behaviour using whole blood techniques, and assessed the neonatal effect of the maternal ingestion of 60 mg aspirin daily.. Cross sectional and randomised, double-blind, placebo-controlled.. University hospital.. 1. Eight normal women, studied before conception, and their infants. 2. Twenty-four infants whose mothers had been randomised to receive either 60 mg aspirin daily, or placebo, in double-blind fashion.. The Clay Adams Ultra Flo 100 whole blood single platelet counter was employed to measure platelet aggregation in response to various agonists. The platelet release reaction was also measured in whole blood, and serum thromboxane B2 (TxB2) production was measured by radio-immunoassay. Umbilical cord blood samples were obtained at delivery.. 1. Neonatal platelet aggregation induced by adrenaline, ADP and platelet activating factor was reduced in comparison with their mothers (P < 0.01), whereas the neonatal platelet release reaction was reduced when stimulated by collagen and U46619 (a thromboxane mimetic) (P < 0.01). Serum TxB2 production was similar in mothers and babies. 2. Neonatal platelet aggregation, release reaction and serum TxB2 production were not significantly reduced in infants exposed to maternal aspirin in comparison with those neonates exposed to maternal placebo. This is in contrast to the effect on maternal platelets.. Although only a small number of patients were studied, we interpret this as a relative sparing of neonatal platelet reactivity due to the presystemic action of low dose aspirin.

Topics: Adult; Aspirin; Double-Blind Method; Female; Fetal Blood; Humans; Hypertension; In Vitro Techniques; Infant, Newborn; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Some of the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors occur through nonangiotensin II-mediated mechanisms. One of these is through decreased kinin degradation, leading to enhanced production of vasodilator arachidonic acid metabolites. It was reasoned that if ACE inhibition also leads to an increase in the production of the potent vasoconstrictor thromboxane A2, then maneuvers that selectively inhibit thromboxane production without reducing prostaglandins (PG) E2 + PGI2 might enhance the antihypertensive effect of ACE inhibition. This double-blinded, randomized, crossover study was therefore undertaken to determine: (1) if captopril increases platelet and/or renal thromboxane production; and (2) if low-dose aspirin enhances the antihypertensive effect of captopril. Patients with mild essential hypertension and no other significant medical problems were studied. In a double-blinded, random order, patients took captopril alone (25 mg every 12 h) for 2 wk and captopril plus aspirin (75 mg/day) for another 2 wk. Active treatment periods were preceded by 2 wk of single-blind placebo. Fifteen patients with a mean age of 53 yr and an average mean arterial pressure (MAP) of 114 +/- 8 (+/- SD) mm Hg were studied. Serum thromboxane B2 was higher (P < 0.05) during treatment with captopril/placebo (600 +/- 46 (+/- SE) pg/mL) than during the two washout periods combined (420 +/- 57 and 553 +/- 78) and was lowest (P < 0.0005) during treatment with captopril/aspirin (302 +/- 36). Captopril treatment significantly increased the urinary excretion of PGE2 (P = 0.038). Captopril/placebo significantly lowered MAP (P < 0.05) to 105.0 +/- 3.7 mm Hg compared with the washout period. However, the addition of aspirin to captopril caused no additional lowering of MAP (105.2 +/- 2.8 mm Hg). It was concluded that treatment with captopril does increase platelet thromboxane production. However, lowering platelet thromboxane with low doses of aspirin may not enhance the antihypertensive effect of captopril.

Topics: Adult; Aspirin; Blood Platelets; Blood Pressure; Captopril; Double-Blind Method; Drug Interactions; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Thromboxane B2; Thromboxanes

Short-term effects of ridogrel, a combined thromboxane synthase inhibitor and receptor antagonist, were investigated in 16 patients with uncomplicated essential hypertension. After a 2-week placebo period without antihypertensive medication, patients were admitted to the hospital overnight on two occasions 3 weeks apart. On each occasion, they received two doses of either placebo or ridogrel (300 mg) 12 hours apart according to a double-blind crossover protocol. Renal and systemic thromboxane A2 and prostacyclin biosynthesis were investigated by measuring urinary excretion of thromboxane B2, 6-oxo-prostaglandin F1 alpha, and their respective 2,3-dinor metabolites using gas chromatography/mass spectrometry. Responses of platelets to a thromboxane A2 mimetic and to adenosine diphosphate were studied turbidometrically. Blood pressure was measured automatically at 20-minute intervals. Ridogrel reduced excretion of 2,3-dinor-thromboxane B2 and thromboxane B2 compared with placebo (21 +/- 6 versus 279 +/- 28 and 14 +/- 4 versus 39 +/- 9 ng/g creatinine, respectively; P < .0001 and P < .05). Excretion of 2,3-dinor-6-oxoprostaglandin F1 alpha and 6-oxoprostaglandin F1 alpha was increased by ridogrel compared with placebo (184 +/- 20 versus 146 +/- 11 and 86 +/- 9 versus 58 +/- 6 ng/g creatinine, respectively; P < .05). Ridogrel selectively antagonized platelet aggregation to the thromboxane mimetic (P < .0001). Blood pressure did not differ significantly between ridogrel and placebo treatment periods. Thus, in patients with essential hypertension, acute administration of ridogrel reduces renal and extrarenal thromboxane A2 biosynthesis, increases renal and extrarenal prostacyclin biosynthesis, inhibits thromboxane receptor-activated platelet aggregation, but has no effect on systemic arterial pressure.

Topics: Adult; Aged; Blood Pressure; Double-Blind Method; Eicosanoids; Female; Humans; Hypertension; Male; Middle Aged; Pentanoic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase

Twenty patients with mild to moderate hypertension took part in this study consisting of a two-week placebo treatment period, followed by treatment with an extended-release calcium channel blocker, felodipine-ER (5 to 20 mg once daily) for 12 weeks. The study evaluated the effects of felodipine-ER on blood pressure, platelet function and rheological properties in hypertension. Felodipine-ER significantly reduced systolic and diastolic blood pressure without changing heart rate. There was a significant decrease in adenosine diphosphate-induced platelet aggregation and platelet intracellular calcium concentration, but no significant change in plasma thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and platelet cyclic 3'5'-adenosine monophosphate concentrations. Adverse effects on biochemical and rheological properties were not found. In conclusion, felodipine-ER is an effective and metabolically safe antihypertensive drug. It reduces platelet aggregability and intracellular free calcium concentration without altering the production of TXB2 and 6-keto-PGF1 alpha.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Platelets; Blood Pressure; Blood Viscosity; Calcium; Cyclic AMP; Delayed-Action Preparations; Erythrocyte Deformability; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Single-Blind Method; Thromboxane B2

Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension.. Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled "run-in" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery.. Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06).. Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia.

Topics: Adult; Aspirin; Eclampsia; Female; Humans; Hypertension; Parity; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Thromboxane B2

60 cases with Yang Hyperactivity due to Yin Deficiency type of hypertension were randomly divided into two groups. One was treated with TCM and the other with WM as control. The results showed that: (1) there were no significant differences in the total effective rate and the amplitude of lowering of blood pressure between two groups; (2) the improvement of symptoms and disturbance of autonomic nerve was significant in TCM group in comparison with control; (3) there were some changes in HR, SV, plasma PRA, TXB2 and 6-keto-PGF1 alpha level in both groups, but the decrease of TXB2/6-keto-PGF1 alpha ratio was significant in TCM group only (P < 0.05); (4) TC and TG in patients with hyperlipemia showed a remarkable drop in TCM group (P < 0.02; P < 0.005). All these revealed that Qianxining was a satisfactory hypotensive remedy and a further exploration of its mechanism is suggested.

Topics: 6-Ketoprostaglandin F1 alpha; Cholesterol; Drugs, Chinese Herbal; Female; Humans; Hypertension; Male; Middle Aged; Thromboxane B2; Triglycerides; Yin Deficiency

To investigate the effect of 60 mg aspirin daily on platelet reactivity and prostaglandin production in various groups of patients. Similar regimens, which are thought to act through inhibition of platelet thromboxane production, are currently undergoing clinical assessment for the prevention of pre-eclampsia and intrauterine growth retardation.. A prospective randomized placebo controlled study.. University Hospital, Nottingham.. 12 non-pregnant female volunteers, 18 normal primigravidae before 16 weeks gestation and 16 pregnant women admitted with gestational hypertension (GH) at a mean gestation of 38 weeks.. In the non-pregnant women blood samples were taken before and after a 10-day course of 60 mg aspirin daily. The primigravidae had blood samples taken at 16 weeks and then they were randomized to receive either 60 mg aspirin daily or a matched placebo. Further blood samples were obtained at 28, 32 and 36 weeks.. Changes in platelet reactivity and release reaction, and serum thromboxane production, were estimated in whole blood.. 60 mg aspirin daily significantly inhibited cyclo-oxygenase dependent platelet aggregation, release reaction and serum thromboxane production in non-pregnant and pregnant women, and in women with GH (P less than 0.01). When adrenaline was used as the aggregating agent, the cyclo-oxygenase pathway was recruited in the increased reactivity seen in the third trimester of normal pregnancy, and was sensitive to inhibition by low dose aspirin.. Low dose aspirin would appear to be an appropriate agent for the inhibition of platelet reactivity associated with hypertensive pregnancy.

Topics: Adult; Arachidonic Acid; Aspirin; Collagen; Female; Humans; Hypertension; Platelet Aggregation; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Compliance; Double-Blind Method; Enalapril; Epoprostenol; Female; Hemodynamics; Humans; Hypertension; Ibuprofen; Lisinopril; Male; Middle Aged; Thromboxane B2; Vascular Resistance

To evaluate whether perindopril, a carboxyl-containing new angiotensin-converting enzyme (ACE) inhibitor, exerts its antihypertensive action through the stimulation of prostaglandin synthesis, 10 uncomplicated essential hypertensive patients randomly received indomethacin (50 mg b.i.d.) or the corresponding placebo for 1 week and the reverse treatment after 2 weeks. Perindopril alone tended to reduce serum and urinary thromboxane B2 (TxB2) and to raise urinary 6-ketoPGF1 alpha and PGE2 and inhibited serum ACE activity 24 h post dosing by about 85%. Indomethacin, which significantly inhibited serum TxB2 and urinary TxB2, 6-ketoPGF1 alpha, and PGE2 without interfering with the inhibitory effect of perindopril on ACE, significantly reduced the antihypertensive action of perindopril alone by about 30%, but decreased though not significantly that of perindopril plus placebo. Although the size of the study limits the interpretation, these findings suggest that the stimulation of prostaglandin synthesis plays only a minor role in the antihypertensive action of perindopril.

Topics: Adult; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Drug Interactions; Heart Rate; Humans; Hypertension; Indoles; Indomethacin; Male; Middle Aged; Peptidyl-Dipeptidase A; Perindopril; Prostaglandins; Random Allocation; Renin; Thromboxane B2

Topics: Adult; Blood Pressure; Double-Blind Method; Female; Humans; Hypertension; Indomethacin; Male; Middle Aged; Renin; Thromboxane B2

The effects of eight weeks of treatment with isradipine (1.25 mg twice daily for four weeks, followed by 2.5 mg twice daily for four weeks) on ex vivo platelet function were investigated in ten male patients with hypertension. Systolic and diastolic blood pressures, platelet aggregation in response to adenosine diphosphate (ADP), serum thromboxane B2, and beta-thromboglobulin levels were significantly decreased (P less than .05) at rest before exercise ergometry, during exercise, and at rest after exercise. The platelet count and plasma levels of 6-oxo-prostaglandin F1 alpha (PGF1 alpha) were not affected by isradipine. It is concluded that treatment of hypertension with a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit when routinely applied in hypertensive patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Antihypertensive Agents; beta-Thromboglobulin; Blood Platelets; Blood Pressure; Exercise; Exercise Test; Humans; Hypertension; Isradipine; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Pyridines; Rest; Thromboxane B2; Time Factors

Cromakalim, a novel potassium channel-activating drug, was administered for a 3-day period in eight untreated hospitalized patients with established hypertension. The fixed and single dose of 1.5 mg/day produced a significant reduction in systolic and diastolic blood pressure with a small increase in heart rate. Glomerular filtration rate was unchanged and effective renal plasma flow was slightly increased with a concomitant small decrease in filtration fraction and in renal vascular resistance. No significant change was observed in urinary prostaglandin (PG)E2, PGF2 alpha, and thromboxane B2, while 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) rose from 189 +/- 6 to 368 +/- 115 ng/day. The renal excretion of 6-keto-PGF1 alpha correlates with the modification observed in renal plasma flow, suggesting a compensatory role for prostacylin in preserving renal hemodynamics during antihypertensive therapy with cromakalim.

Topics: Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Benzopyrans; Blood Pressure; Chlorides; Cromakalim; Dinoprost; Dinoprostone; Eicosanoids; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Potassium; Prostaglandins; Pyrroles; Regional Blood Flow; Renin-Angiotensin System; Sodium; Thromboxane B2; Time Factors; Vascular Resistance

The present study was designed to clarify the possible role of renal prostaglandins (PGs) on blood pressure (BP) regulation during calcium (Ca) restriction or supplementation. Twelve normotensive women with a mean age of 21.2 years participated in the study. After 1 week of normal Ca intake (mean +/- SE, 536 +/- 2 mg/day), a low-Ca diet (163 +/- 1 mg/day) was given for a further 1 week. Additional asparagine Ca (3 g as Ca/day) was also given to half of the subjects. BP, heart rate, and serum total and ionized Ca concentrations were measured at the end of each period. Levels of Ca, sodium, PGE2, 6-keto-PGF1 alpha and thromboxane (TX) B2 excreted into urine were also determined. The plasma level of ionized Ca was significantly increased without any change in total Ca in both groups. Low and high Ca intake decreased and increased urinary Ca excretion by 28% and 56%, respectively. BP was not altered after Ca deprivation or loading. However, urinary PGE2 excretion was significantly augmented from 668.9 +/- 68.1 to 959.7 +/- 183.1 ng/day by Ca loading, whereas Ca deprivation decreased PGE2 excretion (695.4 +/- 108.1 to 513.2 +/- 55.2 ng/day). No changes were observed in 6-keto-PGF1 alpha or TXB2 urinary excretion. These results suggest that renal PGE2 synthesis is stimulated or decreased by 1-week Ca loading or deprivation, indicating a possible antihypertensive role of renal PGE2 during high-Ca intake in hypertensives.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Antihypertensive Agents; Blood Pressure; Calcium, Dietary; Dinoprostone; Female; Heart Rate; Humans; Hypertension; Kidney; Prostaglandins; Sodium; Thromboxane B2

Forty-seven male patients with mild essential hypertension were randomly allocated to three subgroups. After a run-in period of 4 weeks, the first subgroup (n = 16) received propranolol (80 mg/day) for 36 weeks followed by a placebo period of 4 weeks. The second subgroup (n = 15), after a run-in period of 4 weeks, was given a supplement of encapsulated fish oil (9 g/day) for 36 weeks with a subsequent period of 4 weeks in which fish oil placebo was given. The third subgroup (n = 16), after a run-in period of 4 weeks, was given propranolol (80 mg/day) for 12 weeks, propranolol (80 mg/day) plus fish oil capsules (9 g/day equivalent to 1.8 g/day of eicosapentaenoic acid and 1.1 g/day of docosahexaenoic acid) for 12 weeks, propranolol plus fish oil placebo (same doses for 12 weeks) with a subsequent period of 4 weeks when propranolol placebo was administered. The results indicate a blood pressure-lowering effect of fish oil, which was comparable with that of propranolol. The simultaneous intake of fish oil plus propranolol was more effective than propranolol or fish oil alone. Propranolol treatment resulted in a decrease of plasma norepinephrine, plasma renin activity, and thromboxane B2 formation. After fish oil supplementation, plasma norepinephrine and thromboxane B2 formation were likewise reduced, whereas plasma renin activity appeared increased. The decrease of serum triglycerides, total and low density lipoprotein cholesterol as well as the rise of high density lipoprotein cholesterol are concomitant beneficial effects, which justify the consideration of fish oil alone or in combination with antihypertensive drugs for the treatment of mild hypertension.

Topics: Adult; Blood Pressure; Cholesterol; Docosahexaenoic Acids; Drug Combinations; Drug Synergism; Eicosapentaenoic Acid; Fish Oils; Humans; Hypertension; Male; Norepinephrine; Propranolol; Renin; Thromboxane B2; Triglycerides

Both n-3 and n-6 polyunsaturated fats have been suggested to lower blood pressure, an effect ascribed to altered biosynthesis of eicosanoids. To test these hypotheses, we studied blood pressure and eicosanoid production during supplementation of dietary fat for four weeks in 32 men with mild essential hypertension. Supplementation was preceded and followed by four-week run-in and recovery periods. Groups of eight subjects received either 10 ml or 50 ml of fish oil (3 or 15 g of n-3 fatty acids) daily, 50 ml of safflower oil (39 g of n-6 fatty acids), or 50 ml of a mixture of oils that approximated the types of fat present in the American diet. The biosynthesis of eicosanoids was assessed by the measurement of urinary metabolites. Blood pressure decreased in the men who received the high dose of fish oil (systolic pressure by a mean of 6.5 mm Hg [P less than 0.03] and diastolic pressure by 4.4 mm Hg [P less than 0.015]), but not in the other groups. Although the formation of vasodilatory prostacyclins (prostaglandins I2 and I3) increased initially, this increase was not maintained as blood pressure fell. The level of thromboxane A2 metabolites fell; metabolites of thromboxane A3 were detected in the groups receiving fish oil. The formation of prostaglandin E2 increased during supplementation with safflower oil and tended to decrease with fish oil; no prostaglandin E3 metabolite was detected. Our data indicate that high doses of fish oil can reduce blood pressure in men with essential hypertension. However, the clinical usefulness and safety of fish oil in the treatment of hypertension will require further study.

Topics: Blood Pressure; Clinical Trials as Topic; Dietary Fats; Epoprostenol; Erythrocytes; Fatty Acids, Unsaturated; Fish Oils; Humans; Hypertension; Male; Phospholipids; Prostaglandins E; Safflower Oil; Thromboxane B2; Thromboxanes

There is evidence that aspirin in low doses favorably influences the course of pregnancy-induced hypertension, but the mechanism, although assumed to involve suppression of the production of thromboxane by platelets, has not been established. We performed a randomized study of the effect of the long-term daily administration of 60 mg of aspirin (n = 17) or placebo (n = 16) on platelet thromboxane A2 and vascular prostacyclin in women at risk for pregnancy-induced hypertension. Low doses of aspirin were associated with a longer pregnancy and increased weight of newborns. Serum levels of thromboxane B2, a stable product of thromboxane A2, were almost completely (greater than 90 percent) inhibited by low doses of aspirin. The urinary excretion of immunoreactive thromboxane B2 was significantly reduced without changes in the level of 6-keto-prostaglandin F1 alpha, a product of prostacyclin. Mass spectrometric analysis showed that aspirin reduced the excretion of the 2,3-dinor-thromboxane B2 metabolite--mainly of platelet origin--by 81 percent and of thromboxane B2, probably chiefly of renal origin, by 59 percent. The urinary excretion of 6-keto-prostaglandin F1 alpha and of its metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was not affected. Low doses of aspirin only partially (63 percent) reduced neonatal serum thromboxane B2. No hemorrhagic complications were observed in the newborns. Thus, in women at risk for pregnancy-induced hypertension, low doses of aspirin selectively suppressed maternal platelet thromboxane B2 while sparing vascular prostacyclin, but only partially suppressed neonatal platelet thromboxane B2, allowing hemostatic competence in the fetus and newborn.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Blood Platelets; Epoprostenol; Female; Fetus; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Random Allocation; Thromboxane A2; Thromboxane B2; Thromboxanes

CGS 13080, a selective thromboxane synthetase inhibitor, was given intravenously (0.6 mg/kg over 6 hours) to eight hypertensive (diastolic 95-115 mm Hg) euvolemic caucasian females on their customary salt intake (24 hour urine Na: 142.9 +/- 14.8 meq). No change occurred in blood pressure or glomerular filtration rate (GFR): 95.2 +/- 7.2, control versus 95.0 +/- 9.0, CGS 13080 (ml/min); or renal plasma flow (RPF): 363.2 +/- 34.2, control, versus 373.2 +/- 31.2, CGS 13080, (ml/min). Prostaglandin production was altered: platelet generation of thromboxane B2 83.3 +/- 10.9, control, versus 5.4 +/- 1.8, CGS 13080 (ng/hr) (P less than .001); urinary prostaglandin E (PGE) 249.0 +/- 56.3, control, versus 443.9 +/- 79.8, CGS 13080 (ng/6 hr) (P = .06); urinary 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) 188.6 +/- 23.4, control, versus 287.9 +/- 21.8, CGS 13080 (ng/6 hr) (P = .01); urinary thromboxane B2 54.8 +/- 12.9, control, versus 58.6 +/- 20.3 CGS 13080 (ng/6 hr) (P = NS). Serum levels of renin, angiotensin II and aldosterone were not altered by CGS 13080. Captopril when dosed to lower diastolic blood pressure 5-7 mm Hg did not significantly affect GFR, RPF or RVR. Nor did it affect platelet generation of thromboxane B2 or urine concentrations of PGE, 6-keto-PGF1 alpha or thromboxane B2. Captopril did increase renin levels 1.2 +/- 0.2, control, versus 2.9 +/- 1.1, captopril (ng/ml/hr) (P = NS), but did not statistically change angiotensin II, or aldosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Clinical Trials as Topic; Female; Hemodynamics; Humans; Hypertension; Imidazoles; Kidney; Middle Aged; Potassium; Prostaglandins; Pyridines; Renin-Angiotensin System; Sodium; Thromboxane B2; Thromboxane-A Synthase

Sixteen patients with mild to moderate essential hypertension were randomly allocated to 6 weeks of treatment with nifedipine and captopril in a crossover trial. Nifedipine and captopril lowered blood pressure significantly both 2 and 12 h after the last dose. Apart from an increased heart rate 2 h after the last dose of nifedipine, the heart rate did not change. Platelet factor 4, thromboxane B2, 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and cyclic (c)AMP did not change during either therapy. There was no correlation between the plasma concentration of nifedipine measured 2 and 12 h after the last dose and the platelet variables described above. The findings show that nifedipine and captopril in therapeutic doses do not affect platelet activity in patients with mild to moderate essential hypertension.

Topics: Adult; Blood Platelets; Blood Pressure; Captopril; Cyclic AMP; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Male; Nifedipine; Platelet Factor 4; Thromboxane B2

We evaluated the influence of indomethacin on the pharmacological actions of Enalapril in 9 uncomplicated essential hypertensives. While on chronic treatment with Enalapril, these patients randomly received indomethacin (50 mg bid) or a corresponding placebo for 1 week and the opposite treatment after a 2 week interval. Indomethacin, which decreased serum thromboxane B2 and urinary 6-keto prostaglandin-F1 alpha, reduced the plasma renin activity (PRA) increased by Enalapril. Indomethacin did not modify serum ACE, whose activity had been reduced by the ACE inhibitor. Mean blood pressure (MBP) values, which were significantly and to a similar extent reduced by Enalapril at the beginning of the cross-over, after placebo addition and at the end of the two week interval, were significantly increased by indomethacin, despite being still significantly lower than baseline values. These data show that systemic and renal prostaglandin (PG) synthesis inhibition induced by indomethacin can blunt the antihypertensive effect of chronic Enalapril treatment in patients with essential hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Enalapril; Female; Hemodynamics; Humans; Hypertension; Indomethacin; Male; Middle Aged; Peptidyl-Dipeptidase A; Renin; Thromboxane B2

14 male patients with moderate essential hypertension were treated in the cross-comparison with a mackerel and herring diet, respectively, for two weeks. The mackerel diet contained double as much eicosapentaenic (EPA) and docosahexaenic acid (DHA) as the herring diet which served as control. In the serum triglycerides particularly DHS, in the cholesterol esters above all EPA were enriched. In the phospholipids the increase of the two fatty acids was approximately the same. At the end of the mackerel period the serum triglycerides, the total and LDL-cholesterol, the activity of the lecithin-cholesterol-acyl-transferase (CALT) and the serum sodium were significantly decreased. On the other hand, the HDL-cholesterol and the uric acid in the serum significantly increased. Under influence of the herring diet the parameters mentioned appeared only slightly changed. After the mackerel diet also a significantly lower systolic blood pressure was found. The systolic and diastolic blood pressure during a standardized psychophysiological stress test was more diminished at the end of the mackerel period than after the herring diet. The plasma renin activity (PRA) was increased after the mackerel diet. Its increase under the stress test could no more be proved at the end of the mackerel diet. In similar way the stress-conditioned increase of thromboxane B2 could no more be observe both after mackerel and after herring diet. When the results should confirm themselves in long-term studies, a mackerel diet in practicable dosage can be recommended as non-medicamentous treatment of moderate hypertension.

Topics: Blood Pressure; Cholesterol Esters; Eicosapentaenoic Acid; Exercise Test; Fish Products; Humans; Hypertension; Lipids; Lipoproteins; Male; Renin; Thromboxane B2; Triglycerides

Vasodilator prostaglandins produced in the renal medulla have a role in blood pressure regulation, beyond modulation of sodium and water retention. Systemic vasodilation resulting from effects of renomedullary prostaglandins lowers systemic vascular resistance, and administration of NSAIDs elevates blood pressure in hypertensive patients treated with diuretics and/or beta blockers, in patients with myocardial infarction, and in patients taking sympathomimetic agents such as phenylpropanolamine. Aspirin, which appears in the urine as salicylic acid (which has no effect on cyclooxygenase) has not been implicated as a drug which attenuates blood pressure control. Similarly, sulindac, the active sulfide metabolite of which is not filtered, does not inhibit renal synthesis of prostaglandins, though given in doses sufficient to inhibit serum thromboxane and 6-keto PGF 1-alpha. In a double-blind complete crossover study of blood pressure and renal function in hypertensive patients controlled with timolol-hydrochlorothiazide, sulindac lowered blood pressure significantly, whereas naproxen and piroxicam significantly raised blood pressure, in the absence of any effect on GFR, plasma renin, weight, creatinine clearance, or urinary sodium. It is suggested that for arthritic patients with hypertension, the NSAIDs of choice are aspirin and sulindac.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Humans; Hypertension; Kidney; Sulindac; Thromboxane B2

It has been suggested that deficient formation of vasodilatory prostanoids may be involved in the pathogenesis of hypertension. PUFA can be a source of arachidonic acid, which is partly converted into prostanoids. Increasing the dietary amount of PUFA has been consistently shown to decrease blood pressure in animals and man. The mechanism of the blood pressure lowering action, however, is not clear. We have found that a diet rich in PUFA can lower blood pressure but at the same time reduce the formation of those vasodilatory prostanoids which nowadays are regarded as the most active ones in the circulatory regulation.

Topics: Adult; Blood Pressure; Dietary Fats; Fatty Acids, Essential; Humans; Hypertension; Kidney; Middle Aged; Prostaglandins; Thromboxane B2; Vasomotor System

The contribution, if any, of various prostaglandins to the antihypertensive effects of angiotensin converting enzyme inhibitors (ACEI) is controversial. We studied the effect of the ACEI captopril (CAP) on the urinary excretion of 6-keto-PGF2 alpha (6-KF), the major metabolite of the vasodilatory prostaglandin, prostacyclin, and thromboxane B2 (TxB2), the stable metabolite of the vasoconstrictor TxA2, in 8 patients with essential hypertension after placebo, two weeks of CAP 25 mg t.i.d. alone, and the same dose of CAP in combination with hydrochlorothiazide (HCTZ) 50 mg/day. Mean 6-KF and TxB2 (nmol/8 hr post-dosing, respectively) did not differ significantly with any treatment; the mean ratio of 6-KF/TxB2 was also unchanged. Likewise, the excretion of these prostaglandins was also evaluated after placebo, the ACEI enalapril (ENA) (5 or 10 mg/day), and the combination of ENA and HCTZ in another group of 8 patients with essential hypertension. Mean 6-KF and TxB2 (nmol/24 hr post-dosing, respectively) showed no significant treatment-related differences; the mean ratio was again unchanged. No correlation existed between the magnitude of blood pressure responses with any treatment and either 6-KF or TxB2 excretion. Thus, the antihypertensive action of ACEI, alone or in combination with HCTZ, does not appear to involve alterations in these vasoactive prostaglandins.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Epoprostenol; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes

As well as inducing natriuresis, intravenous furosemide increases renal prostanoid synthesis and induces renal vasodilation and a rapid rise in plasma renin activity (PRA). Patients with hypertension have abnormalities in renin release and renal vascular resistance that might be due to abnormalities in renal prostaglandin synthesis. We investigated responses to furosemide and placebo in normotensive (n = 13) and hypertensive (n = 14) subjects. There were no clear differences in PRA, sodium and water excretion, or excretion of prostanoid hydrolysis products (6-ketoprostaglandin F1 alpha and thromboxane B2) after placebo. In the hours after furosemide, 0.5 mg/kg-1, hypertensive subjects excreted more sodium, 189 +/- 13 mEq (mean +/- SE) and 154 +/- 8, and water, 1990 +/- 116 ml and 1614 +/- 109, than normotensive subjects. Excretion rates of creatinine and 6-ketoprostaglandin F1 alpha were much the same. Thromboxane B2 excretion rose in hypertensive subjects and was greater than in normotensive subjects (117.6 +/- 17.2 and 58.3 +/- 8.2 ng). With timed urine samples the excretion rate of 6-ketoprostaglandin F1 alpha and thromboxane B2 increased transiently for 30 min or less, whereas sodium and water excretion rates remained elevated for 4 hr. PRA rose in both groups 10 min after injection but reached a higher level in normotensive subjects. These differences in excretion of prostanoid hydrolysis products likely reflect renal synthesis of prostanoids and may be responsible for functional abnormalities of the kidney of hypertensive patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Furosemide; Humans; Hypertension; Male; Middle Aged; Sodium; Thromboxane B2

To evaluate the role of the vasoactive prostaglandins prostacyclin and thromboxane A2 in essential hypertension, the stable metabolites 6-keto-PGF1 alpha and thromboxane B2, respectively, were measured in plasma before and after therapy in 7 patients. During the placebo phase, plasma 6-keto-PGF1 alpha levels were significantly greater than normal. Plasma thromboxane B2 levels were not statistically different from those in normal subjects. After intravenous administration of labetalol to the point of blood pressure reduction, neither plasma 6-keto-PGF1 alpha nor thromboxane B2 values changed. With prolonged oral labetalol therapy and concurrent regulation of blood pressure, a significant decrease in plasma 6-keto-PGF1 alpha levels occurred while thromboxane B2 values remained unaltered. Elevation of plasma 6-keto-PGF1 alpha in untreated hypertensive subjects suggests that enhanced vessel wall prostacyclin synthesis may be a protective mechanism to prevent organ damage. As blood pressure is controlled this increase is no longer needed, and prostacyclin generation returns to normal.

Topics: Administration, Oral; Adult; Aged; Blood Pressure; Ethanolamines; Hemodynamics; Humans; Hypertension; Labetalol; Male; Middle Aged; Prostaglandins F; Thromboxane B2

In the heart and heart mitochondria spontaneously hypertensive rats investigated the effect of physical exercise training (swimming in a moderate and excessive training mode) on the physiological indicators of cardiac hemodynamics and biochemical parameters that characterize the level of oxidative and nitrosative stress. The index of coupling Ca(2+)-dependent constitutive NO-synthases (cNOS = eNOS + nNOS) and biochemical index of dysfunction were calculated. It turned out that both modes of training is completely restored, and even exceed the reference values in untrained rats Wistar conjugate cNOS state and Ca(2+)-dependent synthesis of nitric oxide (NO). Intensity regime of exercise on the border of functionality have been ineffective for improving the functional state of the cardiovascular system and hypertension can provoke it further. Moderate physical training regime, on the contrary, improves the diastolic function of the heart due to an increase dP/dtmin, reducing end-diastolic pressure and a significant reduction in end-diastolic stiffness. Moderate exercise decreased peripheral resistance and cardiac afterload, as indicated by the decrease in end-systolic pressure and arterial stiffness, which contributed to more efficient and energy-saving of heart work. Improve physiological indicators of cardiac hemodynamics and functional state of the heart in moderate mode of training correlated with changes in both the calculated indices. Moderate mode of training is recommended as a simple physiological preconditioning method for the prevention of cardiac dysfunction, hypertension as a result of state uncoupling cNOS and the resulting excessive generation of superoxide and, conversely, inhibition of Ca(2+)-dependent synthesis of NO.

Topics: Animals; Blood Pressure; Calcium; Disease Progression; Hydroxyl Radical; Hypertension; Leukotriene C4; Male; Mitochondria, Heart; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Physical Conditioning, Animal; Physical Exertion; Rats; Rats, Wistar; Stroke Volume; Thromboxane B2; Uric Acid; Vascular Stiffness

This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle-treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 ± 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 ± 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 ± 0.14). Compared with normotensive sham-vehicle-treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 ± 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 ± 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II-induced hypertension, possibly by reducing renal T cell infiltration.

Topics: Angiotensin II; Animals; Clopidogrel; Hypertension; Kidney; Male; Purinergic P2Y Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2Y12; Renal Circulation; Thromboxane B2; Ticlopidine

Currently, there are several animal models of diabetes mellitus and hypertension, but relatively little is known about blood platelet function in these models. The aim of this work was to characterise and compare platelet reactivity and activation in db/db mice (mouse model of diabetes) and mice receiving L-NAME (model of chronic inhibition of NO synthesis), using various platelet function assays. We found higher platelet activation (circulating resting platelets) in db/db mice than in db/+heterozygotes, as evidenced by elevated expressions of CD62P and CD40L and a lower expression of CD42b. The expression of COX-1 was significantly increased, and the phosphorylation of vasodilator stimulated phosphoprotein (VASP) Ser(157) significantly reduced in platelets from db/db mice. Similarly, we observed platelet hyperreactivity in db/db mice following the in vitro responses to 20μg/ml collagen (reflected by increased expressions of CD62P and CD40L, and reduced CD42b), 20μM ADP (reduced CD42b) and lower concentrations of thrombin (0.025 U/ml) (increased CD62P, JON/A, bound vWF, and bound fibrinogen). Otherwise, platelet hyporeactivity was revealed for higher thrombin (0.25 U/ml) (reduced CD62P and bound vWF), while hyperreactivity occurred for CD40L and bound Fg in db/db mice compared to non-diabetic control, db/+. Plasma levels of sCD40L, but not of sCD62P, were increased in db/db mice; also plasma TXB2 concentrations were over 3.5-fold higher in this group than in the heterozygous db/+mice (P<0.01). In contrast, in the mice administered with L-NAME, no statistical differences in expressions of platelet activation markers were found between mice supplemented with L-NAME and controls. Likewise, the TXB2 level did not differ between L-NAME mice and controls, but L-NAME mice had significantly higher plasma levels of sCD62P and sCD40L than controls. In conclusion, these two studied models differ in the overall picture of blood platelet activation and reactivity, as they demonstrated opposite time sequence patterns of platelet activation in circulating blood. More generally, our study provides another argument for the opinion that multiparametric analysis of platelet function offers a much better tool for investigation and minimizes the likelihood of artefacts.

Topics: Animals; Blood Platelets; CD40 Ligand; Diabetes Mellitus, Experimental; Hypertension; Male; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; P-Selectin; Platelet Activation; Platelet Aggregation; Random Allocation; Thromboxane B2

This study investigated the effects of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, Fenofibrate, on the secretion of vascular endothelial contraction factors in hypertensive rats to elucidate its possible mechanisms. The vascular ring contraction experiment was used to observe whether rat vascular tension of clean grade spontaneously hypertensive rats (SHR) changes after 1-h incubation of 0.1, 1.0, 10.0 μM Fenofibrate with 10.0 μM Fenofibrate, a PPAR-α antagonist (MK866), and a PPAR-γ antagonist (GW9662) in SHR. The results were compared with Wistar Kyoto rats. Enzyme-linked immunosorbent assay was used to detect the secretion of the serum vascular endothelial contraction factor prostacyclin-1α (PGF-1α), PGF-2α, and thromboxane B2 (TXB2). Western blot was used to detect COX-1 protein expression. A quantity of 10.0 μM Fenofibrate significantly reduced vasoconstriction in SHR compared to the control group (P = 0.013). The PPAR-α antagonist, MK866, significantly improved the vascular contractility of SHR when incubated with 10.0 μM Fenofibrate (P = 0.021). The PPAR-γ antagonist, GW9662, had no significant effect on the vascular contractility of SHR when incubated with 10.0 μM Fenofibrate (P = 0.071). The isolated aorta of SHR released significantly lower PGF- 1α (P = 0.014), PGF-2α (P = 0.023), and TXB2 (P = 0.017) levels in the 10.0 μM Fenofibrate group compared to the control group. COX-1 expression of SHR rat vascular endothelium was significantly depressed in the 10.0 μM Fenofibrate group compared to the control group (P = 0.027). In conclusion, Fenofibrate reduces the secretion of vascular endothelial contraction factors in hypertensive rats, which might arise through the endothelium influencing COX-1 expression.

Topics: Anilides; Animals; Aorta; Cyclooxygenase 1; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Fenofibrate; Gene Expression; Hypertension; Hypolipidemic Agents; Male; Membrane Proteins; PPAR alpha; PPAR gamma; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2; Tissue Culture Techniques; Vasoconstriction

Flos Chrysanthemi is used in a variety of diseases in traditional Chinese medicine including hypertension, and the total flavonoids (rich in luteolin (LUT) and buddleoside (BUD)) of Flos Chrysanthemi is known to modulate vascular functions and reduce the blood pressure. However, the active flavonoids and their synergistic effects on anti-hypertension are still unclear. To investigate the combined anti-hypertension effects of LUT and BUD enriched extracts on spontaneously hypertensive rats (SHR), as well as the anti-hypertensive mechanism of LUT&BUD mixture.. CODA Mouse & Rat Tail-Cuff Blood Pressure System was used to measure the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of SHR after treated with extracts contains with LUT and/or BUD. The expressions of Ang II, PRA, ALD, ET, PGI2 and TXB2 were investigated by ELASA. Serum NO concentration was measured by the method of Nitric acid reductase.. A single administration of LUT, BUD, or LUT:BUD=1:1 significantly reduced SBP by about 3.35 mmHg, 4.39 mmHg and 15.42 mmHg, respectively. Chronic administration of LBM (at 60 mg/kg; p.o. for 30 days) reduced both SBP and DBP by 4.04% and 5.24% of the vehicle group, respectively. Oral administration of LBM at 60 mg/kg inhibited the serum levels of ANG, ALD and ET, but increased serum NO concentration.. This study shows the synergistic anti-hypertension effects of LUT and BUD in SHR. The effects of LBM on blood pressure are associated with RAAS and endothelial system. Thus, our experiments suggest that the combination of luteolin and buddleoside from Flos Chrysanthemi are potentially useful for the therapeutic treatments for hypertension.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Drug Therapy, Combination; Endothelins; Epoprostenol; Glycosides; Hypertension; Luteolin; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Renin; Thromboxane B2

Hesperidin (HES) and glucosyl hesperidin (GHES) have antihypertensive effects. In the present study, to clarify the antihypertensive mechanisms, we compared the effects of continuous ingestion of HES and GHES in spontaneously hypertensive rats (SHRs). HES and GHES ingestion for 8 wk significantly prevented hypertension and suppressed the mRNA expression of NADPH oxidase subunits and thromboxane A2 synthase in SHR aortas. Further, hesperetin, a common metabolite of HES and GHES, reduced thromboxane B2 release from SHR aortas. These findings indicate that continuous ingestion of HES and GHES prevents hypertension via regulating the gene expression related to the modulation of vascular tone.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Dietary Supplements; Endothelium, Vascular; Enzyme Repression; Glucosides; Hesperidin; Hypertension; In Vitro Techniques; Male; NADPH Oxidases; Protein Subunits; Random Allocation; Rats; Rats, Inbred SHR; Solubility; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

To evaluate the effect of peroxisome proliferator-activated receptor (PPAR)α agonist fenofibrate on the secretion of endothelium-derived contracting factors in hypertensive rats.. The changes of vascular tension in SHR rats after having been incubated with 0.1, 1.0, or 10.0 μmol/L fenofibrate or 10.0 μmol/L fenofibrate and PPARα antagonist MK866 or PPARγ antagonist GW9662 for one hour were observed, and the findings were compared with those in WKY rats (control group). The serum levels of vascular endothelial contraction factor prostacyclin (PGF) 1α, 2α, and thromboxane B2 (TXB2) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of COX-1 protein was determined by Western blot analysis.. Compared with the control group, fenofibrate significantly reduced the vasoconstriction ability of the SHR rats(P=0.013). PPARα antagonist MK866 significantly improved the vascular contractility of SHR rats that had been incubated with 10.0 μmol/L fenofibrate (P=0.021). PPARγ antagonist GW9662 had no significant effect on the vascular contractility of SHR rats after having been incubated with 10.0 μmol/L fenofibrate (P=0.071). The serum levels of PGF1α(P=0.014), 2α(P=0.023), and TXB2 (P=0.017) in SHR rats incubated with 10.0 μmol/L fenofibrate were significantly lower than in the control group. With the presence of vascular endothelium, the expression of COX-1 in SHR rats incubated with fenofibrate was significantly lower than that in SHR rats incubated without fenofibrate (P=0.027).. Fenofibrate reduces the secretion of endothelium-dependent contracting factors in SHR rats through lowering the expression of COX-1.

Topics: Animals; Cyclooxygenase 1; Epoprostenol; Fenofibrate; Hypertension; Male; Membrane Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2

To explore the effects of extracts of Radix Scrophulariae (ERS) on blood pressure, vasoconstrictors and morphology of artery in spontaneously hypertensive rats (SHRs).. Fifty SHRs were randomly divided into SHR, SHR plus 40 mg/kg of captopril, SHR plus 70 mg/kg of ERS, SHR plus 140 mg/kg of ERS and SHR plus 280 mg/kg of ERS groups. Wistar-Kyoto (WKY) rats were randomly divided into two groups, namely, WKY and WKY plus 140 mg/kg of ERS groups. The rats were orally administered with the corresponding drugs or drinking water once a day for 20 weeks. The blood pressure was determined every three weeks. At the 21st week, the concentrations of noradrenaline (NA), angiotensin II (Ang II), thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α) in serum and endothelin-1 (ET-1) were detected by enzyme-linked immunosorbent assay. The morphological changes in abdominal aorta were observed under an optical microscope with hematoxylin and eosin staining. The ratio of intima-media thickness/lumen radius of abdominal aorta was calculated.. ERS significantly lowered the blood pressure of SHRs from the 3rd to the 21st week; ERS also reduced the levels of NA, Ang II, ET-1 and TXB(2), decreased the intima-media thickness of abdominal aortal wall and improved the morphological changes in abdominal aorta in SHRs. In addition, ERS did not significantly change blood pressure and vasoactive substances in WKY rats.. ERS possesses beneficial effects in inhibiting hypertension and attenuating arteriosclerosis. The underlying mechanism may be associated with restraining the release of vasoconstrictors, such as NA, Ang II, ET-1 and TXB(2).

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Blood Pressure; Drugs, Chinese Herbal; Endothelin-1; Hypertension; Male; Norepinephrine; Phytotherapy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Scrophularia; Thromboxane B2

Ingestion of deep-frying oil has been reported to cause physiologic and histologic changes in experimental animals' tissue, increase the oxidative stress, and possibly lead to death. The purpose of this study was to investigate the effect of deep-frying oil on oxidative stress and blood pressure in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats.. Deep-frying oil was prepared by frying fresh soybean oil at 180 +/- 5 degrees C for 8 h each day, for 4 consecutive days. Male SHR and WKY rats were fed diets containing 15% fresh soybean oil or deep-frying oil (DO) for 10 wk.. Rats ingesting the DO diet had lower feed efficiency and higher relative liver and kidney weights but deep frying had no significant influence on blood pressure in WKY or SHR rats. The DO diet had no effect on plasma renin activity, aldosterone content, or tissue angiotension-I-converting enzyme activity. WKY rats fed the DO diet showed significantly increased urinary thromboxane B(2) and 8-iso-prostaglandin F(2alpha) excretion, but not urinary 6-keto-prostaglandin F(1alpha) excretion. Diets containing deep-frying oil resulted in increased plasma thiobarbituric acid-reactive substances and nitric oxide contents and decreased plasma total antioxidant capacity in SHR and WKY rats.. The ingestion of deep-frying oil seemed not to influence blood pressure or its related parameters, but altered eicosanoid metabolism and elevated oxidative stress in SHR and WKY rats.

Topics: Animals; Antioxidants; Blood Pressure; Cooking; Dietary Fats; Energy Metabolism; Glycine max; Hot Temperature; Hypertension; Kidney; Liver; Male; Nitric Oxide; Organ Size; Oxidative Stress; Prostaglandins F, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Soybean Oil; Thiobarbituric Acid Reactive Substances; Thromboxane B2

Clinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)].. We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha.. Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.

Topics: Adenylate Kinase; Adiponectin; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Linseed Oil; Male; Myocardial Contraction; Myosin Heavy Chains; Phospholipids; Rats; Rats, Wistar; RNA, Messenger; Thromboxane B2; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Ventricular Remodeling

Microalbuminuria is a predictor of adverse outcome in hypertension.We evaluated in vivo platelet activation, by urinary 11-dehydrothromboxane (TX)B2 and plasma P-selectin, in hypertensives with or without microalbuminuria, and its possible association with oxidative stress, by urinary 8-iso-prostaglandin (PG)F2alpha and endothelial dysfunction. Sixty essential hypertensive patients, with (n=30) or without (n=30) microalbuminuria, and 30 controls were studied. Endothelial function was assessed by nitric oxide products, intercellular adhesion molecule (ICAM)-1, and asymmetric dimethylarginine (ADMA) levels. Urinary 11-dehydro-TXB2 excretion was higher in microalbuminuric (median 805 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (414 and 291 pg/mg, respectively; P<0.0001). Plasma P-selectinwas significantly higher in patients with microalbuminuria (median 136 ng/ml) as compared to those without microalbuminuria or controls (85 and 65 ng/ml; P<0.0001). Urinary 8-iso-PGF2alpha excretion was also enhanced in microalbuminuric (median 279 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (157 and 146 pg/mg, respectively; P<0.0001). A significant impairment in endothelial function was found in microalbuminuric patients, with decreased nitric oxide and increased ICAM-1 and ADMA levels. Multivariate regression analysis showed that urinary 8-iso-PGF2alpha excretion (beta=0.49; P<0.0001) and microalbuminuria (beta=0.36; P<0.001) were independently related to 11-dehydro-TXB2 in hypertensives. Vitamin E supplementation (900 mg daily for 1 month) in 10 hypertensives with microalbuminuria was associated with normalization in median 11-dehydro-TXB2 and 8-iso-PGF2alpha. We conclude that lipid peroxidation is a major determinant of persistent platelet activation in hypertensive patients with microalbuminuria.

Topics: Aged; Albuminuria; Arginine; Biomarkers; Disease Progression; Endothelium; Female; Humans; Hypertension; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Oxidative Stress; P-Selectin; Platelet Activation; Prostaglandins A; Thromboxane B2; Vitamin E

Arachidonic acid's (AA) metabolites, eicosanoids, exert a tremendous influence on circulatory and vascular homeostasis, and in humans are generated by many organs and cell types. In this study we wanted to verify whether platelets AA metabolism play a significant role in pathogenesis of essential hypertension (EH). Participants were divided into the study (EH) and the control group. Plasma and urine concentrations of isoprostanes (8-iPF(2alpha)-III) and thromboxane B(2) (TxB(2)) were determined using the ELISA method. The levels of 5- and 12-hydroxyeicosatetraenoic (HETE) acids, generated by platelets, were analysed using RP-HPLC. In a suspension of not stimulated and AA-stimulated platelets TxB(2) level was statistically lower in the study than in the control group (p < 0.0001 and 0.001 respectively). The concentration of 12-HETE was significantly elevated in EH patients compared to the control group; however, only in the non-stimulated conditions (p < 0.05). Plasma and urine F2-isoprostanes levels were significantly higher in hypertensive individuals than in the control group (p < 0.00002 and p < 0.01 respectively). Moreover, EH patients excreted more TxB(2) in urine than normotensive individuals (p < 0.05). Our results highlight the mutual connections between the platelets AA metabolism and indicate its possible role in the pathogenesis of arterial hypertension. Moreover, we hypothesize that platelets AA metabolism may exert a pro-atherosclerotic effect. Finally, we suggest the use of (5-HETE+12-HETE)/TxB(2) parameter in further studies.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acid; Atherosclerosis; Blood Platelets; Case-Control Studies; Humans; Hydroxyeicosatetraenoic Acids; Hypertension; Male; Middle Aged; Thromboxane B2

Hypertensive basal ganglia hemorrhage (HBGH) accounts for 35%-44% of cases of hypertensive intracranial hemorrhage (ICH), which is one of the most devastating forms of cerebrovascular disease. In this study, intracerebral hematoma was evacuated with a burr hole craniectomy. The relationships of residue hematoma volume to brain edema, inflammation factors and the long-term prognosis of HBGH patients were studied.. One hundred and seventy-six patients with HBGH were randomly divided into gross-total removal of hematoma (GTRH) and sub-total removal of hematoma (STRH) groups. The pre-operative and post-operative data of the patients in the two groups were compared. The pre-operative data included age, sex, hematoma volume, time from the ictus to the operation, Glasgow Coma Scale (GCS) scores, and the European Stroke Scale (ESS) scores. The post-operative information included edema grade, level of thromboxane B2 (TXB2), 6-keto-prostaglandin F1a (6-K-PGF1a), tumor necrosis factor-a (TNF-a) and endothelin (ET) in hematoma drainage or cerebral spinal fluid (CSF), ESS and Barthel Index (BI).. There was no statistical difference between the two groups (P>0.05) in the pre-operative data. The levels of TXB2, 6-K-PGF1a, TNF-a and ET in the GTRH group were significantly lower than those in the STRH group at different post-operative times. The ESS in the GTRH group increased rapidly after the operation and was higher than that in the STRH group. There was a significant difference between the two groups (P<0.05). The post-operative CT scan at different times showed that the brain edema grades were better in the GTRH group than in the STRH group. The BI was higher in the GTRH group than in the STRH group (P<0.05).. GTRH is an effective method to decrease ICH-induced injury to brain tissue. Such effect is related to decreased perihematomal edema formation and secondary injury by coagulation end products activated inflammatory cascade.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Basal Ganglia Hemorrhage; Biomarkers; Brain Edema; Disease Progression; Encephalitis; Endothelins; Female; Follow-Up Studies; Glasgow Coma Scale; Humans; Hypertension; Inflammation Mediators; Male; Middle Aged; Neurosurgical Procedures; Postoperative Complications; Predictive Value of Tests; Prognosis; Thromboxane B2; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

To determine a) whether clinical response to electroconvulsive therapy (ECT) is associated with decreased platelet activation in patients with major depressive disorder (MDD) and b) if any medical/demographic characteristics predict response to ECT or changes in platelet activation. Increased platelet activation may underlie the increased risk of coronary artery disease (CAD) in patients with MDD.. Before their first and sixth ECT treatments, study patients (n = 44) completed the Beck Depression Inventory (BDI) to assess the severity of depressive symptoms. Activity of the platelet thromboxane (TBX) A(2) pathway was assessed by measuring the morning spot urinary concentrations of 11-dehydroxy-thromboxane B(2) (11-D-TBX B(2)), a major metabolite of platelet-derived TBX A(2).. Multivariate logistic regression analyses revealed that improvement on the BDI was significantly more likely in patients without a history of hypertension (p = .02) and in patients who were prescribed a greater number of "platelet-altering" medications (p = .03). During a course of ECT, a decrease in urinary 11-D-TBX B(2) was significantly more likely to occur in ECT nonresponders (p = .01) and younger patients (p = .02).. Clinical response to ECT coadministered may not be associated with decreases in platelet-derived TBX. Future studies will confirm which somatic "antidepression" treatments offer optimal thrombovascular benefits for depressed patients with multiple risk factors for, or clinically evident, cerebral disease or CAD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Personality Inventory; Platelet Activation; Risk Factors; Thromboxane A2; Thromboxane B2; Treatment Outcome

The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.. We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44+/-13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid-induced aggregation and thromboxane B2 production by > or = 99% (P<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r2=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h2=0.266 to 0.762; P<0.01), but direct cyclooxygenase-1 phenotypes were not.. Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.

Topics: Adult; Arachidonic Acid; Aspirin; beta-Thromboglobulin; Black or African American; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Dyslipidemias; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Humans; Hyperglycemia; Hypertension; Male; Membrane Proteins; Middle Aged; Phenotype; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Risk Factors; Sex Characteristics; Smoking; Thrombophilia; Thrombosis; Thromboxane B2; White People

Ferulic acid (FA), a phytochemical constituent, has antihypertensive effects, but a detailed understanding of its effects on vascular function remains unclear. The vasoreactivity of FA was assessed using aortic rings isolated from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).. The effects of FA (10(-5) to 10(-3) mol/L) on vasodilatory responses were evaluated based on contractile responses induced by phenylephrine (10(-6) mol/L) in thoracic aortic rings from male WKY rats and SHR. Basal nitric oxide (NO) bioavailability in the aorta was determined from the contractile response induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/L). The effects of FA on the production of NADPH-dependent superoxide anion were examined in SHR aortas. The impact of hydroxyhydroquinone, a generator of superoxide anions, on the FA-induced enhancement in acetylcholine-stimulated vasodilation was also investigated.. The FA (10(-3) mol/L)-induced relaxation was partially blocked by removal of the endothelium or by pretreating SHR aortas with L-NAME. FA increased NO bioavailability, and decreased NADPH-dependent superoxide anion levels in SHR aortas. Ferulic acid improved acetylcholine-induced endothelium-dependent vasodilation in SHR, but not in WKY. Furthermore, the simultaneous addition of hydroxyhydroquinone significantly inhibited the increase in acetylcholine-induced vasodilation by FA.. Ferulic acid restores endothelial function through enhancing the bioavailability of basal and stimulated NO in SHR aortas. The results explain, in part, the mechanisms underlying the effects of FA on blood pressure (BP) in SHR.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Aorta; Coumaric Acids; Cyclic GMP; Endothelium, Vascular; Hydroquinones; Hypertension; Male; NADP; NG-Nitroarginine Methyl Ester; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides; Thromboxane B2; Vasodilation

Glucocorticoids play a role in the control of vascular smooth muscle tone through the alteration of vasoconstrictor and vasodilator factor production. We studied the effect of dexamethasone on vasoconstriction induced by electrical field stimulation (EFS) in rat mesenteric arteries (MAs) and the role of hypertension in this effect. Endothelium-denuded MAs were obtained from Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs). EFS response was analyzed by isometric tension recordings and cyclooxygenase (COX-1 and COX-2) expression by Western blot. Noradrenaline (NA) release was evaluated in segments incubated with [(3)H]NA. Dexamethasone (0.1 and 1 microM; 2-8 h) reduced vasoconstriction to EFS (200 mA, 0.3 ms, 1-16 Hz), in a dose- and time-dependent manner only in SHRs. However, the EFS-induced release of [(3)H]NA was increased in SHR arteries preincubated with dexamethasone (1 microM; 6 h). The thromboxane A(2) (TxA(2)) synthase inhibitor furegrelate (10 microM), the selective COX-2 inhibitor NS-398 (N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide; 10 microM), or the TxA(2) receptor antagonist SQ 29548 (1 microM), reduced EFS and NA induced vasoconstrictor responses. However, the effect of these drugs was abolished in arteries preincubated with dexamethasone. Both dexamethasone and phentolamine (1 microM) inhibited the increased thromboxane B(2) levels observed after EFS. COX-2 protein expression was reduced by dexamethasone in SHR arteries. Results suggest that dexamethasone reduces vasoconstriction to EFS in MAs from SHRs by decreasing COX-2 expression, thereby decreasing the smooth muscle TXA(2) release induced by alpha-adrenoceptor activation. The undetectable COX-2 expression in MAs from normotensive animals explains the noneffect of dexamethasone in their arteries.

Topics: Animals; Cyclooxygenase 2; Dexamethasone; Dose-Response Relationship, Drug; Electric Stimulation; Hypertension; Mesenteric Arteries; Muscle, Smooth, Vascular; Phentolamine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2; Vasoconstriction

Hypertensive crisis could be found after operation in patients with hypertensive intracerebral hemorrhage (HICH). The aim of this study was to explore the changes and the roles of some vasoactive polypeptides during postoperative hypertensive crisis in patients with HICH.. A total of 31 patients, who were admitted for craniotomy, were enrolled into this study. After the operation, the patients were divided into three groups. Group I consisted of 9 patients with postoperative hypertensive crisis, and group II was composed of 13 patients without postoperative hypertensive crisis. Nine patients, who denied history of hypertension or HICH, were set as group III. The levels of some vasoactivators in the three groups were measured before and after the operation. The differences in the results among the groups were analyzed using the ANOVA. The data collected before and after the operation in the group I was compared by Wilcoxon test.. The concentration of endothelin in group I was significantly higher than that in group III (P < 0.05). The level of thromboxane A2 and the ratio of thromboxane B2 to 6-keto-PGF1a in group I were significantly higher than those in the other two groups (P < 0.05). In group I, the levels of plasma renin activity, angiotensin II, aldosterone, catecholamine, and endothelin before the operation were significantly higher than those determined after the operation (P > 0.05).. Postoperative hypertensive crisis may be due to the increased thromboxane A2 and relatively inadequate prostacyclin, especially 6-keto-PGF1a. The increased level of endothelin and intraoperative stimulation also play a certain role in the development of postoperative hypertensive crisis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Endothelins; Female; Humans; Hypertension; Intracranial Hemorrhage, Hypertensive; Male; Middle Aged; Postoperative Complications; Thromboxane B2

Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR).. Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin.. In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed.. Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Caveolin 1; Endothelium, Vascular; Enzyme Activation; Gene Expression Regulation, Enzymologic; Heart Rate; Hypertension; Luminescent Measurements; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Phosphoproteins; Quercetin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Thoracic Arteries; Thromboxane B2; Vasodilation

To investigate insulin resistance and the effects of intravenous acute saline load on renal production of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) in salt-sensitive hypertensive patients.. The 24-hour excretion of urinary 6-keto-prostaglandin F (PGF) 1alpha and thromboxane B(2) were measured before and after intravenous acute saline load in 53 hypertensive patients whose salt sensitivity had been determined. Oral glucose tolerance test and insulin release test were performed in all the subjects.. after intravenous acute saline load, the 24-hour excretions of urinary 6-keto PGF 1alpha were significantly lower in salt-sensitive (SS) hypertensive patients than that in non-salt-sensitive (NSS) ones (316+/-57 pg/min vs 371+/-68 pg/min, P<0.01), and the decrease from baseline was much greater in SS group than that in NSS group (197+/-99 pg/min vs 136+/-101 pg/min, P<0.01). Both 24 hour urinary excretion of TXA(2) and the increase in urinary excretion of TXA(2) were significantly greater in SS hypertensive patients than those in NSS ones after salt loading (394+/-32 pg/min vs 359+/-44 pg/min, P<0.01, and 80+/-47 pg/min vs 47+/-45 pg/min, P<0.01, respectively). The plasma glucose and insulin concentrations in every time point were much higher in SS hypertensive subjects than that in NSS ones, and the former group had lower insulin sensitivity index than the latter (0.013+/-0.003 vs 0.018+/-0.004, P<0.01). Saline load produces significantly different effects on renal production of PGI(2) and TXA(2) in SS and NSS hypertensive patients, and these changes may be related to the pathophysiology of SS hypertensive patients after acute salt loading. Insulin resistance is greater in SS hypertensive patients than in NSS ones.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Injections, Intravenous; Insulin Resistance; Kidney; Male; Middle Aged; Sodium Chloride; Thromboxane A2; Thromboxane B2

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

To evaluate the effects of transdermal hormone replacement therapy (HRT) on plasma viscosity, serum levels of thromboxane B2 (TXB2) and vascular impedance in the uterine, bladder wall, internal carotid and ophthalmic arteries in normotensive and hypertensive postmenopausal patients.. Thirty postmenopausal patients underwent continuous estradiol transdermal supplementation at a dose of 50 microg/day and 12-day courses of medroxyprogesterone acetate 10 mg/day every 2 months. The women were divided into two groups according to their blood pressure: normotensive women (Group 1, n=14) and hypertensive subjects (Group 2, n=16). Before starting HRT and after 6 months of therapy, the patients underwent: transvaginal ultrasonographic examination of the pelvic organs; Doppler examination of the blood flow velocities in the uterine, bladder wall, internal carotid and ophthalmic arteries; and analysis of plasma viscosity and plasma TXB2.. After 6 months of HRT plasma viscosity had decreased in both groups (mean reduction in Group 1, (14+/-1)%, P=0.005; mean reduction in Group 2, (10+/-1)%, P=0.005) as had the TXB2 levels (mean reduction in Group 1, (93+/-2)%, P<0.001; mean reduction in Group 2, (92+/-3)%, P<0.001). The mean percentage reduction in plasma viscosity was smaller in hypertensive women than in normotensive women (P<0.05). There was also a significant reduction in vascular impedance in the uterine artery (mean reduction in Group 1, (16+/-1)%, P=0.005; mean reduction in Group 2, (19+/-1)%, P=0.005), the bladder wall arteries (mean reduction in Group 1, (23+/-2)%, P=0.005; mean reduction in Group 2, (18+/-1)%, P=0.005), the internal carotid artery (mean reduction in Group 1, (25+/-1)%, P=0.005; mean reduction in Group 2, (26+/-1)%, P=0.005) and the ophthalmic artery (mean reduction in Group 1, (24+/-2)%, P=0.005; mean reduction in Group 2, (16+/-1)%, P=0.005). The percentage reduction in vascular impedance did not differ significantly between the two groups.. Our results show that transdermal HRT is effective in reducing plasma viscosity, TXB2 levels and vascular impedance in the peripheral and central vessels both in normotensive and hypertensive postmenopausal patients.

Topics: Administration, Cutaneous; Analysis of Variance; Arteries; Blood Viscosity; Carotid Artery, Internal; Case-Control Studies; Estradiol; Estrogen Replacement Therapy; Female; Humans; Hypertension; Linear Models; Medroxyprogesterone Acetate; Middle Aged; Ophthalmic Artery; Postmenopause; Regional Blood Flow; Thromboxane B2; Ultrasonography, Doppler; Urinary Bladder; Uterus; Vascular Resistance

To determine the concentrations of nitric oxide (NO) in plasma of women with essential hypertension in prehypertensive phase, its effect on blood pressure, and correlation with other vasoactive substances that regulate systemic and renal vascular tonus.. The study performed at the Department of Nephrology, Hospital Center in Skopje, Macedonia, included 26 women with essential hypertension in prehypertensive phase and 11 normotensive women as healthy controls. Vasodilating factors NO and 6-keto-prostaglandin F1 alpha (6-keto-PGF1alpha) were determined in plasma. Thromboxane B2 (TXB2) as a vasoconstricting factor and electrolytes Na+, K+, and Ca2+ were determined in urine. Blood pressure was monitored over 24 hours. Systolic, diastolic, mean blood pressure were presented as average 24-hour values.. The concentrations of NO and 6-keto-PGF1alpha were significantly lower in women with essential hypertension in prehypertensive phase than in their normotensive controls (NO: median 22, range 11-35 vs median 37.5, range 11-66; 6-keto-PGF1alpha: 64.8+/-14.35 vs 98.21+/-43.45 micromol/L; P<0.001). The index of vascular reactivity (TXB2/6-keto-PGF1alpha ratio) was higher in women in prehypertensive phase than in normotensive women (1.3 vs 0.8, P<0.001). Urinary calcium to creatinine ratio was significantly lower in the prehypertensive group (0.06+/-0.03 vs 0.24+/-0.13, P<0.001). No direct correlations were found between NO, TXB2, and 6-keto-PGF1alpha, or between NO and electrolytes in the urine. Low NO and urinary Ca2+ were significant indicators of increased blood pressure (P=0.013 and P=0.024, respectively; backward stepwise multiple regression analysis).. NO and 6-keto-PGF1alpha were significantly lower in women in prehypertensive phase of essential hypertension. Lower NO correlated with increased systolic blood pressure, but not with on natriuresis and calciuresis. These findings, together with the higher vascular reactivity index, indicate that endothelial dysfunction precedes the establishment of essential hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Hypertension; Nitric Oxide; Thromboxane B2; Time Factors; Vasoconstriction; Vasodilation

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B2, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F2alpha was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB2 was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF2alpha was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB2 and 8-iso-PGF2alpha were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF2alpha, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB2. Logistic regression analysis showed that high urinary 8-iso-PGF2alpha, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB2. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.

Topics: Adolescent; Adult; Aged; Dinoprost; F2-Isoprostanes; Female; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Platelet Activation; Thromboxane B2

We evaluated the vascular reactivity in healthy subjects, heavy smokers, uncompensated type II diabetics, and patients with uncontrolled essential hypertension. Plasma nitrite/nitrate, cyclic 3',5'-guanosine monophosphate (cGMP), and thromboxane (TX)-B(2) levels were measured.. One hundred participants were classified into four groups: normal control subjects (n = 25), heavy smokers (n = 25), uncompensated type II diabetics (n = 25), and patients with uncontrolled essential hypertension (n = 25).. The brachial artery diameter was measured by a high-resolution ultrasound technique before and after reactive hyperemia and glyceryl trinitrate (GTN), 0.4 mg, administration. Plasma nitrite/nitrate, cGMP, and TX-B(2) levels were also measured.. Heavy smokers, uncompensated type II diabetics, and uncontrolled hypertensive patients showed impaired endothelium-dependent, nitric oxide (NO) flow-mediated vasodilatation (8.0 +/- 2.5%, 5.8 +/- 2.7%, and 7.2 +/- 3.3%, respectively [mean +/- SD]) when compared to the control subjects (12.6 +/- 3.6%; p < 0.01). Smokers had a normal endothelium-independent function induced by NO donor (GTN) [25.0 +/- 7.3% vs 25.3 +/- 8.5% for control subjects]. Uncompensated type II diabetics and patients with uncontrolled hypertension had impaired endothelium-independent responses (17.7 +/- 7.1% and 16.8 +/- 6.9%, respectively, vs 25.3 +/- 8.5 for normal control subjects; p < 0.05). Plasma levels of cGMP and TX-B(2) were not significantly different in the four groups, but nitrite/nitrate concentrations were increased in diabetics compared to the control subjects (266 +/- 47 micro mol/L vs 98 +/- 18 micro mol/L, p < 0.05).. Both uncontrolled hypertension and type II diabetes mellitus, but not smoking, are associated with impaired vascular smooth-muscle reactivity induced by NO donors. However, only uncompensated type II diabetics showed an increase in plasma nitrite/nitrate levels, suggesting an association with excessive production and/or inactivation of NO.

Topics: Adult; Blood Flow Velocity; Cyclic GMP; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperemia; Hypertension; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Nitroglycerin; Smoking; Thromboxane B2; Vasodilation; Vasodilator Agents

To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes.. Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured.. Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age.. These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.

Topics: Albuminuria; Animals; Aryl Hydrocarbon Hydroxylases; Blood Glucose; Body Weight; Cyclooxygenase 2; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Diabetes Mellitus, Type 2; Hypertension; Isoenzymes; Kidney; Kidney Cortex; Kidney Glomerulus; Male; Microcirculation; Obesity; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Zucker; Steroid 16-alpha-Hydroxylase; Thromboxane B2

Dihydropyridine Ca2+-blockers, frequently used as antihypertensive and antianginal agents, have been found to exert potent antioxidant and cytoprotective activities against free radical-mediated vascular injury.. In the current study we examined the effect of amlodipine (AMLOD) on oxidative stress-induced hypertension in Sprague-Dawley rats administered buthionine-sulfoximine (BSO), a glutathione (GSH) synthase inhibitor, in the drinking water. The control animals received drug-free water. Blood pressure (BP) was measured by tail-cuff plethysmography. Plasma levels of total 8-isoprostane, thromboxane A2, prostacyclin, nitric oxide, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, kidney, and heart GSH were analyzed by high-performance liquid chromatography.. Administration of BSO significantly increased BP, isoprostane, and thromboxane A2, whereas GSH, PGI2, and cAMP were reduced. When given alone, AMLOD alone reduced BP and the plasma levels of isoprostane and thromboxane A2, and elevated prostacyclin, nitric oxide, cGMP, and cAMP. When administered with BSO, AMLOD reversed the BSO-induced elevation of BP, isoprostane, and thromboxane A2 as well as the reduction in prostacyclin, cAMP, and cardiac GSH levels.. The antihypertensive effect of amlodipine involves a reduction in oxidative stress, which appears to be mediated in part by the prostanoid endothelium-derived factors and nitric oxide.

Topics: Amlodipine; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Cyclic AMP; Cyclic GMP; Dinoprost; Epoprostenol; Glutathione; Heart Rate; Hypertension; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Second Messenger Systems; Thromboxane B2

Recent studies implicate of reactive oxygen species (ROS) in hypertension; however, whether reactive oxygen species promote hypertensive derangements is not fully clear. We thus investigated the effects of an antioxidant, N-acetyl-L-cysteine, on hypertensive Dahl salt-sensitive rats. High-salt intake for 4 weeks markedly elevated systolic arterial pressure, urinary excretion of protein, 8-isoprostane, and H(2)O(2), and the enzyme activity of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase along with the elevated expression of its subunits gp91phox and p47phox at the levels of mRNA and protein. Supplement with N-acetyl-L-cysteine reduced the increase in systolic arterial pressure and counteracted the elevation of urinary excretion of protein, 8-isoprostane, and H(2)O(2), and the increases in NADPH oxidase activity/expression in high-salt-loaded Dahl salt-sensitive rats. N-acetyl-L-cysteine supplement ameliorated plasma and urinary levels of thromboxane B(2) (an end metabolite of thromboxane A(2)), associated with improvement of both the abnormal contraction and the impaired nitric oxide-dependent relaxation in renal arteries. These results revealed that oxidative stress mediates hypertensive changes in Dahl salt-sensitive rats, because thiol antioxidant N-acetyl-L-cysteine attenuated the augmentation of local ROS production by diminishing the elevation of NADPH oxidase expression and ameliorated renal/vascular hypertensive changes.

Topics: Acetylcholine; Acetylcysteine; Animals; Antioxidants; Blood Pressure; Dinoprost; Endothelium, Vascular; Hydrogen Peroxide; Hypertension; Kidney Glomerulus; Male; NADPH Oxidases; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Dahl; Sodium Chloride; Superoxides; Thromboxane B2; Up-Regulation

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Biomarkers; Blood Pressure; Cyclic GMP; Endothelin-1; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Thromboxane B2; Time Factors; Treatment Outcome

Derangements in the production and degradation of reactive oxygen species (ROS) as well as nitric oxide (NO) have been implicated in cardiovascular diseases. We explored how supplementation with l-arginine, an NO synthase substrate, restores such derangements of ROS/NO systems in Dahl salt-sensitive, hypertensive (DS) rats. We detected an increase of NADPH oxidase activity, a key enzyme that produces superoxide, in the membrane fraction of the renal cortex derived from DS rats loaded with high salt for 4 weeks; high salt loading also remarkably increased urinary H2O2, 8-isoprostane, and thromboxane B2 excretion and decreased plasma NO end products. These changes from high salt loading were counteracted by oral l-arginine supplementation. We further examined expression patterns of NADPH oxidase subunits in renal cortex derived from these animals. High salt loading increased gp91phox and p47phox but not p22phox or Rac1 or mRNA abundance, which were counteracted with L-arginine supplementation. Western blot analyses after subcellular fractionation revealed that l-arginine supplementation distinctly decreases membrane localization of p47phox protein, as it decreases total expression of Rac1 protein in DS rats with high salt loading. These results disclose that high salt loading causes a deficiency in available L-arginine amounts for NO synthases and induces NADPH oxidase activation in the renal cortex of DS rats, which l-arginine supplementation markedly restores. Since superoxide rapidly eliminates NO, which inhibits sodium reabsorption in the cortical collecting duct, superoxide production caused by upregulated NADPH oxidase activity in the renal cortex of high salt-loaded DS rats may accelerate sodium reabsorption and hypertension.

Topics: Animals; Arginine; Blood Pressure; Dinoprost; F2-Isoprostanes; Gene Expression Regulation; Hypertension; Kidney Cortex; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide; Phosphoproteins; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium Chloride; Thromboxane B2

Chronic infusion of angiotensin-(1-7) [Ang-(1-7)] lowers blood pressure in salt-induced and spontaneously hypertensive (SHR) rats. In the present study, we have examined the acute effect of Ang-(1-7) in salt-induced hypertension using Dahl salt-sensitive rats placed on low (0.3%) or high (8.0% NaCl) salt diets for 2 weeks. Rats fed a high salt diet showed a greater rise in BP than those fed a low salt diet. Ang-(1-7) (24 microg/kg) reduced mean arterial pressure (MAP), enhanced the release of prostacyclin and nitric oxide, and suppressed thromboxane A(2) levels. A-779 (48 microg/kg, i.v), a selective Ang-(1-7) antagonist, partially blocked these effects of Ang-(1-7). The Ang-(1-7)-induced depressor response observed in these animals was related to an increase in vasodilatory prostanoids, a decrease in the constrictor prostanoid thromboxane A(2), and an increase in nitric oxide levels in both plasma and isolated aortic rings.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Cyclic GMP; Dinoprostone; Epoprostenol; Hypertension; Male; Nitric Oxide; Peptide Fragments; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Salts; Thromboxane A2; Thromboxane B2; Time Factors

Previous studies from our own laboratory have shown that abdominal aorta rings from two kidney - two clip hypertensive rats (HT) develop hypersensitivity to serotonin (SER) which is related to a decreased nitric oxide (NO) availability and enhanced thromboxane A2 production. In the present study we investigated whether calcium and prostanoid-NO interactions are involved in these findings. To this purpose, the aortic responses to SER were analyzed in calcium-free medium and in calcium-depleted aorta placed in normal medium. Moreover, effects of ridogrel (RID, an antagonist of TxA 2/PGH2 receptors and inhibitor of thromboxane synthetase) were analysed by cumulative dose-response curves to SER in the presence and in the absence of the NO synthase inhibitor N(omega)-nitro-L-arginine (NOLA). Vascular responses to SER in vessels from HT rats were associated with increased intracellular calcium mobilization. In addition, hypersensitivity to SER in HT group respect to sham group (SH) disappeared in the presence of RID, NOLA and RID plus NOLA. RID decreases the maximum tension to SER and this effect was prevented by NOLA. This inhibition was of a greater magnitude in rings from sham rats (SH): 34 +/- 6% than in HT rats: 15 +/- 6% (p < 0.05). Besides, RID decreased the sensibility to SER in the presence of NOLA only in the HT group. In conclusion, the present study suggests that SER hypersensitivity observed in HT rats is related to a facilitated intracellular calcium mobilization and enhanced TxA2-endoperoxide response. Changes in membrane SER-gated calcium channels opening are observed only during the early hypertensive period. Besides, the lower depressor effect of RID on the maximal tension to SER in aorta rings from HT rats are related with a decreased NO availability in this model of renovascular hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Pressure; Calcium; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Hypertension; Kidney; Male; Muscle Contraction; Nitroarginine; Pentanoic Acids; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyridines; Rats; Rats, Wistar; Serotonin; Thromboxane B2; Time Factors

To investigate the role of thromboxane A(2) in the development of hypertension in the fructose-fed rat, we treated male fructose-fed rats with dazmegrel (a thromboxane synthase inhibitor) and monitored blood pressure, fasting plasma parameters, and insulin sensitivity for 7 weeks. Systolic blood pressure was measured each week using tail plethysmography, and an oral glucose tolerance test was performed at the end of the study to assess insulin sensitivity. Treatment with a 60% fructose diet and dazmegrel (100 mg. kg(-1). d(-1) via oral gavage) was initiated on the same day. Plasma triglyceride levels increased 2-fold in both fructose- and fructose/dazmegrel-treated groups, and plasma insulin levels tended to be higher in these groups, although not significantly. Systolic blood pressure increased significantly throughout the study in the fructose-fed group only (132+/-3 versus 112+/-4 mm Hg in control rats, 118+/-2 mm Hg in control-treated rats, 116+/-2 mm Hg in fructose-treated rats). Both fructose groups demonstrated a higher peak insulin response to oral glucose challenge and had 40% to 60% lower insulin sensitivity index values. The results of this study show that treatment with a thromboxane synthase inhibitor, dazmegrel, can prevent the development of hypertension but does not improve insulin sensitivity or other fructose-induced metabolic impairments. Based on these data, we conclude that the potent vasoconstrictor thromboxane is involved in the link between hyperinsulinemia/insulin resistance and hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Glucose; Blood Pressure; Enzyme Inhibitors; Epoprostenol; Fructose; Hypertension; Imidazoles; Insulin; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Triglycerides

1. Hydrogen peroxide (H(2)O(2)) caused a transient contraction in endothelium-intact (E+) and -denuded (E-) mesenteric arteries (MA) from 8 - 10-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) in a concentration-dependent manner (10(-5) M to 10(-3) M). 2. The contraction to H(2)O(2) in MA (E+ or E-) was greater in SHR than in WKY. Removal of endothelium potentiated the contraction to H(2)O(2) in WKY but not in SHR. Tachyphylaxis to H(2)O(2) was less prominent in SHR than in WKY. 3. The contraction of aorta to H(2)O(2) (5 x 10(-4) M), expressed as a percentage of 80 mM KCl-induced contraction, was approximately half of that found in the MA. A greater contraction was found in E+ but not E- SHR aortic rings. 4. The contraction of MA to H(2)O(2) (5 x 10(-4) M) was greatly inhibited by SQ 29548 and ICI 192605 (thromboxane A(2) (TXA(2))/prostaglandin H(2) receptor antagonists), quinacrine (a phospholipase A(2) (PLA(2)) inhibitor), indomethacin and diclofenac (cyclooxygenase (COX) inhibitors), and furegrelate (a TXA(2) synthase inhibitor). 5. Production of thromboxane B(2) induced by H(2)O(2) (5 x 10(-4) M) was greater in SHR MA than in WKY, and was inhibited by quinacrine, indomethacin and diclofenac, and furegrelate, but not by SQ 29584 and ICI 192605. 6. These results suggested (1) that SHR MA exhibits a higher contraction involving an increased smooth muscle reactivity and less tachyphylaxis to H(2)O(2) than WKY; (2) that a greater production of TXA(2) through activation of PLA(2)-COX-TXA(2) synthase pathway appeared to be responsible for the enhanced contraction in SHR MA. The enhanced vascular response to H(2)O(2) may be related to hypertension in SHR.

Topics: Animals; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Culture Techniques; Dioxanes; Endothelium, Vascular; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Hydrogen Peroxide; Hypertension; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tachyphylaxis; Thromboxane A2; Thromboxane B2

Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt-treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt-hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt-treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 +/- 12 and 190 +/- 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 +/- 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 +/- 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules.

Topics: Animals; Blood Pressure; Chlorides; Desoxycorticosterone; Disease Models, Animal; Hydronephrosis; Hypertension; Ligation; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium; Sodium Chloride, Dietary; Thromboxane B2; Ureteral Obstruction

The roles of platelet function, plasma lipids and nitric oxide (NO) were studied in adolescent patients with essential hypertension (JEHT group), with chronic renal failure (CRF) associated with hypertension (CRFH group), and CRF patients with normal blood pressure (CRF group), as compared with normal controls (cont. group). Platelet aggregation and the thromboxane B(2)(TxB(2)) level were significantly higher in the JEHT and CRFH groups as compared with the cont. group, whereas they were significantly lower in the CRF group. On the other hand, the platelet cAMP level was significantly lower in the JEHT and CRFH groups than in the cont. group. The plasma NO level was significantly higher only in the JEHT as compared with the cont. group (120 +/- 39 and 89 +/- 21 microM, respectively). The plasma total cholesterol, triglyceride and LDL cholesterol concentrations were normal in the JEHT group, but high in the CRF and CRFH group, the HDL cholesterol level was lower in the CRF and CRFH groups as compared with the cont. and JEHT groups. There was a positive correlation between the platelet aggregation and the TxB(2)level and between the BP and the platelet aggregation. In conclusion, hyperlipidaemia is commonly present in uraemia with haemodialysis, but is not specific for hypertension in children, while an increased platelet function is frequently associated with hypertension. The increased NO level might play a compensatory role in JEHT.

Topics: Adolescent; Blood Pressure; Child; Cyclic AMP; Dialysis; Female; Humans; Hyperlipidemias; Hypertension; Lipids; Lipoproteins; Male; Nitric Oxide; Platelet Aggregation; Renal Insufficiency; Thromboxane B2

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds; Dinoprostone; Fatty Acids, Monounsaturated; Hypertension; Male; Potassium; Prostaglandin Antagonists; Prostaglandins; Prostaglandins H; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Prostaglandin; Receptors, Thromboxane; Renin; Sodium; Thromboxane B2; Time Factors

Nitric oxide (NO) has been identified as an effective vascular relaxant. This study analyses the contribution of the precursor L-arginine (L-arg) by oral administration in two kidney-two clip hypertension in the rat (2K-2C). Two groups were studied: sham (SH, n=21) and hypertensive (HT, n=15). After 4 weeks of surgery, a group of rats remained as controls (SHc and HTc, respectively), while others were supplemented with L-arg (1.25 g/L) in drinking water (SHa and HTa) for 3 weeks. Blood pressure was significantly increased in 2K-2C rats but remained unchanged after L-arg treatment. Plasma nitrite/nitrate concentrations were not different among groups. The contractile response of aorta to KCl, serotonin and the protein kinase C (PKC) stimulant, phorbol 12,13-dibutyrate (PDBu) was also evaluated. Higher contractile responses to PDBu (p<0.001) and lower relaxation to acetylcholine (Ach 10(-6) M, p<0.05 and 10(-5)M, p<0.02) were observed in aortic rings of HTc vs SHc; L-arg supplementation significantly diminished tension development to all agonists (p<0.05) but failed to modify the lower relaxation to Ach in HTa. Thromboxane (TxA(2)) - synthesis in rings of HTc was higher than in SHc under basal conditions (p<0.05). In the groups with supplement of L-arg, PDBu significantly stimulated prostacyclin (PGI(2)) synthesis more in HTa rats than in SHa ones (p<0.05). To conclude: 1) L-arg fails to modify hypertension development in 2K-2C rats; and 2) L-arg exerts a beneficial effect on the vascular wall, by reducing contractility in rings from HTa rats; it also improved PGI(2) synthesis under PDBu stimulation. 3) greater PKC activation and TxA(2) production rather than lower NO availability might result in systemic hypertension in 2K-2C rats.

Topics: Acetylcholine; Administration, Oral; Animals; Arginine; Blood Pressure; Body Weight; Epoprostenol; Hypertension; Isotonic Solutions; Kidney; Male; Muscle, Smooth, Vascular; Nitrates; Nitrites; Organ Size; Phorbol 12,13-Dibutyrate; Potassium Chloride; Protein Kinase C; Rats; Rats, Sprague-Dawley; Serotonin; Thromboxane B2; Time Factors

This study is aimed at evaluating the influence of the cytochrome P450 arachidonate metabolites on the renal alterations exhibited by the Lyon hypertensive (LH) rat. To that purpose, kidneys were isolated from LH rats and their normotensive (LN) controls and single-pass perfused at different pressure levels before (control conditions) and after cytochrome P450 inhibition by 7-ethoxyresorufin (7-ER, 1 microM). In control conditions, LH kidneys differed from LN ones by an increased preglomerular resistance and a blunted pressure natriuresis. 7-ER, which did not affect the function of LN kidneys, decreased the vascular resistance of LH kidneys, increased their glomerular filtration rate but had no effect on their pressure natriuresis. These results indicate that the renal cytochrome P450 arachidonate metabolism differs between LN and LH rats and is presumably involved in the functional alterations exhibited by LH kidneys.

Topics: Animals; Arachidonic Acid; Cyclic GMP; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Hypertension; In Vitro Techniques; Kidney; Kidney Function Tests; Male; Prostaglandins F; Rats; Renal Circulation; Sodium; Thromboxane B2

The aim of this study was to evaluate the renal response in the elderly with isolated systolic hypertension (ISH) when an adrenergic activation, as induced by mental stress, is applied. Renal hemodynamics and kidney neurohumoral response to mental stress were studied in 8 elderly patients with ISH (aged 63 to 82 years) along with 8 elderly normotensive subjects. The study encompassed four 30-minute experimental periods (baseline, mental stress, and recovery I and II). In these patients, the mental stress-induced blood pressure rise was associated with a significant increase in both effective renal plasma flow ((131)I-labeled hippurate clearance) and glomerular filtration rate ((125)I-labeled iothalamate clearance) (+42% and +29%, respectively; P<0.01 for both), without variations in filtration fraction, while elderly normotensives reacted to adrenergic stimulation with renal vasoconstriction but with the glomerular filtration rate constant. Variations in renal vasoactive substances, which paralleled hemodynamics of the kidney, differed in the 2 groups. In normotensives, excretion (radioimmunoassay) of endothelin-1, prostaglandin E(2), and cGMP increased during the stimulus (+50%, +54%, and +59%, respectively; P<0.05). In ISH patients the release of these autacoids did not vary in any of the experimental periods. In conclusion, in patients with ISH the renal adaptive capacity to sympathetic activation is impaired, and the data may suggest that the glomerulus passively suffers the blood pressure increase, probably because of the insufficiency of the neurohumoral response, particularly in regard to the increase of endothelin-1. This hemodynamic pattern may predispose ISH patients to a higher risk of renal injury.

Topics: Adaptation, Physiological; Aged; Aged, 80 and over; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Middle Aged; Renal Circulation; Stress, Psychological; Thromboxane B2

Cyclosporin A plays an important role in preventing rejection in allograft transplant recipients. However, the therapeutic use of cyclosporin A is associated with increased incidence of thromboembolic complications and drug-related hypertension. In order to study the mechanisms by which cyclosporin A induces these abnormal pathophysiological situations, we have assessed the platelet serotonin contents and whole blood platelet aggregation in control rats as well as in rats treated (orally) with 30 and 5 mg/kg/day of cyclosporin A, after 2 and 7 weeks of treatment. These doses correspond respectively to CsA "peak" and "trough" concentrations achieved in human blood in clinical practice (immediately following an intake of a daily dose of CsA and when the blood concentration stabilizes, respectively). Both trough and peak doses caused an increase in blood pressure after 2 and 7 weeks. Platelet serotonin content decreased in the cyclosporin-treated groups, in contrast with the control. Collagen-induced whole blood platelet aggregation increased drastically for the peak concentration-treated group, while adenosine 5'-diphosphate-induced platelet aggregation did not reach statistical significance. Finally, in vitro platelet thromboxane A2 generation increased in cyclosporin A concentrations when platelets were stimulated with either collagen or adenosine 5'-diphosphate. In conclusion, both tested cyclosporin A concentrations induced important changes in platelet serotonin and thromboxane content and aggregation, factors which may play a decisive role in the development and/or maintenance of hypertension and thrombotic complications.

Topics: Animals; Blood Platelets; Blood Pressure; Cell Size; Collagen; Cyclosporine; Hypertension; Male; Platelet Aggregation; Platelet Count; Rats; Rats, Wistar; Serotonin; Thromboxane A2; Thromboxane B2; Time Factors

Regular exercise is recommended for the non-pharmacological treatment of hypertension, but the mechanisms underlying the lowering of blood pressure remain controversial. Therefore, we studied the effects of 22-week-long training on blood pressure, arterial reactivity, and metabolic abnormalities in a model of genetic obesity and moderate hypertension.. Obese and lean Zucker rats were subjected to treadmill exercise from 8 to 30 weeks of age. Blood pressures were measured by the tail-cuff method, and urine was collected in metabolic cages. At the end of the study, the samples for biochemical determinations were taken, and reactivity of isolated mesenteric and carotid arterial rings was examined in standard organ chambers.. The exercise prevented the elevation of blood pressure which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. The relaxations of norepinephrine-preconstricted mesenteric and carotid arterial rings to acetylcholine and nitroprusside were clearly improved by exercise in the obese rats. In the lean rats exercise enhanced vasorelaxation to nitroprusside in the mesenteric and carotid rings, and to acetylcholine in the carotid preparations. The exercise-induced improvement of endothelium-mediated dilatation to acetylcholine was abolished by nitric oxide synthesis inhibition with NG nitro-L-arginine methyl ester, but not by cyclooxygenase inhibition with diclofenac or functional inhibition of endothelium-dependent hyperpolarization by precontractions with KCl. The urinary excretion of the systemic prostacyclin metabolite (2,3-dinor-6-ketoprostaglandin F1 alpha) was increased two-fold by exercise in the obese and lean rats, whereas that of the thromboxane A2 metabolite (11-dehydrothromboxane B2) remained unaffected. Treadmill training reduced blood glucose, cholesterol, and triglycerides, but did not affect the high levels of insulin in obese Zucker rats.. These results suggest that the antihypertensive effect of long-term exercise in experimental obesity related hypertension is associated with improved vasodilatation. This is expressed as enhanced relaxation via endogenous and exogenous nitric oxide, and increased endothelial prostacyclin production. The improved control of arterial tone after training could be attributed to the alleviation of hyperlipidemia and insulin resistance, whereas hyperinsulinaemia per se remained unaffected.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Analysis of Variance; Animals; Blood Glucose; Carotid Arteries; Cholesterol; Cyclooxygenase Inhibitors; Diclofenac; Endothelium, Vascular; Hypertension; In Vitro Techniques; Insulin; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Obesity; Physical Exertion; Rats; Rats, Zucker; Thromboxane B2; Triglycerides; Vasodilation; Vasodilator Agents

Chronic insulin infusion in rats increases mean arterial pressure (MAP) by a mechanism dependent on angiotensin II (Ang II). However, the fact that plasma renin activity (PRA) decreases with insulin infusion suggests that Ang II sensitivity is increased and that the parallel reduction in Ang II may partly counteract any hypertensive action of insulin. This study tested that hypothesis by clamping Ang II at baseline levels during chronic insulin infusion. Sprague-Dawley rats were instrumented with artery and vein catheters, and MAP was measured 24 hours per day. In seven angiotensin clamped rats (AC rats), renin-angiotensin II system activity was clamped at normal levels throughout the study by continuous intravenous infusion of the angiotensin-converting enzyme inhibitor benazepril at 5 mg/kg per day (which decreased MAP by 18+/-2 mm Hg) together with intravenous Ang II at 5 ng/kg per minute. Control MAP in AC rats after clamping averaged 99+/-1 mm Hg, which was not different from the 101+/-2 mm Hg measured before clamping Ang II levels. Control MAP in the 8 vehicle-infused rats averaged 105+/-2 mm Hg. A 7-day infusion of insulin (1.5 mU/kg per minute IV) plus glucose (20 mg/kg per minute IV) increased MAP in both groups of rats; however, the increase in MAP was significantly greater in AC rats (12+/-1 versus 5+/-1 mm Hg). This enhanced hypertensive response to insulin in AC rats was associated with a greater increase in renal vascular resistance (153+/-10% versus 119+/-6% of control) and a significant increase in renal formation of thromboxane (149+/-11% of control). Thus, decreased Ang II during insulin infusion limits the renal vasoconstrictor and hypertensive actions of insulin, and this may be caused, at least in part, by attenuation of renal thromboxane production.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Drug Synergism; Glucose; Hypertension; Insulin; Kidney; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Thromboxane B2; Vascular Resistance

The endothelial cell regulates vessel tone by elaborating a number of vasoactive substances such as thromboxane and endothelin, both of which are highly vaosconstrictive, and prostacyclin and nitric oxide, both of which are vasodilatory. The current study examines the postulate that one of the mechanisms responsible for the increased vessel tone found in hypertension is the presence of substances in the sera of patients with this disorder that stimulates selectively the endothelial cell production of thromboxane and endothelin. Sera from ten patients with mild hypertension and from 11 age-matched controls were incubated with human umbilical arterial endothelial cells and the concentrations of endothelin, thromboxane, prostacyclin, and nitric oxide produced by the cells was measured in the supernatant. The results of the assays showed that the amounts of thromboxane and endothelin produced by endothelial cells in response to stimulation by hypertensive sera were significantly higher than the amounts produced in response to control sera; in comparison, the amounts of prostacyclin and nitric oxide produced by the cells in response to either hypertensive sera or control sera were not significantly different. The findings suggest that a mechanism that may be responsible for the increased vascular tone found in hypertension is the presence of substances in hypertensive sera that stimulate endothelial cells selectively to produce increased amounts of the vasoconstrictive hormones, endothelin and thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Endothelins; Endothelium, Vascular; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Thromboxane B2; Vasoconstrictor Agents

Since obstructive sleep apnea syndrome (OSAS) is often linked with systemic hypertension, we sought to clarify the characteristics of prostanoid metabolism in OSAS. In 7 OSAS patients (apnea-hypopnea index, 51.0 +/- 23.4) and 7 non-snorers as control, nocturnal urine was sampled and analyzed for stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), [6-keto-PGF1alpha and thromboxane B2 (TxB2)]. The ratio of 6-keto-PGF1alpha to TxB2 was significantly higher in OSAS (2.97 +/- 1.52) than in control (1.38 +/- 0.38). Successful treatment with nasal continuous positive airway pressure (8.3 +/- 1.5 cmH2O) for 3 days caused a significant decrease in mean blood pressure in OSAS. Moreover, the 6-keto-PGF1alpha to TxB2 ratio also significantly decreased to 1.74 +/- 0.58, a level which may not significantly different from control. These results suggest that the production ratio of PGI2 to TxA2 is shifted toward vasodilatation in untreated OSAS. We conclude that the production of prostanoids plays a role in compensating for the systemic hypertension in OSAS.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Case-Control Studies; Humans; Hypertension; Male; Middle Aged; Oxygen; Positive-Pressure Respiration; Sleep Apnea Syndromes; Thromboxane B2

To determine whether cyclosporine A-induced hypertension in renal transplant recipients is accompanied by impairment of endothelium-dependent vasodilatation, which has been suggested by in-vitro and in-vivo animal experiments.. In-vivo endothelium-dependent and endothelium-independent vasodilatation, and plasma concentrations of vasoactive hormones in 16 renal transplant patients were determined while they were being treated with cyclosporine A, and 16 weeks later, after their treatment had been changed to azathioprine therapy. The vasodilator response of the forearm vascular bed was measured by strain gauge venous occlusion plethysmography during intra-arterial infusion of acetylcholine (endothelium-dependent vasodilatation) and nitroprusside (endothelium-independent vasodilatation). Postischemic reactive flow was measured after 10 min of arterial occlusion. In addition, plasma concentrations of norepinephrine, and the prostanoids prostaglandin E2 and thromboxane B2, and also concentration of cyclosporine A in blood, were measured. Glomerular filtration rate and renal blood flow were estimated 1 day before the plethysmography study during each treatment period.. Upon changing from cyclosporine A to azathioprine treatment, mean arterial pressure fell significantly by 12+/-3% (P< 0.05). Glomerular filtration rate and renal blood flow increased by 13+/-5 and 19+/-8%, respectively (both P< 0.05), while renal vascular resistance fell by 48+/-11% (P< 0.01). Both baseline forearm blood flow and baseline forearm resistance did not change after conversion (5.7+/-0.7 versus 4.9+/-0.6 ml/100 ml/min, and 27.3+/-4.2 versus 26.2+/-3.2 arbitrary units). The absolute and relative forearm blood flow responses, and forearm vascular resistance responses to infusions of acetylcholine and nitroprusside were similar during treatments with cyclosporine A and azathioprine. Peak postischaemic forearm blood flow was 42+/-12% higher during cyclosporine A treatment than it was during azathioprine treatment (P< 0.05), but the minimal postischaemic forearm vascular resistance did not differ for these treatments. Plasma prostaglandin E2 and thromboxane B2 levels decreased by 34+/-7 and 45+/-8%, respectively, after changing treatment, but norepinephrine levels did not change.. Our data indicate that cyclosporine A-induced hypertension in renal transplant recipients is not accompanied by an increase in forearm vascular resistance. In addition, changing from cyclosporine A to azathioprine treatment did not cause changes in endothelial vasodilator functioning, although mean arterial pressure decreased significantly. Our results do not support the hypothesis that attenuation of endothelial vasodilator functioning contributes to the development of cyclosporine A-induced hypertension.

Topics: Adult; Animals; Azathioprine; Blood Flow Velocity; Blood Pressure; Cyclosporine; Dinoprostone; Endothelium, Vascular; Female; Forearm; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Norepinephrine; Thromboxane B2; Vascular Resistance; Vasodilation

NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Gastric Mucosa; Hypertension; Male; Naproxen; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Stomach Ulcer; Thromboxane B2

To assess the role of renal thromboxane in a salt sensitive pressor response in hypertension, urinary excretion of thromboxane and its release from isolated glomeruli and renal papillae were examined in deoxycorticosterone acetate treated rats with normal (0.6%, n = 12) and high (4%, n = 12) salt diets for 8 weeks. Mean blood pressure, measured directly by an implanted aortic catheter, was higher in the high salt diet group than in the normal salt diet group (146 +/- 2 vs 119 +/- 2 mmHg, P<0.01). Urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1alpha in the high salt group were significantly higher than those in the normal salt diet group, but there was no difference in urinary excretion of prostaglandin E2 between the two groups. Release of thromboxane B2, 6-keto-prostaglandin F1alpha, and prostaglandin E2 from isolated glomeruli in the high salt diet group increased significantly by 104%, 55%, and 74%, respectively, compared with the normal salt diet group. Stepwise multiple linear regression analysis showed that significant contributory factors for mean blood pressure in deoxycorticosterone acetate treated rats were urinary excretion of sodium (F=14.187, P<0.01) and release of thromboxane B2 from isolated glomeruli (F=4.135, P<0.05). The unstandardized coefficient (R) calculated from the regression function using these two factors was 0.875 and R2 was 0.765. The manifest synthesis of thromboxane in renal glomeruli has an important role on salt sensitive pressor response in deoxycorticosterone acetate-salt hypertension of rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Creatinine; Desoxycorticosterone; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Hypertension; Kidney Glomerulus; Kidney Medulla; Multivariate Analysis; Potassium; Prostaglandins; Rats; Rats, Sprague-Dawley; Regression Analysis; Sodium; Sodium Chloride, Dietary; Thromboxane B2; Thromboxanes

The objective of this study was to evaluate the extent to which endothelin and the eicosanoids prostacyclin and thromboxane A2 are involved in the pathophysiology of gestational hypertension and preeclampsia.. In a longitudinal design, venous blood samples and 24-hour urine specimens were collected from 396 women in each trimester of pregnancy. After delivery of all patients, venous plasma endothelin was assessed in 20 subjects with identified preeclampsia, 48 subjects with gestational hypertension, and 59 normotensive subjects. Urinary excretions of the thromboxane A2 and of the prostacyclin metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were assessed in 16 subjects with preeclampsia, 35 subjects with gestational hypertension, and 31 normotensive subjects.. Endothelin levels showed a second-trimester drop in all groups. In all 3 gestational trimesters a high correlation was found between the excretion of thromboxane B2 and that of 6-keto-prostaglandin F1 alpha (P <.001). The overall thromboxane B2 and 6-keto-prostaglandin F1 alpha urinary excretions increased throughout pregnancy and the overall thromboxane B2 /6-keto-prostaglandin F1 alpha ratio decreased. No significant differences in endothelin, thromboxane B2, and 6-keto-prostaglandin F1 alpha excretion levels or in thromboxane B2 /6-keto-prostaglandin F1 alpha ratios were found between women with preeclampsia, gestational hypertension, and normotension. Only in a small group of patients with severe preeclampsia (n = 2) and severe gestational hypertension (n = 2) were increased second-trimester endothelin values and increased thromboxane B2 /6-keto-prostaglandin F1 alpha ratios found.. In this longitudinal study we found no evidence for prostacyclin deficiency or increased endothelin levels in preeclampsia. Only women with severe preeclampsia and severe gestational hypertension expressed increased endothelin levels and thromboxane dominance over prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Eicosanoids; Endothelins; Female; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane A2; Thromboxane B2

Recent studies suggest that thromboxane (TX) mediates a significant component of angiotensin II (ANG II)-induced hypertension. However, there is little information to support the hypothesis that this relationship is important during chronic, physiological increases in ANG II, particularly while controlling for variation in endogenous ANG II levels induced by TX inhibition. This study tested that hypothesis in 27 chronically instrumented rats. After baseline measurements, suppression of endogenous TX was induced and maintained throughout the study in 13 rats by i.v. infusion of the TX synthesis inhibitor (TSI) U63557A: the other 14 rats received vehicle. Baseline mean arterial pressure (MAP) was not different between groups and was unchanged by TSI or vehicle. Continuous inhibition of ANG II production was then initiated in both groups of rats by i.v. infusion of the angiotensin-converting enzyme inhibitor (ACEI) benazepril. ACEI reduced blood pressure similarly in vehicle and TSI rats, from 105 +/- 2 to 91 +/- 2 mm Hg and 103 +/- 1 to 89 +/- 1 mm Hg, respectively. ANG II was then infused at 5 ng.kg-1.min-1 i.v. for 7 days in six rats from each group to restore ANG II activity to baseline levels. This dose increased MAP to 103 +/- 2 and 101 +/- 1 mm Hg in vehicle and TSI rats, respectively, values not different from pre-ACEI levels. Seven TSI rats and eight vehicle rats received a higher dose of ANG II (20 ng.kg-1.min-1 i.v.). After 7 days, MAP was higher in vehicle than in TSI rats (143 +/- 5 versus 120 +/- 4 mm Hg). These results suggest that endogenous TX is an important determinant of MAP in ANG II hypertension but may have a diminished role in blood pressure regulation when ANG II is at normal and subnormal levels.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Glomerular Filtration Rate; Hypertension; Male; Rats; Rats, Sprague-Dawley; Renin; Thromboxane B2; Thromboxanes

In human and experimental hypertension, flow (shear stress)-induced dilation in large arteries is attenuated and resistant to nitric oxide blockade. We tested the hypothesis that a defect in nitric oxide-and/or prostaglandin-dependent flow-induced dilation might occur in mesenteric resistance arteries from spontaneously hypertensive rats (SHR). We measured resistance mesenteric artery diameter in situ by intravital microscopy and simultaneously measured mesenteric arterial pressure in a collateral artery. The flow-diameter-pressure relationship was established in normotensive Wistar-Kyoto rats (WKY) and in SHR under control conditions and after endothelium removal, inhibition of nitric oxide synthesis with N omega-nitro-L-arginine methyl ester (10 micromol/L), or inhibition of prostaglandin synthesis with indomethacin (10 micromol/L). Production of prostaglandins was determined in the perfusate. Endothelium removal decreased artery diameter by 14 +/- 1.6% in WKY and 5 +/- 0.5% (P<.01 versus WKY) in SHR at a flow rate of 400 microL/min. In WKY, N omega-nitro-L-arginine methyl ester and indomethacin decreased resistance artery diameter by 12 +/- 3% (P<.001) and 5 +/- 2% (P<.01), respectively, at a flow rate of 400 microL/min; neither substance had any significant effect in SHR. In both strains, flow induced the production of 6-keto-prostaglandin F1alpha, the metabolite of prostacyclin; prostaglandin F2alpha; and thromboxane B2, the stable metabolite of thromboxane A2. Production of 6-keto-prostaglandin F1alpha and prostaglandin F2alpha was significantly lower in SHR than WKY, and TxB2 production was significantly higher in SHR than WKY. The present findings suggest that in SHR mesenteric resistance arteries, dilation in response to increases in flow was resistant to nitric oxide and prostaglandin synthesis blockade. A modification of the ratio of vasodilator to vasoconstrictor prostaglandins might be at least partly responsible for the decreased dilator response to flow in SHR.

Topics: Animals; Dinoprost; Hypertension; Mesenteric Arteries; Nitric Oxide; Prostaglandins; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Thromboxane B2; Vascular Resistance

The aim of this study was to assess prospectively the urinary excretion of renal and systemic metabolites of thromboxane and prostacyclin in normotensive and chronic hypertensive pregnancies.. Pregnant hospital employees were invited to collect 24-hour urine samples weekly from the seventh week until delivery. Concentrations of renal metabolites (thromboxane B2, 6-keto-prostaglandin F1alpha) were measured by radioimmunoassay after extraction. Systemic metabolites (2,3-dinor-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1alpha) were assessed by enzyme immunoassay after extraction and high-pressure liquid chromatographic separation.. Thromboxane B2 excretion was similar in normotensive and hypertensive pregnancies, whereas a twofold increase of 6-keto-prostaglandin F1alpha was observed in hypertensive compared with normotensive pregnancies (7537 +/- 349 vs 3857 +/- 202 pg/mg creatinine, p < 0.001). During pregnancy in both conditions measurements displayed uniform excretion of thromboxane B2 with progressively increased levels of 6-keto-prostaglandin F1alpha in chronic hypertension (R2 = 0.60, p < 0.005). Mean excretion of 2,3-dinor-thromboxane B2 averaged 1208 +/- 65 and 898 +/- 48 pg/mg creatinine in normotensive and hypertensive pregnancies (p < 0.001), mainly due to significant decreased concentrations in hypertension in the first half of pregnancy. Conversely, 2,3-dinor-6-keto-prostaglandin F1alpha levels were 845 +/- 39 and 1226 +/- 67 pg/mg creatinine in normotensive and hypertensive pregnancies (p < 0.001), mostly because of significantly increased production in hypertension from 22 weeks onward. Ratios of both renal and systemic metabolites favored increased prostacyclin production in chronic hypertension.. In contrast to preeclampsia, uncomplicated mild to moderate chronic hypertensive pregnancies are characterized by an excess production of prostacyclin with unaltered or even lower thromboxane concentrations, which may contribute to the general favorable outcome of this hypertensive condition.

Topics: 6-Ketoprostaglandin F1 alpha; Chronic Disease; Creatinine; Epoprostenol; Female; Humans; Hypertension; Kidney; Longitudinal Studies; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Reference Values; Thromboxane B2

The cardiovascular effects of a partially purified extract of fish oil, enriched in the n-3 series fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were studied in stroke-prone spontaneously hypertensive rats (SHR-SP) fed with high- and low-sodium diets during 5 weeks. Addition of salt to the low-salt control diet at a level commonly found in human food items (6% NaCl of the dry weight of the diet) produced a remarkable rise in blood pressure, an increase in left ventricular weight-to-body weight ratio (LVH-index) and an increase in kidney weight-to-body weight ratio (RH-index). Fish oil (20% of the dry weight of the diet) did not significantly influence the blood pressure or LVH-index or RH-index during the low-salt control diet. However, fish oil completely prevented the remarkable rise in blood pressure and clearly antagonized the rise of both LVH- and RH-indices, induced by the high-salt diet. The fish oil supplementation increased the levels of the polyunsaturated fatty acids of the n-3 series and decreased those of the n-6 series in plasma and kidney, irrespective of the salt content of the diet. Fish oil lowered serum thromboxane B2 concentration by approximately 75%. During the high-salt diet, fish oil markedly decreased water intake and urine volume, and increased urinary sodium concentration by about 60%. Our findings show that, in addition to an antihypertensive effect, fish oil also decreases LVH and RH. These effects appear to be due to an improved ability to excrete sodium and could be explained by the observed changes in the fatty acid composition and metabolism.

Topics: Animals; Eating; Fatty Acids; Fish Oils; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary; Thromboxane B2; Weight Gain

Chronic administration of prostacyclin (PGI2) improves hemodynamics in patients with primary pulmonary hypertension, but abrupt cessation of infusion can cause severe dyspnea of unknown etiology. We hypothesized that the discontinuation of PGI2 results in platelet activation, thromboxane A2 production, and increased pulmonary vascular tone. To test this, six sheep with indwelling catheters were monitored during infusion of PGI2 and after its cessation. Infusion of PGI2 caused a reduction in mean systemic arterial pressure (MAP) and systemic (SVR) and pulmonary vascular resistances (PVR), a rise in cardiac output (CO), and no change in pulmonary arterial or pulmonary capillary wedge pressure (PCWP). After discontinuation of PGI2, MAP and SVR rebounded to 30 and 67% above baseline, respectively, and PVR rose 26%. CO was depressed 23% within 10 min, and PCWP nearly doubled after stoppage of the drug. Concurrent treatment with a cyclooxygenase inhibitor did not attenuate these responses. 11-Dehydro-thromboxane B2 levels were not elevated during infusion or after cessation of PGI2. We conclude that the abrupt cessation of PGI2 infusion leads to systemic and pulmonary hypertension and transient cardiac dysfunction not mediated by cyclooxygenase metabolites of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Hypertension; Hypertension, Pulmonary; Infusions, Intravenous; Platelet Activation; Platelet Aggregation Inhibitors; Pulmonary Circulation; Sheep; Substance Withdrawal Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasodilation

Through a study of 504 cases of observation group with eye-signs in blood stasis syndrome (BSS) and 112 cases of control group without eye-signs in BSS, it has been found that in the observation group, the scores of the blood concentration, viscosity, aggregability and coagulability, level of plasma thromboxane B2 (TXB2), and the ratio of TXB2/6-keto-PGF1 alpha were obviously higher than those in the control group, but level of 6-keto-PGF1 alpha was obviously lower than that in the control group; the above-mentioned parameters of blood hyperviscosity syndrome, was obviously higher than that in the control group (90.08%:2.68%); comparisons between the two groups were significantly different (P < 0.001). Certain findings of the pathological base of eye-signs in BSS were found in the investigations.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Viscosity; Coronary Disease; Eye Diseases; Female; Hemorheology; Humans; Hypertension; Male; Medicine, Chinese Traditional; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Thromboxane B2

The authors examined some indicators of platelet activity in patients with hypertension stage II (according to WHO). They revealed an increased platelet activity which was manifested by an increased concentration of platelet factor 4 (50.2 +/- 28.2 ng/ml) and thromboxane B2 (49.9 +/- 20.1 pg/ml) in plasma. The increase of indicators of platelet activation associated with hypertension is a molecular marker of activation of haemostasis and according to data in the literature it is an indicator of vascular complications in hypertension. It is not clear whether the increased platelet functions in hypertension is primary or an induced change.

Topics: Adult; beta-Thromboglobulin; Blood Platelets; Female; Humans; Hypertension; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Factor 4; Thromboxane B2

1. In previous works we have described the development of hypertension and aggravation of proteinuria in rats who became pregnant after the administration of Adriamycin. This was associated with an increase in the glomerular thromboxane B2-prostaglandin E2 ratio. 2. To assess the pathogenetic role of thromboxane in this model, female Wistar rats were mated 2 weeks after receiving Adriamycin (3.5 mg/kg intravenously). Rats were then treated with the thromboxane-receptor antagonist daltroban, 60 mg day-1 kg-1 orally, beginning on day 11 of pregnancy. Systolic blood pressure, proteinuria and the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 were measured serially before mating, and on days 14 and 21 of pregnancy. The results were compared with those in Adriamycin-(treated) pregnant rats not treated with daltroban, Adriamycin-treated virgin rats and normal virgin or pregnant rats either treated or untreated with daltroban. 3. In daltroban-treated pregnant and virgin rats treated with Adriamycin, systolic blood pressure remained normal, whereas it increased significantly (P < 0.05) in untreated animals. On day 14, blood pressure was higher in non-daltroban-treated Adriamycin-treated pregnant rats than in non-daltroban-treated Adriamycin-treated virgin rats. Treatment had no effect on blood pressure in normal virgin or pregnant rats. Proteinuria was higher in pregnant rats treated with Adriamycin than in Adriamycin-treated virgin rats, but it was not reduced by daltroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Doxorubicin; Female; Hypertension; Phenylacetates; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Wistar; Receptors, Thromboxane; Sulfonamides; Thromboxane B2; Thromboxanes

By combining serial measurements of the circulating concentrations of thromboxane A2 and prostacyclin with measurements of venous distensibility (taken during the pregnancies of both normal women and those with pregnancy induced hypertension or pre-eclampsia), to test the following hypotheses: 1. that changes in the venous plasma ratio of thromboxane (TXB2) and 6-keto-PGF1 alpha would correlate with changes in the blood pressure of women developing and recovering from pregnancy induced hypertension or pre-eclampsia and 2. that changes in venous distensibility would correlate with changes in arterial blood pressure in pregnancy induced hypertension or pre-eclampsia.. Prospective, longitudinal cohort study.. John Hunter Hospital clinic, Newcastle, Australia.. One hundred and sixty primiparous women, recruited when presenting for their first routine antenatal visit, were investigated at, or close to, 19, 28 and 37 weeks of gestation; a subgroup was also studied in the postnatal period. The measurements of the patients who developed pregnancy induced hypertension or pre-eclampsia were compared with those of controls selected from the cohort.. Serial measurements of the circulating concentrations of the stable metabolites of thromboxane A2 and prostacyclin (TXB2 and 6-keto-PGF1 alpha, respectively), venous distensibility and immediate (no rest) and resting (for at least 30 min) blood pressures.. There was no significant difference between the subject and control groups at any time during or after the pregnancy in the concentrations of prostaglandin metabolites, their ratio or venous distensibility. In contrast, there was a significant difference between the groups at 19 weeks for immediate and resting readings of diastolic pressure (6 mmHg (95% CI 1.5 to 10.5) and 4 mmHg (95% CI 0.1 to 7.9), respectively). These differences increased through the pregnancy but mean postnatal readings for the groups were almost identical suggesting that the subjects were not intrinsically hypertensive compared with controls. Blood pressures for the subject group, both immediate and resting, were significantly different from the 19 week readings at 28 weeks (diastolic) and at 37 weeks (systolic and diastolic). The only significant change from first readings among controls was in postnatal systolic pressure which was significantly higher than 19 week values, probably reflecting the vasodilatation, with accompanying hypotension, of early, normal pregnancy. This difference was not observed in those who subsequently developed pregnancy induced hypertension or pre-eclampsia.. Our study was unable to demonstrate differences in circulating metabolites or venous distensibility between normotensive women and those with pregnancy induced hypertension or pre-eclampsia. If pregnancy induced hypertension or pre-eclampsia in humans represents not so much the presence of abnormal constrictor influences as a process initiated by failure of normal vasodilatation in early pregnancy, studies carried out later may detect mainly adaptive and secondary changes.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Cohort Studies; Elasticity; Female; Hand; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prospective Studies; Thromboxane A2; Thromboxane B2; Veins

Our objective was to evaluate prostanoid release from the placentae of pregnancies complicated by severe intrauterine growth retardation (IUGR) and without hypertension, compared with placentae from normal, uncomplicated term pregnancies. A perifusion system was utilized to study the release of prostanoids 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2(TxB2), prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) from human placentae from pregnancies complicated by normotensive severe IUGR (n = 9, five at term and four preterm) and normal control pregnancies (n = 6). For each placenta, triplicate chambers of tissue were perifused at a rate of 6 ml/h, and samples were collected from hours 5-10. Prostanoids were measured using specific and sensitive radioimmunoassays. In the IUGR group, the basal placental production of the vasoconstrictor thromboxane was not increased, nor was the ratio of cumulative TxB2 to 6-keto-PGF1 alpha elevated compared with normal term controls. In three term IUGR placentae, the ratio was significantly decreased compared with controls. The basal placental production of the vasoconstrictor PGF2 alpha was likewise not increased compared with controls, nor was the ratio of PGF2 alpha to PGE2 elevated. Two of the placentae in the term IUGR group demonstrated significant elevations of PGE2 and 6-keto-PGF1 alpha. Overall, the IUGR placentae released normal or low normal levels of the prostanoids studied. The pattern of placental prostanoid release over time was similar to that of the normal term placentae. The term and preterm placentae of pregnancies complicated by severe IUGR did not exhibit an excess production of vasoconstrictor prostanoids. Therefore, strategies designed to reduce thromboxane production in severe IUGR without hypertension may be unjustified.

Topics: Case-Control Studies; Female; Fetal Growth Retardation; Humans; Hypertension; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Thromboxane B2

1. The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary excretion of TX and its release from blood platelets and renal papilla, and pathological change of glomeruli were evaluated in Dahl salt-sensitive rats. 2. Average daily intakes of OKY-046-treated rats were 0.93 mg/kg (low dose), 9.8 mg/kg (moderate dose), and 88 mg/kg (high dose). 3. Systolic blood pressure tended to decrease by 6.3, 11.4, and 10.9% in three OKY-treated groups. 4. OKY-046 suppressed the release of TX from platelets in a dose-dependent fashion. Both TX in urine and released from renal papilla decreased in OKY-treated groups with moderate and high dose. OKY-046 resulted no change in urinary excretion or release from renal papilla of prostaglandin E2 or 6-keto-prostaglandin F1alpha. 5. Glomerular sclerosis score decreased significantly in both groups treated with moderate and high doses of OKY-046. 6. An inhibition of renal TX synthesis by TX synthetase inhibitor has a protective effect on the development of hypertensive renal damage with minor antihypertensive effect in Dahl salt-sensitive rats.

Topics: Animals; Antihypertensive Agents; Enzyme Inhibitors; Female; Hypertension; Kidney; Kidney Glomerulus; Methacrylates; Rats; Rats, Inbred Strains; Sclerosis; Sodium Chloride; Thromboxane B2; Thromboxane-A Synthase

To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterioles; Blood Urea Nitrogen; Creatinine; Hypertension; Kidney; Kidney Diseases; Male; Nifedipine; Rats; Rats, Inbred SHR; Renal Artery; Renin; Tacrolimus; Thromboxane B2; Vasoconstriction

Topics: Blood Platelets; Female; Fetal Growth Retardation; Humans; Hypertension; Platelet Activation; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

To investigate the effect of dietary eicosapentaenoic acid (EPA) on plasma lipoprotein levels, lecithin:cholesterol acyltransferase (LCAT) activity and liver acetyl CoA carboxylase activity, highly concentrated EPA (78%) purified from sardine oil was fed to stroke-prone spontaneously hypertensive rats (SHRSP) for 30 days. Significantly (P < 0.05) lower systolic blood pressure and plasma total cholesterol were observed in rats fed an EPA diet. In addition, higher HDL cholesterol and lower VLDL cholesterol levels were found in rats fed the EPA diet as compared with rats fed the control diet. However, no significant change of plasma LDL cholesterol was observed in rats between the two dietary groups. EPA supplementation increased the activity of plasma LCAT in rats. In addition, rats fed an EPA diet had lower liver total lipids and adipose tissue weights. However, higher liver acetyl CoA carboxylase activity was observed in rats fed the EPA diet. Results from the present study suggest that dietary EPA might stimulate the plasma lipoprotein metabolism and also alter lipogenesis in the liver of SHRSP rats.

Topics: Acetyl-CoA Carboxylase; Administration, Oral; Animal Feed; Animals; Cerebrovascular Disorders; Eicosapentaenoic Acid; Hypertension; Lipoproteins; Liver; Organ Size; Phosphatidylcholine-Sterol O-Acyltransferase; Rats; Rats, Inbred SHR; Thromboxane B2

The effects of ridogrel (a thromboxane synthetase inhibitor/endoperoxide receptor antagonist) were assessed in an ovine model of pregnancy-induced hypertension. Maternal serum prostacyclin and thromboxane levels were quanitiated using RIA, and maternal and neonatal coagulation status was assessed. Pregnancy and neonatal outcome were recorded. Ridogrel, (E)-5-[[[3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amin++ +] oxy]pentanoic acid, was administered in one bolus dose at 0.1 or 1.0 mg/kg IV, three hours following the onset of a 27 hour magnesium sulfate infusion given hypertensive ewes to prevent maternal seizures. At both doses, ridogrel improved neonatal outcome (0% neonatal mortality in each ridogrel group versus 67% neonatal mortality in the magnesium sulfate group), and ridogrel at 0.1 mg/kg IV normalized birth weights. Abnormalities of maternal platelet function (abnormal or no response to collagen), occurring during the ovine syndrome, resolved following ridogrel treatment. Ridogrel's effects on maternal and neonatal coagulation were more dramatic at the 0.1 mg/kg IV dose. Ridogrel appeared to be beneficial in this model of pregnancy-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Female; Fetus; Homeostasis; Hypertension; Pentanoic Acids; Placebos; Pregnancy; Pregnancy Complications, Cardiovascular; Pyridines; Radioimmunoassay; Sheep; Thromboxane B2; Thromboxane-A Synthase

A 6-month program of exercise with a daily swimming time of 30 minutes 3 times a week was carried out in female spontaneously hypertensive rats (SHR) to assess the roles of catecholamine and prostaglandin metabolism in the antihypertensive effect of chronic exercise conditioning. Swim training resulted in a significant reduction of mean blood pressure in SHR by 13.3 mmHg as compared with sedentary controls (158.8 +/- 5.0 versus 172.1 +/- 3.3 mmHg, p < 0.05). The increase in plasma levels of norepinephrine and epinephrine after acute blood loss of 2% of body weight were smaller in trained than control SHR. The daily urinary excretion of thromboxane B2, a stable metabolite of thromboxane A2, was significantly decreased by 33% in swim trained SHR as compared with control SHR (p < 0.01), while there was no difference in urinary excretion of prostaglandin E2 or 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. These findings indicate that both the suppression of the sympathoadrenal system and decrease in vasoconstrictory prostaglandins in the kidney may have shared in the antihypertensive effect of exercise training in SHR.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Catecholamines; Dinoprostone; Epinephrine; Female; Hypertension; Norepinephrine; Physical Conditioning, Animal; Prostaglandins; Rats; Rats, Inbred SHR; Swimming; Thromboxane B2

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Epoprostenol; Female; Gestational Age; Homeostasis; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2

Penile hypercoagulability during erection may predispose to aging vascular changes and, eventually, arteriogenic impotence. The relationship of penile blood thromboxane B2 and 6-keto-prostaglandin F1 alpha in both psychogenically and arteriogenically impotent patients after intracavernosal treatment with papaverine plus phentolamine or prostaglandin E1 was evaluated. No significant change in penile blood thromboxane B2 was observed with treatment of these vasoactive drugs. On the other hand, penile blood 6-keto-prostaglandin F1 alpha was significantly increased with the injection of 30 mg of papaverine plus 0.5 mg of phentolamine, and of 20 micrograms prostaglandin E1. Furthermore, the prostacyclin-to-thromboxane A2 ratio for the patient who received papaverine plus phentolamine was significantly lower than that for the same individual receiving prostaglandin E1. Our preliminary findings suggest that penile blood prostacyclin may participate in the pathogenesis of arteriogenic impotence and priapism.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Alprostadil; Diabetes Complications; Epoprostenol; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Papaverine; Penis; Phentolamine; Radioimmunoassay; Thromboxane B2

Hypertensive diseases represent the most frequent disorders among medical complications of pregnancy. Numerous studies have proven the central role of prostaglandins in these complex diseases. Thus, determination of urinary prostaglandins may lead to a better understanding of the pathomechanismus and may be a basis for therapeutic approaches. Our study included 59 patients with pregnancy-induced hypertension. From these 18 women had a proteinuria > 300 mg/l and were classified as pre-eclamptic. As controls 53 normotensive pregnancies were investigated. Quantification of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha, TxB2, 11-Dehydro-TxB2 and PGE2 was performed with radio or enzyme immunoassays after purification with solid phase extraction and partly HPLC. In the third trimester of pregnancy following alterations were found in urine concentrations of prostaglandins in preeclamptic women compared to controls: 6-keto-PGF1 alpha - 54%, 2,3-dinor-6-keto-PGF1 alpha - 29%, PGE beta 2-41%, TxB2-29% and 11-Dehydro-TxB2 + 21%. Thus, our results show a disturbed balance between vasodilatory and vasoconstrictive prostaglandins in PIH patients. This imbalance correlated to the severity of the disease and was more pronounced in preeclamptic patients. The decrease of PGI2- and PGE2-production was more distinct than the increase of thromboxane production. We conclude that the endothelial damage, rather than an overproduction of TxA2 predominantly is responsible for some pathophysiological events in PIH.

Topics: Adult; Epoprostenol; Female; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prostaglandins; Reference Values; Thromboxane B2; Vascular Resistance

The aim of the present study was to investigate the occurrence of changes in the plasma levels of vasoactive prostanoids and inhibitors of blood coagulation in normal pregnancy and in cases of pregnancy induced hypertension. Levels of the coagulation inhibitors antithrombin III, protein C, Protein S as well as the prostaglandin metabolites thromboxane B2 and 6-oxo-prostaglandin F1 alpha were measured between 13 and 37 weeks gestation in 36 primigravidae. In 8 of the examined patients persistently raised blood pressure values of 140/90 and above were measured after 20 weeks of gestation. Our results indicated that an imbalance of vasoactive prostanoids may precede the appearance of clinical symptoms of PIH. The determination of coagulation factors before blood pressure is elevated has no predictive value regarding the later development of PIH. The reduced levels of protein C associated with our PIH group are considered to be the result of an activated coagulation followed by consumption of clotting factors. Reduced measured levels of protein S in normotensive as well as hypertensive pregnancies offer an explanation for the increased risk of thromboembolic disease. This increased susceptibility to thromboembolic disorders is further enhanced by the altered balance between the platelet aggregator and vasoconstrictor thromboxane A2 and its antagonist prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Antithrombin III; Antithrombins; Epoprostenol; Female; Humans; Hypertension; Infant, Newborn; Longitudinal Studies; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Prostaglandins; Protein C; Protein S; Thromboxane A2; Thromboxane B2; Vascular Resistance

This study examined plasma and urinary endothelin 1 and urinary metabolites of prostacyclin and thromboxane, in women with pre-eclampsia and age and gestation matched controls. To determine if changes in endothelin 1 and urinary prostanoids in pre-eclampsia were due to hypertension per se, a comparison was made to a group of age and gestation matched pregnant uncomplicated essential hypertensive women. Measurements were taken prior to delivery, and at 6 weeks and 6 months post-partum, and were compared to a group of age matched non-pregnant controls. Plasma endothelin 1 was significantly elevated and the urinary metabolite of prostacyclin (2,3-dinor-6-keto-PGF1 alpha) was significantly suppressed in pre-eclamptic pregnancy, compared to normal pregnancy and essential hypertensive pregnancy. As the level of blood pressure was similar in the pre-eclamptic and essential hypertensive groups, these changes are not due to an increase in blood pressure per se. Urinary endothelin 1 was not different in the 3 pregnant groups prior to delivery but fell significantly after delivery. Urinary endothelin 1 was significantly lower in the essential hypertensive group at 6 weeks post-partum compared to pregnant controls with a similar trend at 6 months. Urinary 11-dehydro-TXB2 was elevated in pregnancy, but no further elevation was seen in women with pre-eclampsia. Platelet counts were lower, and circulating neutrophil counts higher in pre-eclampsia prior to delivery. A combination of increased plasma endothelin 1 and reduced tissue prostacyclin synthesis may contribute to hypertension, placental insufficiency, foetal growth retardation and renal dysfunction in pre-eclampsia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Blood Pressure; Endothelins; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane B2

Cyclosporine induces hypertension and wide-spread vasoconstriction after transplantation in addition to reducing kidney function. We studied hemodynamic, renal, and hormonal effects of monotherapy with nifedipine XL (n = 37) in liver transplant recipients within a year after transplant (median, 4.4 months). Systemic hemodynamics were determined with thoracic electrical bioimpedance. Blood pressure before therapy was 172 +/- 4/108 +/- 2 mm Hg. Sixty-four percent of recipients achieved blood pressures less than 140/90 mm Hg mediated by a fall in systemic vascular resistance index (2427 +/- 245 dyne.s.cm-5.m-2 in responders versus 2905 +/- 281 in nonresponders, P < .01). Despite the fall in systemic vascular resistance, glomerular filtration rates were not changed during nifedipine therapy, as measured by both creatinine and iothalamate clearances. Urinary prostacyclin (6-ketoprostaglandin F1 alpha) was suppressed below normal from 2468 +/- 323 ng/d before transplant to 1103 +/- 99 ng/d (P < .01) after transplant and did not change during nifedipine therapy. Urinary thromboxane B2 and plasma renin activity also fell after transplant and remained low during nifedipine. These data demonstrate that nifedipine can reverse systemic vasoconstriction associated with hypertension after transplantation. Systemic effects were not transmitted to the kidney sufficiently to improve glomerular filtration rate or reverse hormonal changes within the kidney. Hence, vascular and functional regulation of the kidney was dissociated from the systemic circulation during nifedipine administration after transplantation.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Blood Pressure; Cardiac Output; Cyclosporine; Diastole; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Liver Transplantation; Male; Middle Aged; Renin; Systole; Thromboxane B2; Vascular Resistance; Vasoconstriction

Low dose Aspirin in pregnancy reduces the incidence of intra uterine growth retardation (IUGR) and pregnancy induced hypertension (PIH) in women at risk for these complications. To investigate if this drug, even in a low dose, could expose the newborn to hemorrhagic complications, we studied ten neonates whose mothers had been taking 50 mg/day of Aspirin from the 12th week of pregnancy until delivery and compared them with eight newborns whose mothers didn't take the drug. No hemorrhagic complications (emathemesis, ecchymoses or petechiae, subconjunctival hemorrhage, cephaloematomas etc.) were observed in the fetuses exposed to Aspirin or in the control group. No hemorrhagic lesions were found by ultrasound brain scan on the fourth day of life. Newborns exposed to Aspirin showed a significantly lower thromboxane concentration on the first day of life (median 73 ng/ml versus 217 ng/ml); however on the fourth day the level of serum thromboxane in the cases exposed reached the values of the unexposed ones (median 146 ng/ml versus 143 ng/ml). In conclusion low dose Aspirin in pregnancy can be considered a safe drug without and adverse effect on the newborn.

Topics: Aspirin; Birth Weight; Cerebral Hemorrhage; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Hypertension; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane B2

1. Experiments were designed to determine the effects of low concentrations (5-500 nmol/L) of naftidrofuryl, a 5-hydroxytryptamine (5-HT) antagonist, on renal functions and prostanoid synthesis responses to noradrenaline (NA) and 5-HT. Isolated kidneys of 8 week old male spontaneously hypertensive rats were perfused at a constant flow rate in a single-pass system. 2. In baseline conditions, naftidrofuryl did not modify the renal vascular resistance and the glomerular filtration rate (GFR), although it elicited a significant but not dose-dependent increase in the venous excretion of 6-keto-prostaglandin (PG) F1 alpha and thromboxane (Tx)B2, the stable end-products of PGI2 and TxA2, respectively. 3. NA increased renal vascular resistance and GFR in a dose-dependent manner and enhanced the venous excretion of 6-keto-PGF1 alpha and TxB2. Naftidrofuryl significantly attenuated the effects of NA on renal vascular resistance, abolished those on GFR and enhanced, at the highest concentration (500 nmol/L) only, those on 6-keto-PGF1 alpha excretion. 4. 5-HT increased renal vascular resistance but not GFR. It did not change the sodium excretion and the release of 6-keto-PGF1 alpha and TxB2. Naftidrofuryl blunted the RVR response to 5-HT without change in the prostanoid release. The inhibitory action of naftidrofuryl was not modified by indomethacin which, by itself, prevented the vasoconstrictor response to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Glomerular Filtration Rate; Hypertension; In Vitro Techniques; Kidney; Male; Nafronyl; Norepinephrine; Rats; Rats, Inbred SHR; Serotonin; Thromboxane B2; Vascular Resistance

1. Plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF 1 alpha, a major metabolite of prostacyclin), plasma thromboxane B2 (TXB2, a major metabolite of thromboxane A2) and five antioxidants (indirect markers of reactive oxygen species) namely, plasma thiol, erythrocyte lysate thiol, erythrocyte superoxide dismutase, plasma total glutathione and erythrocyte membrane thiol, were measured in 25 healthy non-pregnant women, 36 normotensive pregnant women and 35 women with pregnancy-induced hypertension (PIH). 2. The levels of TXB2 were significantly increased in normal pregnant women and PIH women with or without proteinuria compared with non-pregnant women. The concentrations of TXB2 in PIH women with proteinuria were higher than those without proteinuria (P < 0.05). 3. The levels of 6-keto-PGF1 alpha in healthy non-pregnant women and PIH women with or without proteinuria were significantly lower than that in normotensive pregnant women (all of three P < 0.01). There were no significant differences between healthy non-pregnant women and PIH women with and without proteinuria. 4. The ratio of TXB2 to 6-keto-PGF1 alpha was markedly elevated in PIH women with or without proteinuria compared with normotensive pregnant women and healthy non-pregnant women. The difference between PIH women with proteinuria and those without proteinuria was not significant (P > 0.05). 5. The levels of plasma thiol, superoxide dismutase and glutathione were significantly decreased in PIH women compared with normotensive pregnant women. 6. There were significant positive correlations between the levels of prostaglandins and antioxidant activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Biomarkers; Epoprostenol; Female; Humans; Hypertension; Oxidation-Reduction; Pregnancy; Pregnancy Complications, Cardiovascular; Reactive Oxygen Species; Thromboxane A2; Thromboxane B2

The influence of indapamide on the prostaglandin system was studied in spontaneously hypertensive rats (SHR) and compared with SHR control and normal WKY rats. The results show that the synthesis of vasoconstrictive prostaglandins (PGE2 and PGF2 alpha) in the renal medullary tissues of SHR is higher than that of normal rats, and this may have something to do with the development and maintenance of high blood pressure in SHR. After indapamide administration, the synthesis of prostacyclin in SHR aorta increased significantly as compared with the SHR control group, whereas PGE2 and PGF2 alpha production in renal medullary tissues decreased markedly. The results support the idea that the prostaglandin system, especially PGE2 and PGF2 alpha, plays an important role in the antihypertensive mechanism of indapamide.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Dinoprost; Dinoprostone; Female; Hypertension; Indapamide; Kidney Medulla; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2

The aim of this study was to investigate the growth factor activity in plasma (GFAP) in hypertension, and the correlation of GFAP to blood pressure levels, cardiac structural changes and platelet activation at rest and during exercise.. Fifteen untreated hypertensive subjects and 15 normotensive controls were recruited from a blood pressure screening programme.. GFAP before and after 30 min of strenuous exercise was analysed as the ability of patient or control plasma to stimulate incorporation of 3H-thymidine in cultured human smooth muscle cells. M-mode echocardiography was performed and platelet activity was measured by the excretion of the urinary metabolite of thromboxane A2.. There were no significant differences in GFAP or platelet activation at rest or after exercise between the groups. The fractions of labelled cells were 52.6% vs. 56.6% (HT vs. NT) at rest. Septum and posterior wall end-diastolic thicknesses (PWT[D]) were significantly increased in the HT group (10.4 +/- 0.3 vs. 9.2 +/- 0.3 mm and 11.4 +/- 0.5 vs. 10.0 +/- 0.4 mm, respectively, P < 0.05). PWT(D) was significantly correlated to GFAP (r = 0.40, P = 0.04) and to blood pressure (r = 0.53, P < 0.005) but there was no correlation between blood pressure and GFAP.. The data suggest that GFAP could play a role in the early development of cardiac hypertrophy in hypertension, but that this effect does not seem to be directly linked to blood pressure levels alone.

Topics: Adult; Blood Pressure; Echocardiography; Exercise; Growth Substances; Humans; Hypertension; Male; Middle Aged; Myocardium; Platelet Activation; Regression Analysis; Rest; Thromboxane B2

Topics: Female; Fetal Growth Retardation; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Thromboxane B2

Umbilical artery flow velocity waveforms (UAFVW's) were measured by Doppler ultrasound in 35 pregnant women with pregnancy induced hypertension. The stable hydration products of the vasoconstrictor and proaggregatory thromboxane A2 and vasodilatory and anti-aggregatory prostacyclin (i.e. thromboxane B2 (TxB2) and 6 ketoprostaglandin F1 alpha (6 keto PGF1 alpha) respectively) were measured in blood obtained from the umbilical vein and were assayed by radioimmunoassay. Abnormal umbilical artery Resistance Index (UARI) was associated with higher thromboxane B2 levels, lower 6-ketoprostaglandin F1 alpha levels and lower 6-keto PGF1 alpha/TxB2 ratio. Moreover, the umbilical artery Resistance Index was significantly correlated with the 6-keto PGF1 alpha/thromboxane B2 ratio suggesting an association between abnormal umbilical artery blood flow and altered prostacyclin/thromboxane balance in the fetoplacental compartment in patients with pregnancy induced hypertension (PIH).

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxane B2; Umbilical Arteries; Umbilical Veins; Vascular Resistance

Black essential hypertensive patients with a mean arterial pressure of 125 +/- 3 mm Hg (mean +/- SEM), and age and sex matched normotensive subjects with a mean arterial pressure of 89 +/- 2 mm Hg were studied under baseline conditions, after five days of salt restriction and after five days of salt loading. Salt sensitivity was defined as an increase of mean blood pressure exceeding 5% when progressing from low to high sodium intake. In vitro platelet responsiveness was assessed by aggregometry, and in vitro platelet activity by estimation of beta-thromboglobulin (BTG) in plasma and thromboxane B2 (TXB2) excretion rate. Salt sensitivity was present in 66% of hypertensive and 55% of the normotensive subjects. An increased platelet aggregability to ADP (25%), to epinephrine (34%) and to collagen (12%) was found in parallel with an increased in vivo platelet activity (BTG increased by 55% and TXB2 by 18%) in the hypertensives. All changes were significantly exaggerated in the salt sensitive as compared to salt resistant hypertensive patients.

Topics: Adenosine Diphosphate; Adult; beta-Thromboglobulin; Black People; Blood Pressure; Drug Resistance; Female; Humans; Hypertension; In Vitro Techniques; Male; Platelet Activation; Platelet Aggregation; Sodium Chloride, Dietary; Thromboxane B2; Zimbabwe

The study describes the changes in basic hemodynamic parameters after long-term antihypertensive therapy with cilazapril--a new ACE inhibitor lacking a sulfhydryl group--in hypertensive patients and the drug effects on renal function, glucose tolerance and lipid metabolism. 30 patients (18 males, 12 females, mean age: 53.3 +/- 18 years) with mild to moderate essential hypertension were studied. The following determinations were performed in patients, before and after 4.5 months of cilazapril monotherapy at a dose of 5 mg/24 h: (a) antihypertensive action of the drug (arterial pressure at rest and during a 24-hour recording); drug effects on left ventricular (LV) mass index; its contractility indexes (%FS, EF) and the left atrial emptying index were studied by means of echocardiography; (b) plasma insulin concentration during oral glucose tolerance tests, in the fasting state, after the administration of 75 g glucose per os, as well as the changes in the insulinogenic index and the 6-keto-PGF1 alpha/TXB2 ratio, and (c) drug effect on renal function (urea, creatinine, uric acid, plasma electrolytes), blood lipid profile (total cholesterol, triglycerides, HDL-CH) and serum transaminases. Long-term drug administration exhibits an effective antihypertensive action, without causing reflex tachycardia and also reduces the LV mass index without affecting its EF, while improving its diastolic function. It does not significantly affect the various biochemical parameters, and achieves glucose regulation, both in the fasting state and after glucose loading, with a decrease in the insulinogenic index, and simultaneously increases the 6-keto-PGF1 alpha/TXB2 ratio. The existence of a direct cause-effect relationship between the changes in the above hormone systems is possible.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Glucose; Blood Pressure; Cilazapril; Female; Glucose Tolerance Test; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin; Kidney Function Tests; Lipids; Long-Term Care; Male; Middle Aged; Thromboxane B2

We designed experiments to determine the role of endothelium-derived contracting factor or factors in the response to endothelin-1 and endothelin-3 in the aorta of normotensive and hypertensive rats. Rings of thoracic aortas, with and without endothelium, from normotensive and spontaneously hypertensive rats were suspended in organ chambers for recording of isometric tension in the presence of nitro-L-arginine, an inhibitor of nitric oxide synthase. The removal of endothelium decreased the contractions evoked by both endothelins in the aorta of spontaneously hypertensive but not of normotensive rats. Indomethacin (inhibitor of cyclooxygenase), dazoxiben (inhibitor of thromboxane synthase), and SQ-29,548 (antagonist of thromboxane A2 receptors) reduced, in aortic rings of spontaneously hypertensive rats, the contractions to endothelins in rings with but not in those without endothelium, whereas their effect was not endothelium-dependent in tissues of normotensive rats. BQ-123, a selective endothelin-A receptor antagonist, shifted the concentration-response curve to endothelin-1 to the right in a concentration-dependent manner and abolished the endothelium-dependent component of the contractions evoked by the peptide. The presence of the endothelium increased the basal and endothelin-stimulated release of thromboxane B2, the stable metabolite of thromboxane A2, in aortas of spontaneously hypertensive rats but not in those of normotensive rats. These data suggest that endothelium-derived thromboxane A2 contributes to contractions evoked by endothelin-1 and endothelin-3 in the aorta of the spontaneously hypertensive rat but not in that of the normotensive rat. Both the receptors on the endothelial cells (mediating the release of thromboxane A2) and those on vascular smooth muscle belong to the endothelin-A subtype.

Topics: Animals; Aorta, Thoracic; Bridged Bicyclo Compounds, Heterocyclic; Endothelins; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Hypertension; In Vitro Techniques; Indomethacin; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2; Vasoconstriction

A series of 1H-imidazol-1-yl- and 3-pyridyl-substituted 3,4-dihydroquinolin-2(1H)-ones was designed and synthesized as combined inhibitors of thromboxane (TXA2) synthase and cAMP phosphodiesterase (PDE) in human blood platelets. A number of structures, e.g. 4b, 7a, 7e, 13a, and 21-25, were superior to dazoxiben 26 as inhibitors of TXA2 synthase in in vitro ADP-induced aggregation experiments with human blood platelets. The TXA2 synthase inhibitory activity was confirmed by measurement of the prostanoid metabolites derived from 14C-labeled arachidonic acid. Three compounds (7a, 7e, and 25) demonstrated in vitro inhibition of human platelet cAMP PDE at micromolar concentrations in conjunction with their TXA2 synthase inhibitory activity. Synergistic enhancement of antiaggregatory and antithrombotic actions was expected when simultaneous stimulation of adenylate cyclase (through increased PGI2 production) and inhibition of platelet cAMP PDE were possible from the same compound. Ex vivo and in vivo experiments were conducted in rats and mice, respectively, to evaluate the effects of compounds 7e and 23 on platelet aggregation and thrombotic events within these animals. Compound 7e, which has a comparable level of TXA2 synthase (IC50 1.2 microM) and human platelet cAMP PDE (IC50 6.4 microM) inhibitory activities, was found to be orally bioavailable with a long duration of action and offered effective protection against mortality in a collagen-epinephrine-induced pulmonary thromboembolism model in mice. Significant blood pressure and heart rate effects were observed for several compounds, e.g. 7e, 9e, 13a, 13d, 18, 20, 21, and 23, when dosed orally in conscious spontaneously hypertensive rats.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Aorta; Blood Platelets; Fibrinolytic Agents; Humans; Hypertension; Male; Microsomes; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Swine; Thromboembolism; Thromboxane B2; Thromboxane-A Synthase

Spontaneously hypertensive rats (SHR) were injected with streptozotocin (STZ-SHR) to induce diabetes. The effect of DP-1904, a thromboxane A2 synthetase inhibitor, on diabetic nephropathy was then studied by administering it for 5 months (1 or 10 mg/kg). DP-1904 did not affect renal 6-keto prostaglandin (PG)F1 alpha production in STZ-SHR, but markedly inhibited renal thromboxane (TX) B2 production, so that the 6-keto PGF1 alpha/TXB2 ratio was significantly increased (P less than 0.05). STZ-SHR showed significant uraemia and proteinuria, plus increases in urinary gamma-glutamyl-transpeptidase and urinary N-acetyl-beta-glucosaminidase. DP-1904 significantly decreased (P less than 0.01) the urinary changes. STZ-SHR also showed an increase in mesangial periodic acid-Schiff-positive substance and in relative renal weight, both of which were significantly inhibited by DP-1904 (P less than 0.05). Thus, DP-1904 inhibited both TXB2 production and the progression of renal damage in STZ-SHR.

Topics: Acetylglucosaminidase; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; gamma-Glutamyltransferase; Heart Rate; Hypertension; Imidazoles; Kidney; Prostaglandins; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Adrenaline was infused in incremental doses of 0.05 up to 0.1 microgram/kg/min over a 60-min period in nine patients with mild essential hypertension and six age-matched normotensive controls. Blood samples were drawn at preset time intervals and plasma adrenaline, platelet count, serum thromboxane B2 (TxB2) and plasma beta-thromboglobulin (beta-TG) were measured. Adrenaline levels (m +/- SEM) rose significantly, from 0.078 +/- 0.01 (baseline) to 0.902 +/- 0.03 ng/ml (60 min), in the hypertensive group; a similar increase was observed in the control group (from 0.049 +/- 0.007 to 0.877 +/- 0.03 ng/ml). Platelet count increased significantly at early time points and remained high throughout infusion in both groups (hypertensive from 250 +/- 25 to 305 +/- 24 x 10(3)/microliters, control from 219 +/- 16 to 260 +/- 18 x 10(3)/microliters). TxB2 levels likewise increased significantly from 15 minutes after initiation of infusion. In hypertensive subjects the mean resting value of 186 +/- 17 ng/ml rose to 312 +/- 42 ng/ml, while in control subjects the resting value of 174 +/- 29 ng/ml rose to 286 +/- 32 ng/ml. Baseline levels of TxB2 were found to be higher in the hypertensive patients but not significantly. beta-TG levels increased from an initial value of 43.84 +/- 3.69 ng/ml to 59.5 +/- 4.69 ng/ml at 60 min in the hypertensive group, while a similar change from 28.7 +/- 19.2 ng/ml to 40.36 +/- 3.16 ng/ml was observed in the control group. These changes were significant, as was the difference between basal values in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; beta-Thromboglobulin; Cytoplasmic Granules; Epinephrine; Female; Humans; Hypertension; Infusions, Intravenous; Male; Platelet Activation; Platelet Count; Stress, Physiological; Thromboxane B2

1. To investigate possible mechanisms of increased systolic blood pressure after 1 weeks treatment with dexamethasone and its amelioration by fish oil feeding, we have examined the reactivity of aortic rings and perfused mesenteric resistance vessels. 2. Thirty six Sprague-Dawley rats were initially divided into two groups and fed a semisynthetic diet containing either (10% by weight) hydrogenated coconut oil and safflower oil mixture (HCO/S) (24 rats) or fish oil (12 rats) for 5 weeks. From the end of the fourth week, dexamethasone (1.25 mg ml-1) in drinking water, was given to half the rats on hydrogenated coconut oil (HCO/S+Dex) and to the fish oil-fed group (fish oil+Dex). 3. One week of dexamethasone treatment raised systolic blood pressure in the HCO/S+Dex rats but not in the fish oil+Dex group. 4. Endothelium-dependent relaxation to acetylcholine (ACh) was decreased in aortic rings taken from HCO/S+Dex rats compared to rats on HCO/S alone. Relaxant responses to ACh of aortic rings from rats given fish oil+Dex were intermediate between the three groups. Aortic endothelium-independent responses to sodium nitroprusside (SNP) were unchanged between the groups, while aortic contractile responses to noradrenaline were similar in all the groups. 5. In the perfused mesenteric resistance artery, sensitivity to noradrenaline was decreased in rats given fish oil and dexamethasone compared to the other two groups. There were no differences in resistance vessel relaxation to ACh or SNP between groups. 6. Serum corticosterone levels, used as a marker of dexamethasone absorption, were substantially suppressed in dexamethasone-treated rats but levels were higher in rats on fish oil than on HCO/S diets. 7. We suggest that the glucocorticoid-induced rise in systolic blood pressure may be due in part to decreased aortic compliance as a consequence of impaired endothelium-dependent relaxation and perhaps reduced nitric oxide synthesis. Fish oil feeding may ameliorate this rise in blood pressure through (i) changes in dexamethasone absorption, (ii) decrease in reactivity to noradrenaline of perfused mesenteric resistance arteries, (iii) an increase in endothelium-dependent relaxation to ACh or a combination of these three factors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Corticosterone; Dexamethasone; Electrolytes; Endothelium, Vascular; Fatty Acids; Fish Oils; Glucocorticoids; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Thromboxane B2; Vascular Resistance

Increased serum levels of immunoreactive thromboxane B2 (iTXB2) were observed in spontaneously hypertensive rats of the Okamoto-Aoki strain (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Serum iTXB2 levels in whole blood allowed to clot at 37 degrees C for 1 hour were significantly greater in SHR than WKY at 8, 16-20, and 38 weeks of age, whereas formation of iTXB2 by thrombin-stimulated whole platelets from 6 16-week-old SHR and 6 age-matched WKY was 399 +/- 44 and 377 +/- 38 ng/10(9) platelets/30 min, respectively. No significant difference in radioconversion of exogenous arachidonic acid to TXB2 was observed in whole platelets from SHR (18.2 +/- 2.5%, n = 4) and WKY (20.1 +/- 3.0%, n = 4) at 16 weeks of age. These results support the proposal that enhanced ability of blood from SHR to generate iTXB2 is independent of the stage of hypertension development. This enhancement probably depended on factors or blood elements other than platelets since no difference in formation was observed on stimulation of whole platelets.

Topics: Animals; Arachidonic Acid; Blood Platelets; Hypertension; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thrombin; Thromboxane B2

We reported previously that stroke risk factors prepared the brain stem for the development of ischemia and hemorrhage and induced the production of tumor necrosis factor following an intrathecal injection of lipopolysaccharide, a prototypic monocyte-activating stimulus. This study evaluates whether blood or brain cells of hypertensive rats produce more proinflammatory and prothrombotic mediators than do blood or brain cells of normotensive rats.. Levels of tumor necrosis factor, platelet-activating factor, 6-ketoprostaglandin F1 alpha, and thromboxane B2 in the cerebrospinal fluid and blood of spontaneously hypertensive and normotensive Wistar-Kyoto rats were monitored before and after a challenge with lipopolysaccharide.. Little or no activity from these mediators was found in the cerebrospinal fluid or blood of saline-injected control animals. Intravenous administration of lipopolysaccharide (0.001, 0.1, and 1.8 mg/kg) produced dose-dependent increases in blood levels of all mediators in hypertensive rats. In normotensive rats the levels were less than in hypertensive rats and were not clearly dose-related. When lipopolysaccharide was injected intracerebroventricularly, more tumor necrosis factor was measured in the cerebrospinal fluid than in the blood, suggesting local synthesis of this cytokine. Levels of tumor necrosis factor and platelet-activating factor in the cerebrospinal fluid were higher in hypertensive than in normotensive rats. The thromboxane A2/prostacyclin ratio was not altered significantly between the two rat strains.. It is suggested that the higher incidence of brain stem ischemia and hemorrhage after the intrathecal injection of lipopolysaccharide in hypertensive rats than in normotensive rats might be related to the higher levels of the two cytotoxic factors tumor necrosis factor and platelet-activating factor produced in response to such challenge.

Topics: Animals; Brain; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Hypertension; Injections, Intravenous; Injections, Intraventricular; Leukocyte Count; Lipopolysaccharides; Platelet Activating Factor; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Risk Factors; Thromboxane B2; Tumor Necrosis Factor-alpha

To define the role of the renal eicosanoid system in sustaining renal homeostasis in hypertension, we investigated the alterations in urinary excretions of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a stable metabolite of vasodepressor prostacyclin, and thromboxane B2 (TXB2), a stable metabolite of vasoconstrictor TXA2, when norepinephrine was continuously infused for 90 min in hypertensive (n = 13) and normotensive subjects (n = 14). There was no difference in plasma norepinephrine concentration after the infusion between the hypertensive and the normotensive subjects. Moreover, the percent changes in renal vascular resistance elicited by norepinephrine in the hypertensives were equal to those of the normotensive subjects. In the normotensive subjects, the norepinephrine infusion significantly increased urinary 6-keto-PGF1 alpha excretion and decreased urinary excretion of TX, both of which are beneficial for sustaining renal function. In fact, the greater the production of renal 6-keto-PGF1 alpha was, the less the reduction of renal blood flow and urinary sodium excretion was. In the hypertensive subjects, however, these normal responses of the renal eicosanoid system, seen in the normotensives, were abolished; urinary 6-keto-PGF1 alpha was unaltered and thromboxane generation was rather increased. Thus, the renal eicosanoid system dysfunctions in hypertensive subjects when the renal circulation is challenged by norepinephrine. These abnormal responses are likely to cause sodium retention and could contribute, in part, to the hypertensive mechanism in patients with essential hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Eicosanoids; Female; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Norepinephrine; Thromboxane B2

To prove the effect of aging on the synthesis of renin-angiotensin-aldosterone system, renal kallikrein-kinin system, prostaglandin (PG), and thromboxane (TX) which regulate blood pressure, normotensive subjects and patients with essential hypertension (EH) were investigated in the present study. Although plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were decreased with aging in both groups, there is no significant differences between each groups while compared among each age-groups. Urinary excretion of kallikreins (active, inactive and total) in EH were decreased with aging as similar extent to that of normal subjects. There was no age-related change of kallikrein activation ratio in EH in contrary to normal subjects. In comparison with each age-group, the amount of urinary kallikrein excretion in EH were already small in young age-groups. The amount of urinary PGE2 excretion in female EH group was smaller than that of normal subjects, and there were no age-related changes in both groups. Urinary excretion of TXB2 and 11-dehydro-TXB2, which are the urinary major metabolites of TXA2 which has potent vasoconstrictive action, were increased in the age-group of 80-93 year-old both normal subjects and EH. There were no age-related change in both groups. Although these hypertensive vasoactive substances as renin, aldosterone and TXA2 in EH show the same profile as that in normal subjects, the synthesis of renal antihypertensive vasoactive substances as kallikrein and PGE2 in EH already decrease in younger patients. These results suggest that the lower activities of renal antihypertensive system is a cause of the development of hypertension.

Topics: Adult; Aged; Aged, 80 and over; Aging; Dinoprostone; Female; Humans; Hypertension; Kallikrein-Kinin System; Male; Middle Aged; Renin-Angiotensin System; Thromboxane B2

The effects of svate on platelet morphology and aggregation were studied and compare with Radix Salviae Miltiorrhizae. The results showed that svate remarkably inhibited platelet aggregation in patients with coronary heart disease and hypertension. Svate could increase plasma 6-keto-PGF1 alpha and decrease plasma TXB2. After treatment with svate, levels of platelet cAMP was increased. Svate enhanced platelet 5-HT and reduced plasma 5-HT. Electron microscopic study showed that the percentage of discoid and dendritic platelets were increased, while those of spread and aggregate platelets were decreased following svate therapy. It was found that svate is superior to Radix Salviae Miltiorrhizae in inhibition of platelet function. The results indicate that svate inhibits platelet aggregation and release through increasing prostacyclin generation in the vascular wall, raising platelet cAMP and inhibition of TXA2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Cyclic AMP; Drug Combinations; Drugs, Chinese Herbal; Elapid Venoms; Female; Humans; Hypertension; Male; Middle Aged; Phenanthrolines; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Salvia miltiorrhiza; Serotonin; Thromboxane B2

In the present study, the influence of sodium ferulate (SF) on hypotensive effect and urinary excretion of TXB2 after captopril (CAP) was observed in 44 patients with essential hypertension. A single oral dose of CAP (50 mg) decreased mean arterial pressure (MAP) from 16.25 +/- 0.85 to 13.65 +/- 1.14 kPa, n = 28, (P less than 0.01), and increased urinary TXB2 excretion significantly from 119.12 +/- 57.12 to 183.32 +/- 78.61 pg/min, n = 16, (P less than 0.05). The administration of SF 300 mg/d for one day did not affect the MAP. CAP in combination with SF induced a decrease both in MAP from 16.33 +/- 1.14 to 13.83 +/- 1.77 kPa, n = 16, (P less than 0.01) and urinary TXB2 excretion from 155.89 +/- 69.64 to 133.43 +/- 60.01 pg/min, n = 16, (P greater than 0.05) though the latter was not so significant. Compared with the administration of CAP alone, the combination of CAP and SF induced stronger hypotensive effect (P less than 0.05) and the increased urinary TXB2 excretion could be inhibited by SF, but the inhibition to angiotensin converting enzyme was the same. These results suggested that the increased urinary TXB2 excretion by CAP can be inhibited and the hypotensive effect of CAP is potentiated by SF in essential hypertensive patients.

Topics: Antihypertensive Agents; Captopril; Coumaric Acids; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Thromboxane B2

We studied the aggregation of collagen and ADP-stimulated platelet-rich plasma (PRP) and the formation of thromboxane B2 (TxB2) by collagen-stimulated PRP in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto control rats (WKY). In addition, we evaluated the inhibition of the aggregation of PRP following homologous or heterologous perfusions through isolated aortas, the release of 6-keto-prostaglandin (PG)F1 alpha from these arteries perfused with PRP, and the sensitivity of PRP to the antiaggregatory activity of the stable PGI2 analogue, iloprost, in both SHR and WKY. The lower activities (aggregation induced by ADP and collagen, collagen-stimulated TxB2 production) of SHR platelets, were not accompanied by morphological differences from WKY platelets. These changes were associated with a greater release of arterial 6-keto-PGF1 alpha, with greater platelet antiaggregatory activity of the arterial wall and with higher sensitivity of platelets to iloprost. The lower reactivity of platelets to aggregating agents, and the greater sensitivity to prostacyclin, associated with a greater production of arterial prostacyclin were the major changes observed in SHR animals. These alterations in the SHR vs. normotensive WKY may lead to an enhanced risk of hemorrhage in the hypertensive state.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Aorta; Blood Platelets; Collagen; Hypertension; Iloprost; Male; Perfusion; Platelet Aggregation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2

In order to study the connection of diastolic activity of smooth muscles of blood vessels with development of hypertension, plasma cAMP, cGMP, TXB2, 6-K-PGF1 alpha, ANP, SP were determined with radioimmunoassay, of 173 hypertension patients with Liver Yang exuberance (LYE) 91 cases, and Yin deficiency and Yang exuberance (YDYE) 82 cases. In addition, 228 health subjects served as control. The results showed that the levels of cAMP, cGMP and TXB2 in both LYE and YDYE groups were higher than those in the control group, but the levels of ANP, SP and cAMP/cGMP ratio in LYE and YDYE groups were lower than those in the control. As to the level of 6-K-PGF1 alpha, no significant variance was found between these groups. After TCM-WM treatment, the levels of cAMP, cGMP and TXB2 in LYE and YDYE groups got down, as compared with those in the control, adversely the levels of ANP, SP and 6-K-PGF1 alpha in LYE and YDYE groups turned up significantly. However the cAMP/cGMP ratio had no remarkable change between these groups. The linear regression analyses between the diastolic pressure and ANP or SP both proved negative correlation (r = -0.36, P less than 0.05; r = -0.35, P less than 0.05). The findings indicated that the TCM-WM treatment was the most effective among the therapies employed in the study, and that this therapy affected the diastolic activity of smooth muscles by modulating the above factors existing in the nervous and endocrine systems of the patients with hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Drugs, Chinese Herbal; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Substance P; Thromboxane B2

To determine the nature and extent of changes in platelet reactivity in gestational hypertension and pre-eclampsia (using whole blood techniques which may be more physiological than those previously employed).. Cross-sectional observational study.. 8 normal primigravidae, 16 women with gestational hypertension and 12 women with pre-eclampsia, studied at around 36 weeks gestation.. Platelet reactivity (aggregation and release reaction) induced by stimulation with adrenaline was decreased in the pre-eclamptic group. Serum thromboxane B2 production was unchanged in both hypertensive groups compared with the control group.. In the context of evidence of platelet activation in pre-eclampsia, our findings are interpreted as reflecting platelet exhaustion.

Topics: Adult; Blood Platelets; Cross-Sectional Studies; Female; Humans; Hypertension; Platelet Activation; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Linoleic acid and fish oil omega-3 fatty acids, but not arachidonic acid, exerted antihypertensive effects in a model of angiotensin II-induced hypertension in rats. Indomethacin did not influence the systolic arterial pressure of arachidonic acid-treated hypertensive rats whereas compound L-641,953, a prostaglandin H2/thromboxane A2 receptor antagonist, caused a notable but statistically nonsignificant decrease in blood pressure in these animals. Although these results do not exclude entirely the possibility that the lack of antihypertensive effect of arachidonic acid may be due, in part, to the concomitant formation of vasoconstrictor prostanoids, they do not support it. These observations, as well as those of a previous study, indicate that linoleic acid and fish oil omega-3 fatty acids exert antihypertensive effects of their own, independently of the prostanoid system, and that these properties are not shared by arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Antihypertensive Agents; Arachidonic Acid; Fatty Acids, Omega-3; Hypertension; Indomethacin; Linoleic Acid; Linoleic Acids; Male; Rats; Rats, Inbred Strains; Thromboxane B2

To study the modulatory role of renal eicosanoids on renal hemodynamics and electrolyte excretion, pressor doses of norepinephrine (NE) were infused in 10 control subjects (mean age, 26 y) and 13 patients (mean age, 25 y) with borderline hypertension. The highest NE dose used (150 ng/kg/min) produced comparable increases in mean blood pressure in control subjects (20 +/- 2 mmHg) and in patients (23 +/- 3 mmHg). NE induced a significant increase in renal vascular resistance (p less than 0.01, both groups), with a smaller decrease in glomerular filtration rate resulting in a concomitant increase in filtration fraction (p less than 0.01, both groups). The renal hemodynamic changes tended to be more pronounced in borderline hypertension. NE infusion led to similar decreases in electrolyte clearances in the two groups. Urinary prostaglandin (PG)E2, PGF2 alpha (p less than 0.01), and 6-keto-PGF1 alpha increased with NE infusion. Urinary thromboxane (TX)B2 increased slightly in control subjects and decreased in borderline hypertension (p less than 0.05). The 6-keto-PGF1 alpha/TXB2 ratio, an index of vasodilation, was significantly increased (p less than 0.05) in borderline hypertension. These results demonstrate that in both groups pressor infusion of NE induced significant modifications in renal hemodynamics and in urinary electrolyte and eicosanoid excretion. The vasodilatory component of the renal eicosanoid system appears hyperresponsive in borderline hypertension, which may represent an early antihypertensive defense mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Dinoprostone; Eicosanoids; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Norepinephrine; Thromboxane B2; Vascular Resistance

Urinary 6-keto-PGF1 alpha, TXB2, PRA, ATII, blood pressure, urine volume, urinary sodium and potassium were measured by RIA in SHR after administration of captopril and indomethacin. The results suggested that captopril would significantly decrease ATII, and showed marked effects of hypotension, diuresis and caused variation of PG system. Urinary 6-keto-PGF1 alpha and TXB2 were significantly increased in both rat groups, but changes of TXB2/PGI2 ratio were different. The studies yet suggested indomethacin could antagonize the hypotensive effects of captopril.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Captopril; Female; Hypertension; Male; Rats; Rats, Inbred SHR; Renin; Thromboxane B2

To test the hypothesis that prostanoids contribute to angiotensin II-induced vascular contraction, we compared the effect of angiotensin II on isometric tension development by rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer with and without indomethacin (10 microM) to inhibit cyclooxygenase, CGS13080 (10 microM) to inhibit thromboxane A2 synthesis, or SQ29548 (1 microM) to block thromboxane A2/prostaglandin endoperoxide receptors. The comparisons were made in rings of aorta taken from normotensive rats and from rats with aortic coarctation-induced hypertension at 12 days and 90-113 days after coarctation. These rings released thromboxane B2, which was found to be endothelium dependent, increased in hypertensive rats, and stimulated by angiotensin II (10(-6) M) in normotensive rats and in hypertensive rats at 12 days after coarctation. The angiotensin II (10(-6) to 10(-5)M)-induced contraction of aortic rings was increased by about 30% at 12 days after coarctation and decreased at 90-113 days after coarctation. Removal of the endothelium increased the contractile effect of angiotensin II (10(-6) M) in aortic rings of normotensive rats and hypertensive rats at 90-113 days after coarctation but decreased the effect in aortic rings of hypertensive rats at 12 days after coarctation. In rats at 12 days after coarctation, the angiotensin II (10(-6) M)-induced contraction of aortic rings with endothelium was attenuated by indomethacin and SQ29548 but not by CGS13080. These data suggest that a prostanoid-mediated and endothelium-dependent mechanism of vasoconstriction contributes to the constrictor effect of angiotensin II in aortic rings of rats in the early phase of aortic coarctation-induced hypertension.

Topics: Acetylcholine; Analysis of Variance; Angiotensin II; Animals; Aorta; Aortic Coarctation; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Endothelins; Endothelium; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; In Vitro Techniques; Indomethacin; Isometric Contraction; Male; Phenylephrine; Prostaglandin Endoperoxides, Synthetic; Pyridines; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

1. Given the unexplained frequent association between systemic hypertension and obstructive sleep apnoea (OSA), the secretion of prostanoids during sleep was investigated (more specifically, the ratio of prostacyclin (PGI2) to thromboxane A2 (TxA2), since they have marked opposite effects on vascular tone). Prostacyclin has vasodilating effects, whereas thromboxane results in vasoconstriction. 2. In 11 OSA drug-free male patients (age 53 +/- 2 years, mean +/- s.e.m.; apnoea index 55 +/- 15 apnoeas/hour of sleep; body mass index 31 +/- 2 kg/m2), we measured the urinary excretion during sleep of 6-keto-PGF1-alpha and of thromboxane TxB2 (the stable metabolites of prostacyclin PGI2 and of thromboxane A2 respectively). This was done on two consecutive nights; one untreated, the other with nasal continuous positive airway pressure (CPAP) treatment. The results were compared with those of nine normal unobese male subjects. 3. The urinary ratio of 6-keto-PGF1-alpha to TxB2 was significantly (P less than 0.001) lower in the untreated OSA patients (1.7 +/- 0.2) than in the controls (3.1 +/- 0.3). It significantly increased with CPAP treatment to 2.3 +/- 0.2, P less than 0.02, which was no longer different from the controls. 4. These results suggest that OSA is associated with an abnormal release of prostanoids during sleep resulting in a decrease of the prostacyclin to thromboxane ratio which potentially has a vasoconstricting effect. The relationship between these changes and the systemic hypertension often observed in OSA patients remains to be established.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Humans; Hypertension; Male; Middle Aged; Sleep; Sleep Apnea Syndromes; Thromboxane A2; Thromboxane B2

Renal prostanoid excretion was investigated in nine hypertensive pregnant patients before and during treatment with nifedipine 10 mg orally t.i.d. Urinary excretion of prostacyclin (measured as 6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) increased by 77% during nifedipine treatment (P less than 0.05). No changes were found in prostaglandin E2 (PGE2) and thromboxane A2 (as thromboxane B2, TXB2) excretions. A significant reduction in blood pressure did not correlate with an increase in 6-keto-PGF1 alpha excretion. Plasma prekallikrein and urinary kallikrein and catecholamine excretions remained unaltered. In six normotensive non-pregnant women, increase in 6-keto-PGF1 alpha excretion during nifedipine treatment was not significant. No changes in PGE2 and TXB2 excretions were found, whereas plasma prekallikrein was reduced (P less than 0.05) and urinary excretion of kallikrein (P less than 0.05) and noradrenaline (P = 0.06) increased under nifedipine. The results suggest that nifedipine enhances the renal 6-keto-PGF1 alpha excretion in hypertensive pregnancy.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Catecholamines; Creatinine; Dinoprostone; Epoprostenol; Female; Humans; Hypertension; Kallikreins; Nifedipine; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Thromboxane B2

The effects of delapril, an angiotensin converting enzyme (ACE) inhibitor, on renal function and the renin-angiotensin and kallikrein-prostaglandin systems were investigated in 10 hypertensive patients who were treated for between 4 months and 1 year. There was a significant (P less than .05) increase in renal blood flow (RBF) without affecting glomerular filtration rate. Filtration fraction increased, while renal vascular resistance decreased. There were also significant (P less than .05) increases in urinary kallikrein and prostaglandin excretion, while thromboxane excretion decreased. There was no change in urinary aldosterone excretion. These results suggest that renal hemodynamic changes seen during long-term therapy with delapril are caused, in part, by activation of the kallikrein-prostaglandin system, as well as suppression of the renin-angiotensin system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dinoprostone; Humans; Hypertension; Indans; Kallikreins; Kidney; Middle Aged; Renin; Thromboxane B2; Time Factors

Alterations in renal eicosanoid levels have been postulated as a factor in cyclosporin A (CSA) nephrotoxicity. The effects of CSA on renal eicosanoid excretion in rheumatoid arthritis were studied over a 24-week period, during which treatment with nonsteroidal antiinflammatory drugs was discontinued. The initial dosage of CSA was 4 mg/kg/day; at week 24, the mean dosage of CSA was 3.9 mg/kg/day. At week 24, the mean (+/- SD) serum creatinine level (1.04 +/- 0.24 mg/dl) was 32% above the baseline value; renal blood flow had decreased by 21% (P less than 0.03) and the glomerular filtration rate had decreased by 16%. There was a significant increase (P less than 0.03) in the 2,3-dinor thromboxane B2 level at week 2, but there was no significant change in the levels of the other eicosanoids. This study demonstrates that after CSA treatment, there is a selective increase in a thromboxane metabolite that parallels an increase in renal vascular resistance, even in the absence of nonsteroidal antiinflammatory drugs, and with unimpaired formation of other vasodilator eicosanoids.

Topics: Adult; Aged; Arthritis, Rheumatoid; Creatinine; Cyclosporins; Eicosanoids; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Circulation; Thromboxane B2

We investigated the role of prostanoid-mediated pressor mechanisms in setting the level of blood pressure in renin-dependent and renin-independent models of hypertension in unanesthetized rats. Intravenous administration of a blocker of thromboxane A2/prostaglandin endoperoxide receptors, SQ29548 (2 mg/kg bolus injection plus 2 mg/kg/hr for 3 hours), reduced from 162 +/- 4 to 144 +/- 5 mm Hg (p less than 0.05) the blood pressure of rats with aortic coarctation-induced hypertension at 7-14 days after coarctation when plasma renin activity is greatly increased. In contrast, treatment with SQ29548 was without effect on the blood pressure of either normotensive or hypertensive rats (i.e., aortic coarctation-induced hypertension at 90-113 days after coarctation, deoxycorticosterone-salt-induced hypertension) having normal or depressed values of plasma renin activity. The blood pressure-lowering effect of SQ29548 in the early phase of aortic coarctation-induced hypertension was positively correlated with the prevailing plasma renin activity and could not be demonstrated in hypertensive rats pretreated with indomethacin. We attribute the hypotensive effect of SQ29548 to interference with pressor mechanisms that depend on activation of thromboxane A2/prostaglandin endoperoxide receptors and suggest that such prostanoid-mediated mechanisms are operational and contribute to an increase in blood pressure in angiotensin-dependent forms of hypertension. Also prostanoid-mediated vasodepressor mechanisms are operational in the early phase of aortic coarctation-induced hypertension since the blood pressure of rats pretreated with SQ29548 was increased by the subsequent administration of indomethacin. Accordingly, the blood pressure of rats with aortic coarctation-induced hypertension is influenced by the interplay of prostanoid-mediated pressor and vasodepressor mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Desoxycorticosterone; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Male; Prostaglandins; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Prostaglandin; Renin; Thromboxane A2; Thromboxane B2

Urinary levels of 11-keto-thromboxane B2 (11-keto-TXB2), were elevated at all gestational ages (12-41 weeks) compared with non-pregnant levels. 11-keto-TXB2 levels exceeded those of TXB2 throughout pregnancy, which suggested that 11-keto-TXB2 may be the major urinary metabolite of TXA2 in normotensive pregnancy, as in the non-pregnant state. This was reversed in women with mild pregnancy-induced hypertension (P.I.H.), such that urinary levels of TXB2 were higher (p less than 0.01) than those of 11-keto-TXB2. Since the 11-thromboxane dehydrogenase enzyme is found in the placenta, the low levels of 11-keto-TXB2 may be the result of placental damage decreasing the activity of the enzyme. The relationship between these findings and the aetiology of P.I.H. is not clear, but changes in urinary 11-keto-TXB2 may be of use in identifying those women at risk of developing P.I.H.

Topics: Adult; Female; Humans; Hypertension; Platelet Activation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

The anti-hypertensive effect of ketanserin, a new antagonist of 5-HT2-serotonergic receptors, was evaluated in 10 patients with uncomplicated essential hypertension. At the end of 2 weeks of placebo wash-out and following 2 and 4 weeks of treatment with ketanserin (20 mg twice daily), blood pressure and heart rate were measured both in the supine and standing position. In addition, before and at the end of treatment, plasma renin activity (PRA), plasma concentration of aldosterone and the nocturnal urinary excretion of 6-keto-PGF1 alpha and TXB2, the two metabolites that largely reflect the renal synthesis of prostacyclin and thromboxane, respectively, were determined. The study was carried out in a metabolic ward where the intake of sodium was adjusted to 100-120 mmol day-1. Ketanserin significantly reduced blood pressure both in the supine and standing position with no significant change of heart rate. The treatment did not produce any variation of PRA, aldosterone, urinary excretion of 6-keto-PGF1 alpha or TXB2. These results indicate that ketanserin reduces blood pressure without interfering with the renin-angiotensin-aldosterone system or the renal synthesis of prostacyclin and thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Epoprostenol; Female; Humans; Hypertension; Ketanserin; Kidney; Male; Middle Aged; Renin-Angiotensin System; Thromboxane A2; Thromboxane B2

Urinary excretion of thromboxane B2 metabolites as markers of thromboxane A2 synthesis was measured in eight patients with moderate to severe pregnancy-induced hypertension and in six normotensive pregnant women at term. Excretion of both 2,3-dinor-TxB2 (median 3919, range 683-16,680 pg/mg creatinine) and 11-dehydro-TxB2 (median 10,187, range 434-57,203 pg/mg creatinine) was significantly higher in the patients with pregnancy-induced hypertension than in the normotensive pregnant group (927[273-1343] and 774[500-2760] pg/mg creatinine, respectively). Thromboxane metabolite excretion correlated with mean arterial blood pressure, plasma lactate dehydrogenase, and platelet count which are indices of the severity of pregnancy-induced hypertension. Excretion of both metabolites fell rapidly post partum in parallel with resolution of clinical signs. Thus, increased thromboxane A2 biosynthesis correlates with disease severity and may have a pathogenetic role in pregnancy-induced hypertension. These findings provide a rationale for the use of aspirin in the treatment as well as in the prevention of this disorder.

Topics: Adolescent; Adult; Aspirin; Evaluation Studies as Topic; Female; Humans; Hypertension; Platelet Activation; Platelet Count; Pregnancy; Pregnancy Complications, Cardiovascular; Severity of Illness Index; Thromboxane A2; Thromboxane B2

Enalapril produces an inhibition of the angiotensin-renin system, correlating the pre-therapy plasmatic renin activity with blood pressure decrease, during its administration. This does not always happen, data to the contrary existing in literature, suggesting that there are some other acting mechanisms. We studied 34 hypertensive patients, whose blood pressure levels were controlled by Enalapril at a mean dosage of 12.32 +/- 0.9. Determining plasmatic concentration of 6-keto PGF1a (a prostacyclin metabolite), T x B2 (a thromboxane A2 metabolite), their distribution, plasmatic renin activity and a radiological and biochemical study. We found a significant increase in their distribution and plasmatic renin at the end of the essay. The results suggest a possible double active mechanism: angiotension-renin and prostaglandins systems, owing to the imbalance occurring between prostacyclin and thromboxane, the first named being the most favoured. This, together with easy application and the lack of side effects, made this drug useful for treatment of blood hypertension.

Topics: Adolescent; Adult; Aged; Enalapril; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Prostaglandins F; Renin-Angiotensin System; Thromboxane B2; Time Factors

The effects of bopindolol, a new nonselective beta-blocking agent, on platelet function have been studied in 10 male hypertensive patients given the drug (1 mg/day) in turn for eight weeks. Bopindolol significantly (p less than 0.01) decreased the bicycle exercise- (1.5 W/kg body weight for 6 minutes) induced increase in platelet aggregation. During bopindolol-treatment both the slope and the height of the platelet aggregation response curve were moderately decreased at rest before exercise and significantly (p less than 0.05) decreased at rest after exercise. During exercise the slope amounted to 75.4 +/- 44 degrees before and to 70.8 +/- 5.3 degrees after therapy (p less than 0.01), the height to 64.0 +/- 11.9% before and to 58.1 +/- 14.7% (p less than 0.05) after therapy. Furthermore, bopindolol significantly increased the exercise-induced decrease in platelet sensitivity to PGI2 (p less than 0.05; IC-50-value: 2.10 +/- 0.47 vs 1.88 +/- 0.31 ng/ml) and PGD2 (p less than 0.05; IC-50-value: (19.88 +/- 2.10 vs 18.57 +/- 1.63 ng/ml). Bopindolol also significantly (p less than 0.05) decreased the exercise-induced elevation in serum-TXB2 (244.9 +/- 35.2 vs 237.3 +/- 27.2 ng/ml) and plasma-TXB2 (15.7 +/- 6.3 vs 13.1 +/- 3.7 pg/ml). The platelet count, the plasma levels of 6-oxo-PGF1 alpha, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were not affected by bopindolol. It is concluded that bopindolol favourably affects platelet function, in that it lowers exercise-induced platelet aggregation and TXB2-formation in therapeutical doses and increases platelet sensitivity to antiaggregatory prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Basal Metabolism; beta-Thromboglobulin; Blood Platelets; Epoprostenol; Exercise; Humans; Hypertension; Male; Middle Aged; Pindolol; Platelet Aggregation; Platelet Count; Platelet Factor 4; Prostaglandin D2; Thromboxane B2

The purpose of this study was to clarify how the metabolism of vascular prostacyclin (PGI2) and thromboxane (TX) A2 in spontaneously hypertensive rats (SHR) is involved in aging and development of hypertension. We removed the aortic walls from 5-week-old and 20 to 25-week-old SHR and age-matched Wistar Kyoto rats (WKY). At 5 weeks of age, there was no significant difference in basal and maximal (arachidonic acid 0.1 mM) 6-keto-PGF1 alpha production between SHR and WKY, but the TXB2 generation in the SHR aortic wall was markedly enhanced as compared with that in WKY. At 20 to 25 weeks of age, the SHR aortic wall synthesized about 1.5 times more 6-keto-PGF1 alpha in the basal condition and twice as much as in the maximal condition as did the WKY wall. However there was no significant difference in TXB2 production between SHR and WKY. Age-dependent increase of vascular 6-keto-PGF1 alpha was greater in SHR than in WKY. Moreover, the maximal/basal 6-keto-PGF1 alpha production ratio increased with age in SHR, but not in WKY. The synthesis of vascular TXB2 was enhanced with age in WKY, but did not change with age in SHR. These data suggest that not only the enhanced basal generation of vascular 6-keto PGF1 alpha but also a much greater reservoir of 6-keto-PGF 1 alpha synthesis in SHR was induced by both hypertension and maturity. The increased production of vascular TXB2 in young SHR may affect the development of hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Aorta; Epoprostenol; Hypertension; In Vitro Techniques; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

Forty pregnant women (28 to 32 weeks' gestation) were given low-dose aspirin therapy (81 mg/day) from the time of enrollment until delivery; circulating eicosanoid levels and angiotensin II pressor responses were measured before and after 1 week of aspirin therapy. Subsequent clinical outcome was correlated with these results. All women had significant reductions in serum and plasma thromboxane B2 levels with aspirin treatment (p less than 0.01). Eleven women who remained sensitive to the pressor effects of angiotensin II (effective pressor dose less than 10 ng/kg/min) after 1 week of low-dose aspirin treatment exhibited significant decreases (p less than 0.05) in plasma 6-keto-prostaglandin F1 alpha (264 +/- 119 vs 161 +/- 31 pg/ml, mean +/- SD) and prostaglandin E2 (476 +/- 174 vs 351 +/- 112 pg/ml) levels. In contrast, patients who were either nonsensitive (refractory) to angiotensin II (n = 18; greater than or equal to 10 ng/kg/min) before aspirin or became nonsensitive after aspirin administration (n = 11) had no change in either plasma 6-keto-prostaglandin F1 alpha or prostaglandin E2 concentrations. The occurrence of pregnancy-induced hypertension was 100% in the women who remained angiotensin II sensitive during aspirin therapy as compared with 36% and 39% in the other two groups (x2 = 16.14; p less than 0.001). Thus during low-dose aspirin therapy a failure to develop refractoriness to infused angiotensin II is associated with a nonselective inhibition of eicosanoids and the almost certain development of pregnancy-induced hypertension. These observations may reflect a basic defect in vascular adaptation to pregnancy.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Analysis of Variance; Angiotensin II; Aspirin; Blood Pressure; Chi-Square Distribution; Dinoprostone; Eicosanoids; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, Third; Thromboxane B2

Rabbits were given collagen and arachidonic acid intravenously. Blood pressure, platelet counts, plasma thromboxane-B2 (TXB2) and plasma 6-keto-prostaglandin F1 alpha, (6-keto-PGF1 alpha) were determined. Both thrombogenic agents, upon infusion of a lethal dose, caused thrombocytopenia, indicative of in vivo platelet aggregation and hypotension. These changes were associated with an increase in plasma levels of TXB2 and 6-keto-PGF1 alpha measured by radioimmunoassay (RIA). Pretreatment of rabbits with an aqueous extract of garlic (500 mgkg) provided protection from thrombocytopenia and hypotension. Thromboxane-B2 synthesis was significantly reduced in animals pretreated with garlic and then injected with a lethal dose of either collagen or arachidonic acid. The amount of TXB2 synthesized in these animals was not sufficient to induce thrombocytopenia or hypotension. All animals pretreated with garlic were well protected against the effects of collagen or arachidonate infusion, and no apparent symptoms were observed in these animals. These observations indicate that garlic may be beneficial in the prevention of thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Blood Pressure; Collagen; Female; Fibrinolytic Agents; Garlic; Hypertension; Plants, Medicinal; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Rabbits; Thrombocytopenia; Thromboxane B2

The effect of EPA enriched marine oil on platelet function in 12 cases of hypertension, 15 cases of diabetes and 20 cases of coronary heart disease is reported. The result of our study showed that there was platelet hyperfunction of various degrees in patients with those three kinds of diseases. The murine oil had an effect of inhibition, which were manifested by the prolongation on bleeding time, and decreased on platelet adhesion and aggregation. TxB2 in plasma was reduced, while 6-keto-PGF increased. There was no influence of EPA enriched fish oil on blood sugar and liver or kidney function. The authors concluded that platelet hyperfunction is an important element in the development of cardio vascular and cerebro vascular complications and increases the mortality rates in these diseases. Treatment with such a drug has beneficial effect with clinical improvement.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Bleeding Time; Blood Coagulation; Blood Platelets; Coronary Disease; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Female; Fish Oils; Humans; Hypertension; Male; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dihydropyridines; Drug Design; Fibrinolytic Agents; Humans; Hypertension; Imidazoles; Nitrendipine; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

The goal of this study was to determine the role of prostanoids in a new model of mineralocorticoid-dependent hypertension induced by the subcutaneous infusion of aldosterone (1 micrograms/hr) to normal male Sprague-Dawley rats. This regimen caused a mild and gradual increase in systolic pressure over a period of 4 weeks (113 +/- 1 vs. 137 +/- 3 mm Hg) and was associated with an increase in the in vivo formation of prostaglandins I2 and E2 and of thromboxane A2 in the kidney. High sodium intake induced a fall in the urinary levels of prostaglandin E2 and a rise in the arterial pressure of control rats (126 +/- 1 vs. 113 +/- 1 mm Hg) but did not influence aldosterone-induced hypertension. Indomethacin (3.0 mg/kg/day) caused a profound inhibition of the in vivo synthesis of prostaglandin I2 and thromboxane A2 without modifying the renal production of prostaglandin E2. Although indomethacin exerted no effect on aldosterone-induced hypertension in rats fed a normal diet, it caused a further rise in systolic pressure in aldosterone-treated rats fed a high sodium diet (157 +/- 6 vs. 140 +/- 4 mm Hg). The results of this study in a model of aldosterone-induced mild hypertension in the rat indicate that 1) aldosterone exerts a stimulatory effect on the renal synthesis of prostanoid, particularly prostaglandin E2; 2) thromboxane A2 and prostaglandin I2 do not seem to play a role in aldosterone-induced hypertension under conditions of normal dietary salt intake, whereas the role of prostaglandin E2 is unclear; 3) there is enough sodium in a normal diet to allow for the maximal expression of the hypertensive effect of aldosterone; 4) prostaglandin I2 seems to play a significant role in modulating the cardiovascular impact of a high sodium diet in aldosterone-treated rats; and 5) the renal biosynthesis of prostaglandin E2 is particularly resistant to the inhibitory effect of indomethacin in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Animals; Blood Pressure; Hypertension; Indomethacin; Male; Prostaglandins; Rats; Rats, Inbred Strains; Sodium, Dietary; Thromboxane B2; Thromboxanes

The hostile personality characteristic of dominance was shown to be significantly lower in a group of 34 male patients with essential hypertension than in a general illness control group (n = 17) in the USA. This replicates a previous finding from research in Greece into this and other conditions of presumably psychogenic origin. Nonspecific neurotic syndromes (as identified by the Present State Examination, a semistructured interview) were more prevalent in hypertensives than in controls, but no clear neurotic cases were found. Levels of the prostaglandins 6-keto prostaglandin F1A and thromboxane B2 did not differ significantly between groups, but the former was positively correlated with dominance in the control group. An interpretation of these results in terms of the repressed hostility theory is offered.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Pressure; Epoprostenol; Hostility; Humans; Hypertension; Male; Middle Aged; Personality Tests; Prostaglandins; Thromboxane A2; Thromboxane B2

To clarify the role of prostacyclin (PG) I2 and thromboxane (TX) A2 in the regulation of blood pressure from the standpoint of acquired factors and hereditary factors, the following experiments were carried out. [1] A low salt diet (2 g/day) was given for 7 days, followed by a high salt diet (23 g/day) for 7 days to 34 patients with essential hypertension. The percent change in 6-keto-PGF1 alpha by salt loading was directly proportional to that in mean blood pressure, but there was no significant relationship between the percent change in TXB2 and that in mean blood pressure. [2] The aorta was removed from 5-week-old and 20- to 25-week-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) rats. Each aorta was incubated in Tris buffer with and without arachidonic acid (AA). There was no significant difference in 6-keto-PGF1 alpha production between SHRs and WKY rats at the age of 5 weeks, but the aorta obtained from 20- to 25-week-old SHRs synthesized about 1.5 times as much 6-keto-PGF1 alpha as did that from age-matched WKY rats with and without AA. The aorta from 5-week-old SHRs synthesized more TXB2 than did that from age-matched WKY rats with and without AA, but there was no significant difference in TXB2 production between SHRs and WKY rats at the age of 20-25 weeks. These data suggest that the plasma PGI2 may have increased as a homeostatic reaction to the elevation of blood pressure induced by salt loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Animals; Aorta; Blood Pressure; Diet; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride; Thromboxane A2; Thromboxane B2

In young patients with borderline arterial hypertension and, to a greater extent, with Stage 1 hypertensive disease (HD), changes were found in the proatherogenic plasma lipid and apoprotein composition, which were manifested as higher levels of total cholesterol, triglycerides, low and very low density lipoprotein cholesterols along with increased apolipoprotein B and apolipoprotein B:apolipoprotein AI ratio. The prostacyclin-thromboxane system in borderline arterial hypertension was in an activated state by retaining the physiological ratio of its components. The patients with Stage I HD exhibited a considerable increase in thromboxane activity, which determined the system's imbalance towards its predominance. In Stage I HD, the thrombocytic link of hemostasis was characterized by enhanced platelet aggregability mediated by the imbalance of the prostacyclin-thromboxane system in the direction of thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Epoprostenol; Female; Humans; Hyperlipidemias; Hypertension; Lipids; Male; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Time Factors

Urinary TXB2 excretion and the release of TXB2 from vascular and renal cortical tissues are increased in rats with severe AII-salt hypertension. Treatment with an inhibitor of TXA2 synthesis did not change the blood pressure of normotensive or of AII-salt hypertensive rats. Treatment with SQ29,548, a TXA2 receptor antagonist, caused reduction of blood pressure and renal vascular resistance in AII-salt hypertensive but not in normotensive rats. We conclude that the SQ29,548-induced lowering of blood pressure and renal vascular resistance in AII-salt hypertensive rats is the result of blockade of the vascular actions of one or more pressor eicosanoids including TXA2 and the prostaglandin endoperoxides. A corollary of this conclusion is that pressor eicosanoids may be contributory factors in the pathogenesis of severe AII-salt hypertension in rats.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; In Vitro Techniques; Kidney; Kidney Cortex; Muscle, Smooth, Vascular; Rats; Reference Values; Sodium, Dietary; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effects of sodium intake on blood pressure and platelet function were evaluated in 19 subjects with essential hypertension (10 men and 9 women; mean age 49.7 years). The study was conducted under 3 conditions: (1) normal sodium diet (12 g/day of salt was used in cooking), (2) after 5 days of mild sodium restriction diet (6 g/day of salt was used in cooking) and (3) after moderate sodium restriction (no salt was used in cooking). Blood pressure was significantly reduced following sodium restriction without any change in heart rate. The ratio of the plasma level of beta-thromboglobulin to platelet factor IV, regarded as the most reliable index for platelet activation in vivo, increased significantly after mild sodium restriction; this change was maintained after moderate sodium restriction. Plasma thromboxane B2, a stable metabolite of thromboxane A2, increased significantly after sodium restriction; the level of 6-ketoprostaglandin F1 alpha, a stable metabolite of prostacyclin, was unaffected. These results indicate that dietary sodium restriction induces both a reduction of blood pressure and an activation of platelet function in vivo. Thus, one must consider both antihypertensive effects and effects on platelet function as factors in adjusting the dietary sodium intake in the course of antihypertensive therapy.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Blood Platelets; Blood Pressure; Calcium; Diet, Sodium-Restricted; Epinephrine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Platelet Aggregation; Renin; Sodium, Dietary; Thromboxane B2

To elucidate mechanisms of angiotensin II (Ang II)-related hypertension, we infused angiotensin (76 ng/min s.c.) into rats with minipumps for 10-14 days. Control rats received sham pumps. We measured blood pressure by tail-cuff, and the excretion of aldosterone and prostaglandins (PG) (PGE2, prostacyclin derivative 6kPGF1 alpha, and thromboxane [Tx] derivative TxB2). Angiotensin II increased blood pressure by 20 mm Hg by day 2 and by 90 mm Hg by day 10. Aldosterone excretion increased from 10 to 70 ng/day in Ang II rats by day 7. Urine PGE2 did not increase in angiotensin rats; however, both 6kPGF1 alpha and TxB2 excretion increased with angiotensin. Control rats had no changes in any of these parameters. A sympathetic component was tested in a separate group of angiotensin rats that received phenoxybenzamine (300 micrograms/kg/day) during angiotensin infusion; their increase in blood pressure of 40 mm Hg at 10 days was less than in those rats with angiotensin alone but more than in control rats. Phenoxybenzamine did not influence the angiotensin-induced increases in excretion of 6kPGF1 alpha or TxB2. Additional groups of conscious angiotensin and control rats were equipped with splanchnic nerve electrodes on day 14 for recording of sympathetic nerve activity. Angiotensin rats had greater basal sympathetic nerve activity than the control rats. Incremental methoxamine injections demonstrated altered baroreceptor reflex function in rats receiving angiotensin. We conclude that increased blood pressure with chronic angiotensin infusion is accompanied by increased production of aldosterone and increased sympathetic tone. The latter may be modulated by PG.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Angiotensin II; Animals; Blood Pressure; Dinoprostone; Hypertension; Male; Methoxamine; Phenoxybenzamine; Pressoreceptors; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Regression Analysis; Splanchnic Nerves; Sympathetic Nervous System; Thromboxane B2

To clarify the influence of Na balance on the hypotensive effect of calcium antagonists, the changes of blood pressure and humoral factors after a single oral administration of 40 mg nicardipine were evaluated in 15 subjects with essential hypertension under high, normal, and low Na regimens (mean 24 hour urinary Na excretion: 320 +/- 24, 147 +/- 7, 27 +/- 6 mEq, respectively). Nicardipine induced a significant reduction of mean blood pressure and increase in heart rate. The change of mean blood pressure after nicardipine was negatively related to the pretreatment mean blood pressure under the three levels of Na intake (p less than 0.01). The slopes of the correlation lines for high, normal, and low Na regimens were -0.61, -0.69, and -0.52, respectively, without statistical significance. Nicardipine brought about significant increases in plasma renin activity and plasma norepinephrine, but no changes in plasma levels of epinephrine, 6-keto-prostaglandin F1 alpha, thromboxane B2 or serum aldosterone concentration. These results suggest that the magnitude of the untreated blood pressure and thereby the peripheral resistance are major determinants of the blood pressure fall caused by calcium antagonists, and that the failure to increase aldosterone and epinephrine in the face of peripheral vasodilation may be responsible in part for the hypotensive effect of this drug.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Epinephrine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nicardipine; Norepinephrine; Renin-Angiotensin System; Sodium, Dietary; Thromboxane B2

The effects of dietary protein alterations on the synthesis of prostaglandins and kallikrein were examined in subtotally nephrectomized spontaneously hypertensive rats. Three diets containing 40, 24 and 8% protein were prepared. After subtotal nephrectomy, rats were given one of the three diets for the next 12 weeks. During the study, systolic blood pressure, urinary excretions of protein, 6-keto-prostaglandin F1 alpha, thromboxane B2 and kallikrein were measured every 2 weeks. Although the diets did not prevent the further elevation of systolic blood pressure, the rats on the low protein diet displayed lower serum creatinine levels and urinary protein levels. The urinary excretion of thromboxane B2 was unaffected by the amount of dietary protein, but the urinary excretion of 6-keto-prostaglandin F1 alpha was lower in the low protein diet group. Furthermore, the urinary excretion of kallikrein increased significantly in rats on high protein diet. These results suggest that manipulation of dietary protein may alter the natural course of renal failure induced by subtotal nephrectomy in spontaneously hypertensive rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dietary Proteins; Hypertension; Kallikreins; Kidney; Nephrectomy; Prostaglandins; Rats; Rats, Inbred SHR; Thromboxane B2

The aim of this study was to determine the effect of two years of treatment with cyclosporine A on blood pressure and the rates of secretion into the circulation of the vasoconstrictor thromboxane A2 and the vasodilator prostacyclin. Seven patient suffering from multiple sclerosis took part. Their blood pressures and urinary concentrations of 2,3-dinor-thromboxane A2 (a major urinary metabolite of thromboxane A2) and of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) were determined at the end of two years of treatment with cyclosporine A, and once again three months after cessation of this treatment. No other drugs were given during or after cyclosporine A. Mean arterial blood pressure was 113 +/- 5 mmHg (mean +/- SEM) during the cyclosporine A treatment, but fell to 94 +/- 4 mmHg after the three-month's wash-out period. Urinary excretion of the thromboxane metabolite decreased slightly from 674 +/- 150 pg.mg-1 creatinine during cyclosporine A therapy to 503 +/- 90 pg.mg-1-creatinine after the end of therapy. At the same time the prostacyclin metabolite increased significantly from 82 +/- 17 pg.mg-1 creatinine to 113 +/- 23 pg.mg-1 creatinine (P less than 0.05). The ratio of 2,3-dinor-thromboxane B2 to 2,3-dinor-6-keto-prostaglandin F1 alpha (taken as a measure of vasoconstrictor prostanoid activity) fell significantly from 8.4 +/- 0.8 4.7 +/- 0.6 (P less than 0.005). The shift in prostanoid production observed during cyclosporine A treatment could be one causal factor for the hypertensive and thromboembolic events associated with the use of this drug.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cyclosporins; Epoprostenol; Female; Humans; Hypertension; Male; Multiple Sclerosis; Thromboxane A2; Thromboxane B2

Topics: Adult; Aged; Aged, 80 and over; Aging; Aldosterone; Blood Pressure; Dinoprostone; Female; Humans; Hypertension; Kallikreins; Male; Middle Aged; Reference Values; Renin; Sex Factors; Thromboxane B2

This paper shows the basic and clinical evaluations of pressor responsiveness to angiotensin II (A II) using A II sensitivity test (AST) in normotensive and hypertensive pregnant women. The results are as follows: I. Basic findings of A II pressor responsiveness 1. AST was performed sequentially from as early in gestation as possible throughout the remainder of pregnancy. At clinic visit the patients received A II infusions sufficient to raise baseline diastolic blood pressure by 20 mmHg. The dose (ng/kg/min) of A II required to elevate 20 mmHg of diastolic blood pressure was recorded as the EPD. Increased EPD indicates the dullness of refractoriness to A II. The EPD in normotensive women (non-PIH) increased as early as midpregnancy, but EPD in women destined to develop pregnancy-induced-hypertension (PIH) decreased significantly after the 20th week of gestation. 2. Plasma angiotensin level in non-PIH increased significantly compared to that of PIH. There exists a definite correlation between EPD in pregnant women and plasma angiotensin level. 3. The plasma TxB2/6-keto-PGF1 alpha ratio increased significantly in PIH compared with that of non-PIH because of the increase in the amount of TxB2. In the 2nd trimester, the ratio in women destined to developed PIH showed a significantly higher value than that of the non-PIH. 4. In healthy men and castrated rats the EPD significantly increased after the administration of progesterone. At 20 and 30 weeks' gestation, the plasma progesterone/estrogen ratio in women destined to develop PIH decreased significantly compared to that of the non-PIH.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Angiotensin II; Animals; Blood Pressure; Calcium; Eicosapentaenoic Acid; Estrogens; Female; Humans; Hypertension; Male; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Cardiovascular; Progesterone; Rabbits; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Stimulation, Chemical; Thromboxane B2

1. This study examined the effects of eicosapentaenoic acid (EPA) treatment on vascular reactivity and blood pressure in spontaneously hypertensive rats (SHR). 2. Twenty SHR were given pure EPA as the methyl ester (280 mg/kg) by gavage for 10 days. An equal number of control rats received vehicle alone. EPA treatment had no effect on blood pressure compared with control rats. 3. Aortic rings from EPA-treated rats, precontracted with PGF2 alpha showed increased endothelium-dependent relaxations to acetylcholine. Endothelium-independent relaxations to sodium nitroprusside were not altered. Rings from rats fed pure EPA did not show any differences in vasoconstrictor responses to noradrenaline or serotonin. 4. Serum thromboxane B2 (TXB2) levels fell 17% in animals given pure EPA, but prostacyclin production was not affected. These responses are less than those seen following Max EPA fish oil. 5. Thus, pure EPA treatment did not lower blood pressure, but may have a direct effect on aortic endothelia and cause increased endothelium-dependent relaxations in response to acetylcholine in SHR.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Aorta, Thoracic; Blood Pressure; Eicosapentaenoic Acid; Endothelium, Vascular; Fatty Acids, Nonesterified; Hypertension; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Inbred SHR; Thromboxane B2

The purpose of the study was to characterize the renal TxA2, PGI2 and PGF2 alpha release in response to arterial blood pressure (BP) fall induced by systemic and intrarenal vasorelaxation in subjects with essential hypertension. Significantly enhanced TxB2- and PGF2 alpha excretion and no change in ratio TxB2/6-keto-PGF1 alpha were found in urine in hypertensive patients after administration of the Ca++ entry blocker gallopamil, used to induce BP fall. This response was associated with significant PRA elevation in peripheral venous samples. In in vitro experiments, direct and indirect effects of gallopamil on renal tissue could be distinguished. Gallopamil resulted in significant diminution of TxA2 production and a decrease in TxB2/6-keto PGF1 alpha ratio in incubated rat kidney slices. This model was also used to test biochemically the effect of reflex sympathetic activation on prostanoid generation in kidney. It was concluded that this mechanism was only one among the indirect mechanisms by which gallopamil could induce that renal prostanoid response in hypertensive subjects. The response in urinary TxB2- and PGF2 alpha excretion was found to be significantly related to the changes in sodium reabsorption. These results suggested, that the increase in renal TxA2 and PGF2 alpha production in response to systemic and intrarenal "vasodilation" induced by gallopamil in hypertensive subjects can be interpreted as part of counteraction of the kidneys to BP fall.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Blood Pressure; Dinoprost; Female; Gallopamil; Glomerular Filtration Rate; Humans; Hypertension; In Vitro Techniques; Kidney; Male; Middle Aged; Norepinephrine; Rats; Renin; Sodium; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

This study was designed to assess the contribution of thromboxane A2 to high blood pressure in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 M NaCl by infusion of Ang II (125 ng/min i.p.) for 12 days. Relative to values in water-drinking rats without Ang II infusion, Ang II-salt hypertensive rats exhibited augmentation (p less than 0.05) of blood pressure (from 129 +/- 3 to 217 +/- 12 mm Hg), urinary thromboxane B2 excretion (from 5.4 +/- 0.9 to 25.4 +/- 2.1 ng/day), and thromboxane B2 release from renal cortex slices (from 71.3 +/- 6.7 to 121.1 +/- 14.4 pg/mg) and aortic rings (from 28.8 +/- 2.9 to 115.8 +/- 12.8 pg/mg). Treatment with an inhibitor of thromboxane A2 synthetase, UK 38485, had no effect on blood pressure in normotensive and Ang II-salt hypertensive rats. Treatment with a thromboxane A2 receptor blocker, SQ 29548, decreased blood pressure in Ang II-salt hypertensive rats from 191 +/- 9 to 152 +/- 9 mm Hg after 3 hours, but it had no effect on blood pressure in normotensive rats. Since SQ 29548 interfered with the pressor effects of the prostaglandin endoperoxide analogue U-46619, prostaglandin F2 alpha, and 9 alpha,11 beta-prostaglandin F2, we suggest that the SQ 29548-induced blood pressure reduction in Ang II-salt hypertensive rats is the manifestation of blockade of the vascular actions of one or more endogenous prostanoids including thromboxane A2 and prostaglandin endoperoxides. If so, pressor prostanoids may be contributory factors in the pathogenesis of severe Ang II-salt hypertension in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney Cortex; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Decreased incidence of proteinuric hypertension after low-dose aspirin therapy is hypothesized to be a consequence of selective thromboxane A2 inhibition and sparing of prostacyclin. This study was designed to ascertain if low-dose aspirin therapy (81 mg/day for 1 week) alters vascular refractoriness to angiotensin II and the prostacyclin/thromboxane A2 ratio in pregnant women sensitive to angiotensin II (n = 17). Low-dose aspirin increased the effective pressor dose of angiotensin II from 5.9 +/- 2.4 to 10.2 +/- 5.5 ng/kg/min (p less than 0.01, mean +/- SD). Platelet-derived serum thromboxane B2 (a metabolite of thromboxane A2), a measure of therapy compliance, decreased from 1804 +/- 1771 to 132 +/- 206 pg/ml (p less than 0.01). Plasma thromboxane B2 decreased from 130 +/- 107 to 19 +/- 12 pg/ml (p less than 0.01). Inhibition was not selective because 6-keto-prostaglandin F1 alpha (a metabolite of prostacyclin) also decreased from 243 +/- 90 to 163 +/- 90 pg/ml (p = 0.039) and prostaglandin E2 was reduced from 155 +/- 67 to 95 +/- 40 pg/ml (p = 0.014). Decreases in thromboxane B2, however, were significantly greater (75% +/- 19%) than decreases in 6-keto-prostaglandin F1 alpha (21% +/- 33%) or prostaglandin E2 (29% +/- 36%); thus the 6-keto-prostaglandin F1 alpha/thromboxane B2 ratio increased from 3.1 +/- 2.0 to 12.4 +/- 9.9 (p less than 0.01). Although low-dose aspirin increases the effective pressor dose of angiotensin II, it does not return to normal pregnancy values. This observation is consistent with the hypothesis that this represents only a partial selective prostaglandin inhibition.

Topics: Angiotensin II; Aspirin; Blood Pressure; Drug Administration Schedule; Drug Resistance; Female; Humans; Hypertension; Osmolar Concentration; Parity; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Thromboxane B2

Erythrocyte morphologic characteristics and serum chemistry results were studied in 10 gravid ewes during experimental ovine pregnancy-induced hypertension and subsequent administration of the thromboxane synthetase inhibitors CGS13080 and CGS12970. During the hypertensive period mean arterial blood pressure, plasma thromboxane B2 levels, and serum chemistry results, and electrolyte levels were significantly altered. Parameters returned to baseline values or were improved after drug administration. Erythrocyte morphologic features did not change significantly with the onset of the syndrome. Echinocytosis was present during baseline measurement and persisted throughout hypertension. However, after thromboxane synthetase inhibition, percentages of discocytes increased (p less than or equal to 0.005) with the same frequency that echinocyte numbers decreased (p less than or equal to 0.05). Schistocytes were present throughout the study, and changes in their numbers were not detected. Serum phosphorus, blood urea nitrogen, and bilirubin levels and anion gap rose significantly during hypertension and returned to normal levels after drug treatment. We speculate that CGS13080 or CGS12970, by decreasing thromboxane levels and blood pressure, promoted the normalization of erythrocyte membranes.

Topics: Animals; Blood Chemical Analysis; Blood Pressure; Electrolytes; Erythrocytes; Female; Hypertension; Microscopy, Electron, Scanning; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy, Animal; Sheep; Thromboxane B2; Thromboxane-A Synthase

Streptozotocin diabetes in rats was complicated by spontaneous hypertension (SHR) and myocardial infarction (MIC), considered as "risk groups". Renal function was assessed on the basis of blood urea nitrogen (BUN) and albuminuria. BUN increased by 36% in Wistar diabetic group, by 100% in SHR + diabetes, and by 51% in MIR + diabetes. Morphologic changes were assessed by estimation of PAS-positive glycosaminoglycans and measurement of vascular wall thickness of glomerular arterioles. The risk groups showed exaggerated tendency for development of diabetic angiopathy. A significant imbalance between TXA2 and prostacyclin was found, which was reflected by TXB2/6-keto-PGF1 alpha (the stable metabolites of TXA2 and prostacyclin, respectively) ratio, which increased by 38% in Wistar diabetic rats, by 61% in SHR + diabetes, and by 133% in MIR + diabetes. These changes correlated very well with increased platelet aggregability (r = 0.70; p less than 0.05) and with increased lipid peroxide level (r = 0.60; p less than 0.05), but neither with total plasma cholesterol (r = 0.20), nor with plasma triglycerides (r = 0.34). Lipid peroxides increased 5-fold in Wistar diabetic rats, 6-fold in SHR + diabetes, and 5.5-fold in MIR + diabetes. A causative relationship between TXA2/PGI2 imbalance and lipid peroxide changes on one hand, and diabetic angiopathy, on the other, was suggested.

Topics: Animals; Blood Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Hypertension; Kidney; Lipid Peroxides; Lipids; Male; Myocardial Infarction; Pancreas; Platelet Aggregation; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Thromboxane B2

In our previous studies strenuous exercise, adrenaline infusion and surgical stress have been shown to evoke increased plasma thromboxane B2 (TxB2) concentrations and production by platelets. Here we report the effects of acute psychological and physical tests, during 24 h direct monitoring of blood pressure and heart rate, on plasma catecholamine levels and TxB2 production by platelets in normotensive, borderline and mild hypertensive subjects. After psychological tests plasma noradrenaline and adrenaline values in the whole material were slightly elevated as compared to the basal levels measured 24 h after the attachment of the cannula. TxB2 production remained unaltered. After physical tests both plasma noradrenaline and adrenaline were clearly increased as was also the TxB2 production by platelets. When the subjects were divided into normotensive and hypertensive ones, unexpectedly, basal plasma values of catecholamines were higher in normotensive volunteers but TxB2 production was more marked in hypertensive subjects.

Topics: Blood Platelets; Blood Pressure; Epinephrine; Heart Rate; Humans; Hypertension; Norepinephrine; Physical Exertion; Psychological Tests; Reference Values; Thromboxane B2

1. Dietary suppression of prostanoid synthesis with fish oils has had little effect on blood pressure in models of experimental hypertension in rats. However, a pressor effect of dietary fish oils was observed in spontaneously hypertensive rats (SHR) subject to 1 week of salt loading. 2. Animals were allocated to semisynthetic diets containing either 10% by weight Max EPA fish oil or a control diet of coconut oil, and studied after receiving 1.5% saline for 4 weeks. 3. Within the first week of salt loading, SHR-fed fish oil showed an increase in blood pressure (mean = 9 mmHg) relative to controls. This effect was transient, and after the first week of salt loading there was little difference in blood pressure between the two dietary groups. 4. Following dietary treatment there were substantial changes in plasma fatty acid composition with a 48% decrease in arachidonic acid content of fish oil-fed rats compared with control animals. Rats on the fish oil diet showed a threefold decrease in serum thromboxane generation. Prostacyclin production by incubated segments of aorta was reduced by more than 50% compared with the coconut oil-fed control group. 5. SHR on the fish oil diet showed increased urine volume and sodium excretion, presumably due to increased fluid and salt intake. 6. This study shows that dietary suppression of prostacyclin synthesis is associated with only a minor effect on blood pressure in long-term salt loading of SHR.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Chromatography, Gas; Diet; Eicosanoids; Fatty Acids, Nonesterified; Fish Oils; Hypertension; Male; Platelet Activating Factor; Potassium; Rats; Rats, Inbred SHR; Sodium; Thromboxane B2; Urodynamics

The renal and systemic metabolites (the latter as 2,3-dinor derivatives) of prostacyclin and thromboxane A2 were measured, along with renal prostaglandin E2 and kallikrein, in the urine of 15 patients with pregnancy-induced hypertension, 15 normotensive pregnant women matched for both age and gestational age, and 15 normotensive nonpregnant control women. Urinary excretion of all prostaglandin and thromboxane metabolites studied proved significantly higher in normotensive pregnant women than in controls. Prostaglandin E2, 6-keto-prostaglandin F1 alpha, and 2,3-dinor-6-keto-prostaglandin F1 alpha were significantly lower in pregnancy-induced hypertensive women than in normotensive pregnant women, whereas thromboxane B2 and 2,3-dinor-thromboxane B2 showed no significant differences in the two groups. A significant negative correlation (r = -0.636, p less than 0.01) was found between urinary 2,3-dinor-6-keto-prostaglandin F1 alpha and mean blood pressure in the two groups of pregnant women taken as a whole. These data indicate that, in pregnancy-induced hypertension, there is an imbalance between vasodilator and vasoconstrictor factors, not only in the kidneys, but also at the systemic vascular level. This imbalance, which may in itself produce vasoconstriction, may also potentiate the hypertensive effect of catecholamines and angiotensin II.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Chromatography, High Pressure Liquid; Dinoprostone; Epoprostenol; Female; Humans; Hypertension; Kallikreins; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Prostaglandins E; Prostaglandins E, Synthetic; Radioimmunoassay; Thromboxane A2; Thromboxane B2

The relation of brain eicosanoids to progression of cerebral edema was studied in stroke-resistant spontaneously hypertensive rats subjected to incomplete global brain ischemia induced by bilateral occlusion of the common carotid arteries. Thromboxane B2 and 6-keto prostaglandin F1 alpha levels were significantly elevated 5 minutes after reperfusion but returned to control levels by 30 minutes. In contrast, leukotriene C4 levels increased 2 hours after bilateral common carotid artery occlusion and peaked 30 minutes after reperfusion, with higher levels persisting until 60 minutes after reperfusion. Cerebral ischemia was accompanied by cerebral edema early after reperfusion. The edema correlated with increased leukotriene C4 levels. That the increased brain water content was causally related to an increase in leukotriene C4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861. Both inhibitors suppressed the increased leukotriene C4 and brain water contents after reperfusion. Our results indicate that leukotriene C4 is closely associated with an induction of ischemic cerebral edema.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzoquinones; Body Water; Brain; Brain Edema; Cerebrovascular Circulation; Cerebrovascular Disorders; Disease Susceptibility; Eicosanoic Acids; Hypertension; Male; Quinones; Rats; Rats, Inbred SHR; SRS-A; Thromboxane B2

To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH), -resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGF1 alpha did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1 alpha remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF1 alpha observed in the three strains of rats were inversely related (r = -0.78; P less than 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Desoxycorticosterone; Female; Hypertension; Rats; Rats, Inbred SHR; Thromboxane B2

Thromboxane A2 is a prostanoid having potent platelet aggregatory and vasoconstrictor properties. To determine a possible role for thromboxane A2 in the development of severe hypertension and stroke, we chronically administered the selective thromboxane A2 synthase inhibitor UK-38,485 (Dazmegrel) to stroke-prone spontaneously hypertensive rats (SHRSP). Serum thromboxane B2 (the stable hydrolysis product of thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in drinking water to accelerate the occurrence of stroke, treatment with 100 mg/kg/day UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe hypertension was not prevented by UK-38,485. Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of stroke by thromboxane A2 synthase inhibition in these rats.

Topics: Animals; Blood Pressure; Brain; Cerebrovascular Disorders; Disease Susceptibility; Hypertension; Imidazoles; Male; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

The major complication of extracorporeal membrane oxygenation (ECMO) for the treatment of neonatal respiratory failure is bleeding related to heparinization. Systolic hypertension has emerged as another serious side effect in our experience. Thirty-eight of the first 41 newborns we treated with ECMO developed a systolic blood pressure greater than 90 mm Hg. The mean hypertension index (HI blood = hours greater than 90/hr on ECMO) was 0.17 +/- 0.16. Possible biochemical mediators were assayed in 17 patients. Plasma renin activity (PRA), aldosterone, epinephrine, norepinephrine, prostaglandin E2, thromboxane, and antidiuretic hormone were elevated. Angiotensin-converting enzyme (ACE) and prostacyclin were not elevated. Eighteen patients (44%) had intracranial hemorrhage (ICH), and 11 patients (27%) had clinically significant ICH. The HI was significantly (p less than 0.005) lower in those patients without ICH (0.11 +/- 0.01) than in those patients with ICH (0.25 +/- 0.04). PRA at hour 12, day 2, and day 3 was significantly higher (p less than 0.05) in patients experiencing ICH (62 +/- 42; 93 +/- 15; 73 +/- 30 ng/ml/hr) than in those without ICH (27 +/- 25; 14 +/- 8; 12 +/- 4 ng/ml/hr). An aggressive approach to medical management evolved that included hydralazine, nitroglycerine, and captopril, which protected against ICH. Two of 23 patients (9%) treated with the protocol sufferred clinically significant ICH, whereas nine of 18 patients (50%) treated before implementation of the protocol experienced ICH. The ACE inhibitor captopril was most effective in the control of hypertension. We conclude that systolic hypertension is common during neonatal ECMO, is associated with ICH, and is related to a high PRA. Aggressive management of hypertension during ECMO can reduce the incidence of ICH, and captopril is an important component of this aggressive medical management.

Topics: Aldosterone; Cardiac Output; Catecholamines; Humans; Hypertension; Infant, Newborn; Oxygenators, Membrane; Peptidyl-Dipeptidase A; Prostaglandins; Renin; Respiratory Insufficiency; Thromboxane B2; Vasopressins

Topics: Adult; Blood Pressure; Dietary Fats; Eicosapentaenoic Acid; Humans; Hypertension; Lipids; Male; Middle Aged; Thromboxane B2

The role of endogenous angiotensin II and prostaglandins (PGs) in the antihypertensive effect of converting enzyme inhibitor, captopril, was studied in essential hypertension by the separate and the combined administration of captopril and indomethacin. Although plasma angiotensin II was similarly suppressed by the separate and the combined administration of captopril and indomethacin, captopril lowered and indomethacin increased the mean blood pressure. There were negative correlations between the changes in mean blood pressure and in urinary sodium excretion as well as in urinary PGE excretion. These results suggest that endogenous PGs may be implicated in the antihypertensive effect of captopril through the alteration of sodium balance.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Diet, Sodium-Restricted; Female; Humans; Hypertension; Indomethacin; Male; Prostaglandins; Sodium; Thromboxane B2

1. This study investigated the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in DOCA/salt-treated rats. 2. After an initial 4 week period on either a 2-series PG 'inhibitory' diet of fish oil (Max EPA), A 'stimulatory' diet of safflower oil or a control diet of saturated fat, three groups of rats were placed on a DOCA/salt regimen for a further 4 weeks. Another group on the saturated fat diet continued their diet without DOCA/salt administration. 3. All the DOCA-treated groups showed a marked increase in blood pressure. However, both polyunsaturated fat (PUFA)-fed groups had blood pressures significantly lower then the saturated fat control. 4. Rats on the Max EPA showed impaired ability to generate prostanoids in vitro (serum, aorta and kidney) and in vivo (urinary PG excretion). DOCA administration increased urinary PGE2 excretion. 5. Thus, dietary suppression of 2-series PG is not accompanied by accelerated DOCA/salt hypertension. The reduction in blood pressure observed in both the safflower and Max EPA-fed groups may be due to PUFA-induced changes in cell membrane fluidity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Dietary Fats; Electrolytes; Hypertension; Kidney; Lipids; Male; Prostaglandins; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Female; Glomerulonephritis; Humans; Hypertension; Kidney Diseases; Liver Cirrhosis; Male; Nephrotic Syndrome; Radioimmunoassay; Thromboxane B2; Uremia

The activity of basal 24-hour urinary kallikrein activity (UKA), prostaglandin E2 (U. PGE2) and thromboxane B2 (U. TxB2) and their relationship to natriuresis (U. Sodium), urinary aldosterone (U. Aldosterone) and plasma renin activity (in supine position: PRA1; in standing position: PRA2) were evaluated in 20 patients with early-moderate hemodynamically defined (first pass and gate blood pool radionuclide angiocardiography) essential hypertension (H) and in 13 age-matched normotensive patients (N). In basal conditions, UKA and PRA2 were significantly reduced (p less than 0.005 and p less than 0.05, respectively) in H compared with N. However, no differences between N and H were found for U. TxB2, U. PGE2, U. Aldosterone, U. Sodium, and PRA1. All parameters were also evaluated both in H and N before and after the administration of furosemide (40 mg i.v.). In H, but not in N, furosemide induced an increase of UKA (p less than 0.05), U. TxB2 (p less than 0.05) and U. Sodium (p less than 0.001). In both H and N furosemide caused a significant rise of PRA1 (p less than 0.001 in H and p less than 0.01 in N) and PRA2 (p less than 0.001 in H and p less than 0.05 in N). In H a significant correlation was found between percent increases of U. Sodium and U. Kallikrein (r = 0.54, p less than 0.01) and between percent differences of PGE2 and TxB2 (r = 0.59, p less than 0.01). It is proposed that reduction of basal UKA may be an early evidence of the first stages of hypertension, i.e., in absence of renal and cardiovascular alteration. The finding is not accompanied by significant changes in urinary excretion of arachidonic acid metabolites and aldosterone. Finally, any relation between UKA values and systemic hemodynamics is lacking.

Topics: Aldosterone; Female; Furosemide; Hemodynamics; Humans; Hypertension; Kallikreins; Male; Middle Aged; Natriuresis; Prostaglandin Endoperoxides; Prostaglandins G; Renin; Thromboxane B2

To study the involvement of 6 keto prostaglandin F1 alpha (6 keto PGF1 alpha) and thromboxane B2 (TxB2) in mild pregnancy-induced hypertension (PIH), we measured amniotic fluid and plasma concentration of these prostanoids by radioimmunoassay in PIH subjects and normotensive pregnant controls. The results suggest no difference in plasma or amniotic fluid 6 keto PGF1 alpha or plasma TxB2 in PIH and control subjects. The concentration of TxB2 (mean +/- SE) in amniotic fluid, however, were 189.5 +/- 27.7 for PIH and 107.4 +/- 9.7 for controls (P less than 0.05). This increase in vasoconstrictor TxB2 over vasodilator 6 keto PGF1 alpha may have implications in the hypertensive vascular response of mild PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Amniotic Fluid; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Pregnancy-induced hypertension was induced in five ewes (gestational day 135; term 150 days) by 72 hours of food deprivation. Maternal arterial pressure, uterine blood flow, platelet function, renal function, and plasma levels of 6-ketoprostaglandin F1 alpha and thromboxane B2 were measured before and during hypertension and after three intravenous injections of U-63,557A; sodium 5-(3'-pyridinylmethyl) benzofuran-2-carboxylate, monohydrate (30 mg/kg every 8 hours). Blood pressure increased (p less than 0.03), and returned to normal after U-63,557A. Left uterine artery blood flow increased after U-63,557A (p less than 0.03). Creatinine clearance decreased during hypertension (p less than 0.03) and increased after U-63,557A. Urine protein increased during hypertension (p less than 0.03) and decreased after treatment. Platelet count dropped during hypertension (p less than 0.03) and was elevated after treatment. Collagen lag phase decreased during hypertension (p less than 0.03) and increased after treatment. After U-63,557A, 6-ketoprostaglandin F1 alpha levels were higher (p less than 0.04) than baseline or hypertensive values. Administration of a thromboxane synthetase inhibitor caused resolution of hemodynamic, renal, and coagulation dysfunctions that occurred in ovine pregnancy-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzofurans; Blood Pressure; Female; Hypertension; Kidney Function Tests; Platelet Count; Pregnancy; Pregnancy Complications, Cardiovascular; Sheep; Thromboxane B2; Thromboxane-A Synthase; Uterus

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Hypertension; Male; Middle Aged; Reference Values; Smoking; Thromboxane B2

Urinary excretion of thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2), was measured by radioimmunoassay in 7 essential hypertensive patients before and after a converting enzyme inhibitor, SQ 14225, administration. When a single oral dose of SQ 14225 (50mg) was given to 7 patients with essential hypertension, urinary excretion of TXB2 was increased significantly (from 58.9 +/- 18.1 to 116.1 +/- 20.7 pg/min, mean +/- SE, P less than 0.02) with simultaneous increase in plasma renin activity, urine volume, urinary sodium, urinary potassium and urinary excretion of PGE (from 58.8 +/- 12.8 to 135.1 +/- 30.0 pg/min, mean +/- SE, P less than 0.05). These results indicate that SQ 14225 stimulates vasoconstricting TXA2 production as well as vasodilating PGE production.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Humans; Hypertension; Kinetics; Potassium; Prostaglandins E; Radioimmunoassay; Renin; Sodium; Thromboxane B2

Twelve male patients with mild essential hypertension were put on a diet supplemented with 2 cans of mackerel/day (= 2.2 g daily of eicosapentaenoic acid, EPA, C20:5 n-3 and 2.8 g daily of docosahexaenoic acid, DHA, C22:6 n-3) for 2 weeks within an isocaloric regimen and then with 3 cans/week (= 3.3 g/week, equivalent to 0.47 g daily of EPA and 4.2 g/week, equivalent to 0.69 g daily of DHA) for 8 months with a subsequent period of 2 months on normal diet. Eleven male hypertensives matched for age, body weight index, blood pressure and serum lipids with no change in their nutritional habits served as controls. After the first dietary period (2 weeks) a significant decrease of serum triglycerides (TG), total and LDL-cholesterol, blood pressure and thromboxane B2 (TxB2) was found, whereas HDL cholesterol and potassium in erythrocytes were significantly increased. During the second dietary period (8 months) providing the lower dose of EPA, serum lipids and the other biochemical parameters returned to the initial values. Blood pressure, however, remained significantly lower and rose to the basal levels only after the third period (2 months) on normal diet. In the control group no alterations could be seen. The data suggest a dose-related differential effect of dietary EPA on serum lipids, lipoproteins, TxB2 and blood pressure in subjects with mild hypertension.

Topics: Adult; Animals; Blood Pressure; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Fishes; Food Preservation; Humans; Hypertension; Lipids; Male; Thromboxane B2; Time Factors; Triglycerides

A thrombo-embolic stroke model was produced by the internal carotid artery (ICA) infusion of arachidonic acid (AA). The differences in responses to AA ICA infusion were investigated in stroke-resistant spontaneously hypertensive rats (SHRSR) and Wistar-Kyoto (WKY) rats. The SHRSR showed a higher mortality, more severe brain oedema and brain metabolic impairment, more prominent elevation of TXB2 and 6-keto-PGF1 alpha. Electron microscopic observation revealed more severe endothelial damage, mitochondrial swelling and perivascular oedema and earlier thrombus formation in SHRSR than in WKY rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Brain Ischemia; Cerebrovascular Disorders; Hypertension; Male; Microscopy, Electron, Scanning; Rats; Rats, Inbred Strains; Thromboxane B2

In order to assess the pathophysiological role of the renal Thromboxane (Tx)A2 in genetic hypertension, the urinary excretion of its stable metabolite: the TxB2 was followed in groups of 12 hypertensive (LH), normotensive (LN) and low blood pressure (LL) female rats of the Lyon strains at the ages of 5, 9, 21 and 32 weeks. In the 3 strains studied, the urinary TxB2 excretion markedly decreased between 5 and 9 weeks of age and did change thereafter. In addition, 5 and 9 weeks old rats exhibited an increased urinary TxB2 output compared to LN and LL controls. Since TxA2 is a potent vasoconstrictor, it seems likely to hypothesize that the early increase observed in the renal TxA2 biosynthesis could be one of the primary events occurring during the development of hypertension in this rat model.

Topics: Aging; Animals; Body Weight; Female; Hypertension; Kidney; Rats; Thromboxane A2; Thromboxane B2

The production rate of four prostanoids (PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) in human umbilical cords from normal pregnancies (control) and cases with pregnancy-induced hypertension (PIH) were compared. The cords in the PIH-group produced significantly less 6-keto-PGF1 alpha and more TXB2 than did those in the control-group. Production rates of PGE2 and PGF2 alpha were almost equal in the two groups. After stimulation with angiotensin II the PIH-cords displayed a far smaller increase in 6-keto-PGF1 alpha production compared to the control cords. The responses in PGE2 and PGF2 alpha production were again equal in the two groups. The present results indicate that the angiotensin-prostanoid interactions are disturbed in fetal as well as in maternal vessels. Such a disturbance may explain the observed relative hypersensitivity to angiotensin II observed in gravidae prone to develop pregnancy-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Dinoprost; Dinoprostone; Female; Humans; Hypertension; In Vitro Techniques; Perfusion; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2; Umbilical Arteries

Plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolites of two prostanoids with opposing biological effects, TXA2 and prostacyclin, were measured by radioimmunoassay in normal pregnancy (controls) and pregnancy complicated by hypertension (PIH) from 32 to 36 (Period 1; P1) and from 36 to 40 (Period 2; P2) weeks of gestation. The plasma concentration of each compound in the control subjects was 265.6 +/- 58.4 (TXB2), 132.4 +/- 16.5 (6-keto-PGF1 alpha) for P1 (n = 10) and 142.6 +/- 11.8 (TXB2), 68.5 +/- 5.2 (6-keto-PGF1 alpha) for P2 (n = 10) respectively (pg/ml, mean +/- s.e). In the patients with PIH, TXB2 concentrations increased moderately for P1 (419.2 +/- 21.2; n = 7) and significantly (p less than 0.005) for P2 (452.8 +/- 31.0; n = 7) respectively (pg/ml, mean +/- s.e), while the plasma levels of 6-keto-PGF1 alpha revealed a slight to moderate decrease both for P1 (84.5 +/- 4.0; n = 7) and P2 (59.7 +/- 8.1; n = 7) respectively (pg/ml, mean +/- s.e). The physiological balance of TXB2 to 6-keto-PGF1 alpha was significantly greater (p less than 0.005) in the patients with PIH, where the TXB2/6-keto-PGF1 alpha ratio was 5.2 +/- 0.7 for P1 and 9.4 +/- 2.3 for P2 respectively (mean +/- s.e) compared with that of the controls, where it was 2.4 +/- 0.4 for P1 and 2.0 +/- 0.2 for P2 respectively (mean +/- s.e).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Epoprostenol; Female; Gestational Age; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Radioimmunoassay; Thromboxane B2

The effects of a calcium antagonist [Nicardipine hydrochloride (NH)] on the prostaglandin [prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha)] and thromboxane B2 levels in the blood and urine were examined in 6 patients with essential hypertension following intravenous infusion of NH for 120 minutes. At the same time, the plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma and urinary electrolyte levels were also determined. During NH administration, the blood pressure was significantly decreased (p less than 0.05) with an increased pulse rate (p less than 0.05). PRA was significantly increased after NH loading (p less than 0.05) but PAC showed no change. The plasma PGE2 and 6-keto-PGF1 alpha levels tended to increase slightly, while the blood thromboxane B2 level showed a decreasing tendency. The 6-keto-PGF1 alpha to thromboxane B2 ratio was significantly increased after NH loading as compared to the preloading ratio (p less than 0.05), and then returned to the preloading value at about 30 minutes after discontinuation of NH loading. The urinary excretions of PGE2, 6-keto-PGF1 alpha and thromboxane B2, PGE2 and 6-keto-PGF1 alpha tended to decrease after NH loading. In particular, the decrease in PGE2 was statistically significant (p less than 0.05). No change occurred in the urinary excretion of thromboxane B2. The above findings indicate that NH increased the plasma 6-keto-PGF1 alpha to thromboxane B2 ratio but decreased the urinary excretion of prostaglandins. In addition, the possible involvement of an enhanced 6-keto-PGF1 alpha/thromboxane B2 ratio in part of the hypotensive mechanism of NH is suggested.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Blood Pressure; Calcium Channel Blockers; Dinoprostone; Electrolytes; Humans; Hypertension; Injections, Intravenous; Nicardipine; Prostaglandins E; Pulse; Renin; Thromboxane B2

Topics: Adult; Aldosterone; Carrier Proteins; Erythrocytes; Humans; Hydrocortisone; Hypertension; Kallikreins; Male; Natriuresis; Prostaglandins; Renin; Sodium-Potassium-Chloride Symporters; Thromboxane B2; Vasodilation

The possible roles of vasodilatory prostanoids and the kallikrein-kinin system in the antihypertensive action of the angiotensin-converting enzyme (kininase II) inhibitor captopril were examined in spontaneously hypertensive rats. Captopril (20, 50 or 100 mg/kg daily orally) reduced blood pressure markedly and dose-dependently. It also increased water consumption and urine excretion, measured on the 5th day of treatment. The 24-hr urinary excretion of PGE2 was not changed, whereas that of PGF2 alpha and TxB2 tended to be enhanced. A clear increase, significant with all doses of captopril, occurred in the urinary excretion of 6-keto-PGF1 alpha. Kallikrein excretion in urine was suppressed by the two larger doses of captopril. The markedly augmented urinary excretion of 6-keto-PGF1 alpha, the stable metabolite of vasodilatory prostacyclin (PGI2), suggests that increased prostacyclin production may participate in the antihypertensive mechanism of captopril. Vasodilatory kinins can also contribute, since the captopril-induced decrease in kallikrein may reflect accumulation of kinins due to their reduced metabolism.

Topics: Animals; Captopril; Dose-Response Relationship, Drug; Hypertension; Kallikreins; Male; Prostaglandins; Rats; Rats, Inbred SHR; Renin; Thromboxane B2

The object of this study was to develop an assay for platelet activating factor (PAF) in rat plasma, and to utilise this to determine the effects of dietary fish oil on PAF in normotensive and spontaneously hypertensive rats. Measurement of platelet activating factor in blood plasma has proved difficult because of its rapid hydrolysis in vivo to lyso PAF. We describe here a method based on the prior acetylation of lyso PAF extracted from plasma to PAF before bioassay using 14C-serotonin labelled platelets. The active material found in acetylated plasma extracts was characterized as PAF by its chromatographic mobility, the action of phospholipases A2, C and D and by cross-desensitization studies with rabbit platelets. Rats fed dietary fish oil ('max EPA') had significantly decreased plasma lyso-PAF levels compared to control animals fed hydrogenated coconut oil (HCO). Serum thromboxane B2 (TXB2) levels were also significantly lower in animals fed the 'max EPA' diet. Spontaneously hypertensive rats (SHR) had significantly lower plasma lyso-PAF levels than their normotensive Wistar Kyoto (WKY) controls maintained on the same diets. It is proposed that dietary alterations in PAF synthesis may influence platelet behaviour in addition to the well described effects of dietary fish oil on the proaggregatory prostanoid TXA2. Rat strain differences in lyso-PAF synthesis occur, but are unlikely to be related to the maintenance of hypertension in SHR.

Topics: Animals; Chromatography, Thin Layer; Fatty Acids; Fish Oils; Hypertension; Male; Phospholipases; Platelet Activating Factor; Rabbits; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2

Eight bulls and steers (research animals) and 18 bulls (surgical patients) were anesthetized with guaifenesin and thiopental or thiamylal and for 90 minutes with halothane. Arterial blood pressure and heart rate were recorded in all animals. Cardiac output, plasma glucose and lactate concentrations, PCV, plasma proteins and plasma thromboxane B2 values were determined before (control) and every 15 minutes during anesthesia in the research animals. Plasma catecholamine concentrations were measured in 3 of the research animals and 3 of the surgical patients. Arterial pressure, heart rate, and plasma thromboxane B2 and catecholamine concentrations were also measured immediately after the trachea was intubated. All animals, except one, were hypertensive during anesthesia. Heart rate during anesthesia was significantly increased, compared with control measurements, and cardiac output was decreased. Plasma glucose and lactate values significantly increased when the animals were restrained on their sides. Plasma glucose concentrations remained increased during anesthesia, but lactate decreased. Packed cell volume and plasma proteins were unchanged by the induction of anesthesia. Plasma norepinephrine concentration was unchanged during anesthesia, and epinephrine concentration was decreased. Endotracheal intubation caused a transient significant increase in arterial pressure, heart rate, and thromboxane B2 and a nonsignificant increase in norepinephrine.

Topics: Anesthesia, General; Animals; Blood Glucose; Blood Pressure; Blood Proteins; Cattle; Epinephrine; Erythrocyte Volume; Guaifenesin; Halothane; Heart Rate; Hypertension; Lactates; Male; Norepinephrine; Orchiectomy; Thiobarbiturates; Thromboxane B2

Topics: Adult; Aged; Female; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Hypertension; Hypertension, Renovascular; Male; Middle Aged; Thromboxane B2

The effects of a calcium antagonist nifedipine (Adalat) on platelet aggregation was examined in vitro and in vivo. In vitro examination: Platelet aggregation induced by adenosine disphosphate (ADP), epinephrine, collagen, arachidonate, and thrombin was all inhibited dose-dependently in the platelet-rich plasma prepared from the blood of healthy individuals by the addition of nifedipine to a final concentration of 5 or 10 micrograms/ml. In vivo examination: 20 patients with essential hypertension were treated with 30 mg/d of nifedipine for 8 weeks. Significant decreases in both systolic and diastolic pressures were observed 2 weeks after the beginning of the administration, and continued throughout the administration period. ADP-induced platelet aggregation decreased by 25% after 2 weeks, 36% after 4 weeks, and 44% after 8 weeks (p less than 0.05 for all decreases). Plasma thromboxane B2 level also decreased markedly from 217.3 +/- 91.7 pg/ml before the administration to 119.0 +/- 29.7 pg/ml (p less than 0.01) 2 weeks after, and 99.1 +/- 25.4 pg/ml (p less than 0.01) 8 weeks after the beginning of the administration, suggesting suppressed thromboxane A2 production.

Topics: Adenosine Diphosphate; Aged; Blood Pressure; Creatine Kinase; Humans; Hypertension; L-Lactate Dehydrogenase; Middle Aged; Nifedipine; Platelet Aggregation; Thromboxane B2

Fourteen male patients with mild essential hypertension were put on a mackerel and herring diet within a prescribed isocaloric regimen in a cross-over design for 2 weeks. After mackerel diet eicosapentaenoic acid (EPA-C20:5, n-3) appeared more in cholesterol esters (1.7-11.0%), whereas docosahexaenoic acid (DHA-C22:6, n-3) was predominantly incorporated into serum triglycerides (1.0-8.3%). After herring diet, which contained half as much EPA and DHA, their increase was of minor degree. After mackerel diet serum triglycerides, total cholesterol, LDL cholesterol and lecithin cholesterol acyl transferase (LCAT) activity were significantly decreased (by 28%, 9%, 14% and 14%, respectively), returning to the initial levels 3 months later. On the contrary, HDL cholesterol appeared significantly increased (by 12%). After herring diet the differences were not significant. Serum sodium was significantly lower (by 2%) at the end of the mackerel diet as compared to the initial values. On the other hand, uric acid in serum appeared transiently increased (by 24%) at the end of both dietary periods. A significant decrease (by 8%) in casual systolic blood pressure, measured in recumbent position, could be observed only at the end of the mackerel period. Moreover, the level of systolic and diastolic blood pressure before and during a standardized psychophysiological stress test was significantly lower after mackerel diet. Nevertheless, the increments after stress were similar. Plasma renin activity was increased (by 64%) after mackerel diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Animals; Blood Pressure; Cholesterol; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Fishes; Humans; Hypertension; Lipids; Lipoproteins; Male; Norepinephrine; Phospholipids; Renin; Thromboxane B2; Triglycerides; Uric Acid

In summary, prostacyclin, PGE2, and PGD2 are vasodilators and had significantly lower renal cortical and outer medullary concentrations in the borderline hypertensive S rats compared to normotensive R rats. Conversely, thromboxane is a vasoconstrictor which had significantly higher renal cortical and outer medullary concentrations in borderline hypertensive S rats compared to normotensive R rats. Thus, in borderline hypertensive S rats, both renal cortex and outer medulla have a prostaglandin pattern which favors vasoconstriction in cortical vessels and in descending vasa recta. This could partially account for the increased renal vascular resistance and low papillary plasma flows which are integral components of Dahl hypertension. The low PGE2 in S kidneys would also enhance Na reabsorption in collecting tubules and ascending limbs, thereby encouraging Na retention and hypertension.

Topics: Animals; Arterioles; Hypertension; Prostaglandins; Rats; Rats, Inbred Strains; Species Specificity; Thromboxane B2

The effects of orally administered glandular kallikrein on urinary kallikrein, aldosterone and prostaglandin E (PGE) excretion, plasma renin activity (PRA), immunoreactive 6-keto PGF1 alpha and thromboxane B2 concentrations and platelet aggregation were studied in 12 patients with essential hypertension (EH). After a 2-week control period, each patient was given orally 450 KU/day of hog glandular kallikrein for 8 weeks. Urinary kallikrein, aldosterone and PGE excretion, and plasma 6-keto PGF1 alpha and thromboxane B2 concentrations were measured by radioimmunoassay. Platelet aggregation was measured by the addition of ADP, collagen or ristocetin with an aggregometer. Urinary kallikrein excretion and plasma 6-keto PGF1 alpha concentration were significantly decreased in patients with EH. There were no significant differences in PRA, urinary aldosterone excretion and plasma thromboxane B2 concentrations between control subjects and patients with EH. There was a significant decrease in blood pressure in patients with EH coinciding with significant increases of urinary kallikrein and PGE excretion and plasma immunoreactive 6-keto PGF1 alpha concentration after administration of glandular kallikrein. There was also a significant inhibition of platelet aggregation induced by collagen in these patients. Thus, a suppression of the kallikrein-kinin-prostaglandin system in patients with EH was found, and a decrease in blood pressure with an increment of urinary kallikrein, PGE excretion, plasma immunoreactive 6-keto PGF1 alpha and inhibition of platelet aggregation in vivo by the administration of glandular kallikrein.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Blood Pressure; Female; Humans; Hypertension; Kallikreins; Male; Platelet Aggregation; Prostaglandins; Prostaglandins E; Renin; Thromboxane B2

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1 alpha) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1 alpha, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikrein-kinin systems.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atenolol; Blood Pressure; Dinoprostone; Drug Interactions; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension; Indomethacin; Kallikreins; Kininogens; Male; Middle Aged; Prostaglandins; Prostaglandins E; Radioimmunoassay; Renin; Renin-Angiotensin System; Thromboxane B2

This study was designed to examine the effect of dexamethasone treatment on tissue and urinary prostanoids, and to determine whether inhibition of prostaglandin biosynthesis by manipulation of dietary fatty acids accelerates the development of glucocorticoid hypertension. Forty-eight rats were placed on either a 2-series prostaglandin 'inhibitory' diet (cod liver oil/linseed oil) or a control diet of saturated fat for an initial period of 4 weeks. The groups were then divided into two so that half of each received dexamethasone in their drinking water (2.5 mg/l) for 1 week whilst continuing their respective dietary regimens. Rats on the cod liver oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid, and significantly impaired ability to generate serum thromboxane B2 (33%), aortic 6-oxo-prostaglandin F1 alpha (44%), renal homogenate prostaglandin E2 (45%) and 6-oxo-prostaglandin F1 alpha (74%) and urinary prostaglandin E2 (84%) and 6-oxo-prostaglandin F1 alpha (79%). Despite the diminished levels of vasodilator 2-series prostaglandins, the cod liver oil diet prevented the development of glucocorticoid induced hypertension. Relative to their respective dietary controls, dexamethasone treatment resulted in decreased serum thromboxane B2 (20%) but increased aortic 6-oxo-prostaglandin F1 alpha (186%), renal homogenate prostaglandins (127-230%) and urinary excretion of prostaglandin E2 (640-860%) and 6-oxo-prostaglandin F1 alpha (230-365%) in both dietary groups. It therefore seems unlikely that glucocorticoid induced hypertension is a consequence of inhibition of vasodilator prostaglandin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arachidonic Acids; Body Weight; Dexamethasone; Dietary Fats; Dinoprostone; Fatty Acids; Fish Oils; Hypertension; Kidney; Male; Phospholipids; Prostaglandin Antagonists; Prostaglandins E; Rats; Rats, Inbred Strains; Renin; Thromboxane B2

To determine the influence of captopril on prostaglandins, the levels of plasma 6-keto-PGF1 alpha and thromboxane B2, the stable products of prostacyclin and thromboxane A2, respectively, were measured in 9 essential hypertensive subjects by radioimmunoassay before, 1 hour after a single oral 25 mg dose of captopril, and 2 weeks after administration of oral 25 mg captopril twice daily. A significant increase in plasma 6-keto-PGF1 alpha levels occurred after 2 weeks (p less than 0.05), but after 1 hour the increment was not significant. Plasma thromboxane B2 remained unchanged. Mean blood pressure fell significantly (p less than 0.02 after 1 hour, p less than 0.005 after 2 weeks) and plasma renin activity increased significantly after both periods (p less than 0.01 after 1 hour, p less than 0.02 after 2 weeks). There was no significant correlation between changes in blood pressure and 6-keto-PGF1 alpha for either time period. These results suggest that the elevation of plasma 6-keto-PGF1 alpha by captopril therapy was not responsible for reducing blood pressure, while enhanced plasma prostacyclin as a chronic response may contribute to prevention of thrombotic disorders and organ damage.

Topics: Blood Pressure; Blood Urea Nitrogen; Captopril; Creatinine; Electrolytes; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prostaglandins F; Renin; Thromboxane B2

The effects of two angiotensin I converting enzyme inhibitors on the kallikrein-kinin system and prostanoids were studied in spontaneously hypertensive rats. The doses of captopril were 20, 50 and 100 mg/kg X day given twice daily, and those of CI-906 20 and 40 mg/kg once daily. Both drugs were equally effective in reducing the systolic blood pressure. Captopril increased urine volume dose-dependently (up to 3-fold with the largest dose). Only the larger dose of CI-906 was slightly diuretic. Captopril decreased the 24-h urinary excretion of kallikrein, while the excretion of the prostacyclin metabolite 6-keto-PGF1 alpha was increased markedly and that of T X B2 to a lesser extent. CI-906 had no effect on the 24-h urinary excretion of kallikrein, 6-keto-PGF1 alpha and T X B2. Both drugs tended to reduce PGE2 excretion. Captopril and CI-906 did not alter plasma kininogen levels. The marked renal effects of captopril may be caused by a strong local inhibition of converting enzyme in the kidneys. Captopril is mainly excreted unchanged in urine, and it is secreted actively by the proximal tubular cells. CI-906 is eliminated predominantly by biliary excretion. It is also possible that direct stimulation of prostacyclin formation by captopril may be involved in the diuretic action of the drug. However, as it was shown with CI-906, the increase in urine flow and the associated changes in urinary kallikrein and prostanoids are not necessary for the antihypertensive effect caused by the inhibition of converting enzyme.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Dinoprostone; Diuresis; Hypertension; Isoquinolines; Kallikreins; Proline; Prostaglandins; Prostaglandins E; Quinapril; Rats; Tetrahydroisoquinolines; Thromboxane B2

Indomethacin and sulindac were used as tools to study the role of renal and/or systemic prostaglandins in the pharmacological response to atenolol. Patients receiving chronic treatment with atenolol 100 mg received indomethacin 50 mg twice daily or sulindac 200 mg twice daily in a randomised crossover trial. Indomethacin significantly reduced the antihypertensive action of atenolol while sulindac had no effect. The role that systemic and/or renal prostaglandins may play in the antihypertensive action of atenolol is discussed with reference to renal PGI2 production and inhibition of platelet cyclo-oxygenase.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atenolol; Blood Pressure; Body Weight; Drug Interactions; Female; Humans; Hypertension; Indenes; Indomethacin; Male; Middle Aged; Random Allocation; Renin; Sulindac; Thromboxane B2

Plasma concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2), the stable nonenzymatic metabolites of prostacyclin and TXA2, respectively, were assayed in 26 patients with essential hypertension and 25 normotensive subjects to investigate the pathophysiological role of prostacyclin and thromboxane A2 (TXA2) in essential hypertension. A tourniquet test was also performed on the upper limb of each subject to study the reactivity in peripheral vessels. In addition, platelet aggregation was investigated. There were significantly increased plasma TXB2 concentrations and platelet aggregation and significantly decreased plasma 6-keto-PGF1 alpha concentrations in patients with essential hypertension as compared with normotensive subjects. The responses to tourniquet tests were also different. There were significantly increased plasma concentrations of 6-keto-PGF1 alpha and TXB2 and platelet aggregation in normotensive subjects, but no significant changes with essential hypertension as compared to resting values. These results indicate that the reduction of plasma prostacyclin and increase of plasma TXA2 may contribute to the maintenance of blood pressure elevation in patients with essential hypertension. In addition, it is also suggested that increased prostacyclin generation in normotensive subjects during the tourniquet test is a protective mechanism. In patients with essential hypertension, the protective activity is reduced.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Humans; Hypertension; Middle Aged; Platelet Aggregation; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Female; Humans; Hypertension; Male; Reference Values; Thromboxane B2; Thromboxanes

Topics: Adult; Blood Pressure; Glomerular Filtration Rate; Humans; Hypertension; Reference Values; Thromboxane B2; Thromboxanes

In 12 patients with arterial hypertension (stages I and II according to WHO), adrenergic stimulation was induced by the immersion of a hand in ice water for 2 min. Blood samples were withdrawn before, at the end of, and 15 min after the cold application: the experiment was repeated 2 h after the ingestion of 200 mg acebutolol, a selective betablocking agent. The following assays were performed: serum nonesterified fatty acid (NEFA), plasma beta-thromboglobulin (BTG) and PF4 with specific radioimmunoassays; thromboxane B2 (TXB2) in plasma was also estimated with radioimmunoassay, platelet sensitivity to exogenous prostacyclin; furthermore, the thrombin-induced thromboxane production before and after acebutolol ingestion as well as serum TXB2-levels were measured. The blood pressure and the heart rate were also monitored. After cold stimulation, a significant increase of NEFA, BTG, and plasma TXB2 was observed, which was still discernible 15 min after the application of cold. After acebutolol, the cold treatment led to a lower increase of blood pressure with a reduction of the heart rate, as well as to a diminished release of BTG, PF4 and TXB2 no changes in the reduced platelet sensitivity to prostacyclin were noticed.

Topics: Acebutolol; Adult; Blood Pressure; Cold Temperature; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

An experimental radioisotopic study in normotensive male Wistar rats and spontaneously-hypertensive rats (SHR) of Okamoto--Aoki line demonstrated an age-related increase in the biosynthesis of prostacycline (PGI2) from 14C-arachidonic acid by pulmonary and aortal tissues of animals with normal arterial pressure. In SHRs, PGI2 production by lung homogenates did not change essentially with age, but decreased considerably in adult SHRs with stable hypertension. PGI2 biosynthesis by SHR's aortal tissue decreased with age and dropped significantly as arterial hypertension developed. In normotensive rats, the formation of thromboxane B2 (TxB2) by platelets increased with age. Platelet TxB2 biosynthesis was elevated considerably both in young and adult SHRs. Clinically, a significant increase of platelet TxB2 production from exogenous 14C-arachidonic acid was demonstrated in children with essential hypertension.

Topics: Adolescent; Age Factors; Animals; Aorta; Blood Platelets; Child; Epoprostenol; Humans; Hypertension; Lung; Male; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes

Thromboxane B2 (TxB2) was measured in the venous and arterial plasma and in the urine of 15 borderline and 15 sustained essential hypertensive patients, and in the plasma and urine of 12 control normotensive age-matched subjects. Plasma and urine thromboxane B2 were significantly higher in both the borderline and sustained hypertensives than in the control normotensives. There was a significant positive correlation between urinary (i.e. renal)TxB2 excretion and the glomerular filtration rate, and between urinary TxB2 excretion and sodium excretion in the hypertensive but not in the normotensive subjects. Thromboxane A2 participates in pressure natriuresis.

Topics: Adolescent; Adult; Aged; Blood Pressure; Glomerular Filtration Rate; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Thromboxane B2; Thromboxanes

Thromboxane A2 (TxA2) is a vasoconstrictor synthetized by the kidney. Its role in hypertension is unknown. We measured urinary TxB2 (the metabolite of renal TxA2) by radioimmunoassay and studied renal functions in 15 borderline, 15 sustained essential hypertensive patients and 12 age-matched normotensive subjects (6 young and 6 older adults). Results were as follows: Normotensive subjects: Mean arterial blood pressure (MBP) 97 +/- 2 mmHg, urinary TxB2 (UTxB2V) 159 +/- 12 pg/min, glomerular filtration rate (GFR) 120 +/- 8 ml/min, sodium excretion (UNaV) 73 +/- 9 mueq/min. Hypertensive patients: MBP 115 +/- 2 mmHg (p less than 0,001 vs controls), UTxB2V 298 +/- 24 pg/min (p less than 0,005), GFR 128 +/- 6 ml/min, UNaV 51 +/- 4 mueq/min (p less than 0.02). There was a positive significant correlation between UTxB2V and GFR (p less than 0,005) and between UTxB2V and UNaV (p less than 0,005) in hypertensive but not in normotensive subjects. There was no correlation between GFR and UNaV in either group.. 1. Urinary (i.e. renal) TxB2 is significantly elevated in hypertensive patients; 2. TxA2 may be a mediator of pressure natriuresis.

Topics: Adolescent; Adult; Aged; Blood Pressure; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuresis; Thromboxane A2; Thromboxane B2; Thromboxanes

The concentrations of 13,14-dihydro-15-oxo-prostaglandin F2 alpha (PGFM), 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (T X B2) were measured by radioimmunoassay in peripheral plasma from 183 pregnancy women attending routine antenatal clinics. A total of 141 patients (47 nulliparous, 94 parous) remained normotensive and had uncomplicated pregnancies. The results from this group showed that there was no significant difference in the concentration of any metabolite in relation to parity or gestational age. The concentrations (pmol/l; means +/- SD) were PGFM 373 +/- 105, 6-oxo-PGF1 alpha 391 +/- 104 and T X B2 373 +/- 121. Nineteen patients (12 nulliparous, 7 parous) who had pregnancy-induced hypertension (PIH) by the time of sampling (three) or who subsequently developed the symptom (mean time from sampling to diagnosis 11 weeks, range 1-24 weeks) had significantly higher levels of 6-oxo-PGF1 alpha (574 +/- 216; P less than 0.0005, Student's t-test) and T X B2 (603 +/- 268; P less than 0.0005). The concentrations in seven nulliparous patients with PIH and proteinuria were 656 +/- 276 for 6-oxo-PGF1 alpha and 754 +/- 228 pmol/l for T X B2.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Female; Humans; Hypertension; Parity; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins F; Radioimmunoassay; Thromboxane B2; Thromboxanes

The compound 4'-(imidazol-1-yl) acetophenone was demonstrated to be a selective thromboxane (Tx) synthetase inhibitor in spontaneously hypertensive rats (SHR). Serum TxB2 concentrations (from clotted blood) were suppressed by 89.1% (p less than 0.001) and 41.2% (p less than 0.01) at 3 and 24 hours, respectively, following a single subcutaneous injection of 100 mg/kg of 4'-(Imidazol-1-yl) acetophenone suspended in olive oil. In contrast, plasma 6-keto-PGF1 alpha levels were not significantly altered at 3 hours following injection - a time when suppression of TXB2 was maximal. From 4 to 10 weeks of age, SHR were treated with daily injections of either 4'-(Imidazol-1-yl) acetophenone (100 mg/kg) in olive oil or olive oil alone. By 8 weeks of age systolic blood pressures in the treated group were 140.6 +/- 3.2 vs 156.6 +/- 4.5 mmHg in the control group (p less than 0.01). At ten weeks of age the separation was even more pronounced: 155.3 +/- 3.7 vs. 184.8 +/- 4.6 mmHg for treated vs. control animals (p less than 0.001). This data supports the hypothesis that thromboxanes may be involved in the development of SHR hypertension; however, alternative mechanisms are discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Disease Models, Animal; Hypertension; Imidazoles; Kinetics; Rats; Thromboxane B2; Thromboxanes

Topics: Animals; Aorta, Thoracic; Hypertension; Male; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes

Topics: Adolescent; Adult; Aged; Arteries; Aspirin; Cerebrovascular Disorders; Female; Humans; Hypertension; Jugular Veins; Male; Middle Aged; Thromboxane B2; Thromboxanes; Veins

A basic study was conducted on the method for the determination of thiobarbituric acid-reactive substances (TBARS) produced by platelets. Some modifications were introduced which enabled a precise semimicrodetermination. The average values of platelet TBARS production in hypertensives and in patients with cerebral infarction were higher than that in healthy controls. Among patients with cerebral infarction, those with angiographically demonstrated obstruction of internal carotid or middle cerebral arteries showed an increased production as compared with non-obstructive cases, these results may suggest the important role of platelet arachidonate metabolism in obstructive cerebrovascular disorders.

Topics: Aged; Arachidonic Acids; Blood Platelets; Cerebrovascular Disorders; Female; Humans; Hypertension; Lipids; Male; Malonates; Malondialdehyde; Middle Aged; Thromboxane B2

The aggregability of platelets to arachidonic acid (AA) was investigated in 26 control subjects, 40 patients with essential hypertension, 20 patients with ischemic cerebrovascular diseases (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The aggregability of platelets was evaluated on the basis of threshold concentrations of AA to induce irreversible platelet aggregation. The enhanced sensitivity of platelets to AA was observed more frequently in hypertensives and/or CVD patients not taking aspirin than in the controls. The relationship between platelet aggregation induced by AA and thromboxane B2 (TXB2) formation from AA or prostaglandin H2 (PGH2) in platelets was also studied in the subjects taking or not taking aspirin. It was proposed that the assessment of platelet aggregability with AA could provide a tool for identifying a subgroup of patients who might substantially benefit from the secondary preventive treatment with aspirin or other anti-platelet drugs. The clinical usefulness of this aggregation test for the management of the patients taking aspirin was also discussed.

Topics: Adolescent; Adult; Aged; Arachidonic Acids; Aspirin; Blood Platelets; Brain Ischemia; Female; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Prostaglandins H; Thromboxane B2; Thromboxanes

Endogenous biosynthetic capacities for prostaglandin (PG)E2, thromboxane (TX)B2 (a stable degradation product of TXA2) and 6 keto-PGF1 alpha (a stable degradation product of PGI2) in the brain-stem fractions of stroke-resistant spontaneously hypertensive rats (SHRSR) and control Wistar-Kyoto rats (WKR) were determined with novel methods and presented in an original report. In comparison with WKR, it is characteristically found that TXB2 synthesis is increased in excess of threefold in the pons-medulla oblongata of SHRSR, while being decreased by 75% in the hypothalamic region of SHRSR (0.01 less than p less than 0.05). On the other hand, the biosynthesis of PGE2 is adaptively elevated in both hypothalamus and pons-medulla oblongata regions of each animal, although the PGI2/PGE2 ratio was lowered in both these regions of SHRSR.

Topics: Animals; Brain Stem; Cerebrovascular Disorders; Hypertension; Male; Prostaglandins E; Prostaglandins F; Rats; Thromboxane B2; Thromboxanes

The ability of platelets to synthesize thromboxane B2 (TxB2) from arachidonic acid (AA) or prostaglandin H2 (PGH2) was studied in 26 control subjects, 40 patients with essential hypertension, 20 patients with cerebrovascular disease (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The activity of platelets to form TxB2 from AA or PGH2 was measured using 1-14C arachidonic acid or 1-14C PGH2 as a substrate. There was no significant difference in TxB2 generation from AA or PGH2 among the platelets collected from the control subjects, hypertensive patients and CVD patients not taking aspirin. In CVD patients taking aspirin, marked suppression was observed in TxB2 synthesis from AA, but no suppression in TxB2 synthesis from PGH2. At least 750 mg aspirin per day were required for nearly complete suppression of TxB2 generation from AA.

Topics: Adolescent; Adult; Aged; Arachidonic Acids; Aspirin; Blood Platelets; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Middle Aged; Prostaglandins H; Thromboxane B2; Thromboxanes