thromboxane-a2 and Hypertension

Since the discovery of the pivotal role of cyclooxygenase (COX) in the metabolism of arachidonic acid, vascular biologists have been confronted with the duality of this system. Indeed, one substrate (arachidonic acid) transformed by one enzyme (COX) yields end products (endoperoxides) that exist only very briefly before being metabolized to more stable prostanoids by a set of specific downstream synthases that were initially believed to be tissue specific. For instance, platelets contain mainly the synthase that produces thromboxane A(2) (a potent proaggregatory and vasoconstrictor substance), whereas endothelial cells contain mainly the enzyme that generates prostacyclin (an equally potent antiaggregatory and vasodilator substance). The overproduction of thromboxane A(2) by platelets leads to thrombosis; endothelial cells resist vascular occlusion by producing prostacyclin. This duality of the metabolism of arachidonic acid has dominated our thinking about atherothrombosis for decades, and rightfully still does. As scientific understanding progressed, it became evident that two isoforms of COX exist: COX-1 and COX-2. COX-1 was initially considered to be the "good," constitutive isoform, whereas COX-2 appeared to be mainly a "bad" inducible enzyme involved in inflammatory responses. However, more recently, the unexpected events resulting from the widespread use of selective COX-2 inhibitors has suggested that, from a cardiovascular point of view, the products of COX-2 exert a protective role and that this isoform cannot necessarily be regarded as "bad." Likewise, evidence has emerged that initiation of the metabolism of arachidonic acid by COX-1 is not necessarily a "good" thing in terms of vascular protection. This brief review focuses on the potential contribution of endothelial COX-1 to vascular dysfunction. It is based on a number of review articles, to which the reader will be referred in order to identify the original references to the statements made; these references are not cited here because of space limitations.

Topics: Aging; Animals; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Mellitus; Endothelium, Vascular; Humans; Hypertension; Nitric Oxide Synthase; Platelet Aggregation Inhibitors; Prostaglandins; Thrombosis; Thromboxane A2; Vasoconstriction; Vasodilation

Topics: Animals; Arachidonic Acid; Blood Pressure; Cytochrome P-450 Enzyme System; Epoprostenol; Humans; Hypertension; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

Topics: Angiotensin II Type 1 Receptor Blockers; Cardiovascular Diseases; Humans; Hypertension; Platelet Aggregation Inhibitors; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Topics: Arrhythmias, Cardiac; Arteriosclerosis; Biomarkers; Cholesterol, VLDL; Coronary Restenosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hyperlipidemias; Hypertension; Liver; Reference Values; Thrombosis; Thromboxane A2

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Growth Hormone; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Models, Molecular; Receptor, Angiotensin, Type 1; Tetrazoles; Thiophenes; Thromboxane A2

This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2 receptor antagonist. Thromboxane A2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2 levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2- and prostaglandin H2-mediated processes.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypertension; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Ischemia; Oxazoles; Platelet Aggregation Inhibitors; Prostaglandin H2; Prostaglandins H; Randomized Controlled Trials as Topic; Receptors, Prostaglandin; Receptors, Thromboxane; Stroke; Thrombosis; Thromboxane A2

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Topics: Animals; Asthma; Bicarbonates; Colonic Neoplasms; Dinoprost; Dinoprostone; Female; Fever; Hypertension; Inflammation; Labor, Obstetric; Mice; Mice, Knockout; Pregnancy; Prostaglandins; Receptors, Prostaglandin; Reproduction; Thrombosis; Thromboxane A2

Topics: Animals; Arteriosclerosis; Blood Pressure; Blood Vessels; Cardiovascular Physiological Phenomena; Cardiovascular System; Epoprostenol; Fatty Acids, Omega-3; Female; Humans; Hypertension; Male; Thromboxane A2

Our understanding of the pathophysiology underlying the hypertensive diseases of pregnancy has clearly progressed during the past ten years. The key phenomenon is an early defect of placentation occurring at the end of the first trimester and associated with a more widespread endothelial disorder. This results in early activation of the coagulation cascade and imbalance between prostacyclin and thromboxanes. Hypertension and proteinuria only occur after several weeks or months of placental dysfunction. This explains why antihypertensive treatments are ineffective in improving the prognosis of such pregnancies. In contrast, early preventive treatments, such as antiplatelet therapy, seem to be very promising for these patients. In this respect, early prediction of the risk associated with pregnancy has become a key goal.

Topics: Adult; Antihypertensive Agents; Aspirin; Epoprostenol; Female; Hemostasis; Humans; Hypertension; Kidney Diseases; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

Topics: Aspirin; Eicosanoids; Epoprostenol; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

The origin of pre-eclampsia lies in uteroplacental ischemia due to an anomaly of the "vascular insertion" of the placenta. Although the cause of this anomaly remains unknown, it would appear to include both a genetic and an immunological origin possibly favourised by special underlying conditions and certain obstetric circumstances. Prostaglandin imbalance (in particular prostacyclins and Thromboxane A2) appears to be one of the chief factors governing these anomalies. One of the consequences of these mechanisms is the onset of hypertension but other disturbances are essential features. In particular, disseminated intravascular coagulation may occur leading to the release of numerous microthrombi which cause placental (leading to chronic fetal distress), renal, hepatic and cerebral lesions.

Topics: Disseminated Intravascular Coagulation; Epoprostenol; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2; Ultrasonography

Prostacyclin and thromboxane A2, products of separate branches of the arachidonic acid cascade, can have opposing effects on kidney function and on the vascular musculature. Prostacyclin acts as a vasodilator while thromboxane A2 has a vasoconstrictor effect and the balance between these two compounds appears to contribute to the homeostatic regulation of normal blood pressure. In the hypertensive state, this balance is disrupted and, at least in animal models of hypertension, there is excessive production of both. The increase in prostacyclin formation may be a reaction to the elevated blood pressure, possibly due to mechanical stimulation of the vascular smooth muscle cells in the blood vessel wall. However, the increase in thromboxane A2 may be more directly involved in the development and maintenance of hypertension. Not only is thromboxane A2 a vasoconstrictor but it can also stimulate the growth and proliferation of vascular smooth muscle cells which may account for the vascular hypertrophy seen in hypertension. Both of these actions would increase total peripheral resistance and contribute to hypertension. Whether prostacyclin and thromboxane A2 are in fact involved as causative agents in essential hypertension must await future research.

Topics: Animals; Epoprostenol; Humans; Hypertension; Thromboxane A2; Vasomotor System

The aetiology of pregnancy-induced hypertension (PIH) is at present unknown. Epidemiological data lead us to assume, that two main mechanisms could be responsible for the development of PIH. They are not well understood in their complexity, but result in the same pattern of signs and symptoms: Oedema, proteinuria and hypertension. 1. "Goldblatt-Phenomenon" in the uterus, as a result of a disturbed maternal immune response to the cytotrophoblast, followed by the reduction of uterine blood flow and the liberation of vasoactive substances from the placenta. 2. Renal factors, especially in elderly women, result in a manifestation of nephrotic diseases during pregnancy. No screening methods are at the present time available to diagnose PIH in advance. It is therefore necessary, to look at typical clinical manifestations, i.e. the development of hypertension. It is also important to estimate the weight gain and the occurrence of oedema before rising blood pressure demonstrates a general vasoconstriction in the maternal vascular system. The basic therapeutical concept is to reduce the peripheral vascular resistance, to prevent maternal complications and to reduce the uterine vascular resistance to improve foetal oxygenation. In many cases an improvement of the oxygen supply to the foetus is not possible, since irreversible alterations of the uterine arterial vascular bed have already taken place. For the treatment of PIH, different drugs are available which act on different targets. In cases of special medical history, the early application of magnesium and acetyl salicylic acid (ASA) should be included in the therapeutical concept of prophylaxis.

Topics: Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension; Infant, Newborn; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin-Angiotensin System; Thromboxane A2; Uterus; Vascular Resistance

Because of their vasodilator and vasoconstrictor properties, vasoactive prostaglandins and thromboxane A2 have been proposed as modulators of the hemodynamic changes that occur in experimental models of renal disease. Increased synthesis of vasodilatory prostaglandins (PGE2) and perhaps prostaglandin I2 (PGI2) play a role in the maintenance of renal blood flow and GFR during states of impaired perfusion. In contrast, thromboxane A2 has been implicated as the vasoconstrictor responsible for the reduction of renal blood flow and GFR in certain animal models of experimental renal disease. These products and other metabolites of arachidonic acid may also participate in the immunological events underlying the onset and/or progression of experimental renal disease. It is evident that the pathophysiologic role of eicosanoids in experimental renal disease is not fully understood. Additional studies and further understanding of the many other potential roles of eicosanoids on immunological events, hemodynamic states, mesangial cell physiology, etc. are needed to comprehend more fully the extent of the participation of eicosanoids in the pathogenesis and pathophysiology of renal disease.

Topics: Animals; Dietary Fats; Eicosanoids; Glomerulonephritis; Hypertension; Kidney Diseases; Nephritis; Prostaglandins; Rabbits; Rats; Thromboxane A2; Ureteral Obstruction

Platelets contain three types of secretory organelles: the dense granules, the alpha granules, and the lysosomes. Most of the proteins secreted from platelets are stored in the alpha granules, whereas the dense granules contain substances such as adenine nucleotides, serotonin, Ca++, and inorganic pyrophosphate types as well as a heparatinase. Three of the secreted alpha granule proteins have been measured by radioimmunoassay and it has been suggested that levels of these proteins in patient plasmas provide an index of in vivo platelet activation and secretion. These three are beta-thromboglobulin, platelet factor 4, and thrombospondin. In this chapter the chemistry of these proteins will be considered briefly, as will their clearance from the circulation, and then the clinical studies will be reviewed critically. Since radioimmunoassays were developed for these proteins (the first was reported in 1975), there has been a profusion of reports on levels of one or another of these proteins in a wide range of disease states, and these reports have indicated secreted platelet protein levels ranging from normal to grossly elevated in a given disease state. Possible reasons for such variability will be discussed.

Topics: Angina, Unstable; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Catecholamines; Catheterization; Cerebrovascular Disorders; Coronary Disease; Coronary Vessels; Cytoplasmic Granules; Exercise Test; Female; Humans; Hyperlipidemias; Hypertension; Kidney Diseases; Myocardial Infarction; Platelet Factor 4; Pregnancy; Renal Dialysis; Thromboxane A2

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

Topics: Animals; Antihypertensive Agents; Arachidonic Acid; Arachidonic Acids; Dogs; Fatty Acids, Essential; Female; Humans; Hypertension; Kallikreins; Kidney; Male; Prostaglandins; Rabbits; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Renal Artery; Renal Circulation; Renin-Angiotensin System; Thromboxane A2

1. The lack of a general agreement on the definition of PE makes the interpretation of laboratory findings in different series of these patients difficult. 2. Thrombocytopenia is the most common hemostatic abnormality in patients with PE and is caused by platelet consumption. 3. There is little concrete evidence that thrombin mediates the thrombocytopenia in most of these patients. 4. Immune mechanisms or severe vasospasm with resultant endothelial damage may contribute to the thrombocytopenia in some patients.

Topics: Anemia, Hemolytic; Disseminated Intravascular Coagulation; Eclampsia; Epoprostenol; Factor VIII; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Hypertension; Platelet Count; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Thrombin; Thrombocytopenia; Thromboxane A2

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Pressure; Cardiovascular Physiological Phenomena; Coronary Circulation; Epoprostenol; Humans; Hypertension; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Thromboembolism; Thromboxane A2; Thromboxanes; Vascular Resistance

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

Topics: Animals; Epoprostenol; Heart; Humans; Hypertension; Prostaglandins; Rabbits; Rats; Sympathetic Nervous System; Synaptic Transmission; Thromboxane A2

It has been thought that blood vessels apart from the umbilical artery produce little or no thromboxane (TX) A2. However selective inhibitors of TXA2 biosynthesis have substantial effects on vessel physiology, suggesting that small amounts of TXA2 may be important in regulating function. This indirect evidence is now supported by direct measurements of TXB2 (the produce of TXA2 conversion) using both gas chromatography-mass spectrometry (GCMS) and radioimmunoassays. At least four independent laboratories have now demonstrated TXB2 production by various blood vessels. These studies suggest that vessel wall TXA2 is present in amounts more than adequate to exert biological actions on both vascular reactivity and on platelets. This may require re-evaluation and revision of present concepts of hypertension and thrombosis.

Topics: Animals; Blood Vessels; Humans; Hypertension; Thrombosis; Thromboxane A2; Thromboxanes

Topics: Aldosterone; Angiotensin II; Anti-Inflammatory Agents; Arachidonic Acids; Bartter Syndrome; Bradykinin; Dopamine; Edema; Humans; Hyperaldosteronism; Hypertension; Hypotension, Orthostatic; Kallikreins; Kidney; Kinins; Myocardial Infarction; Natriuresis; Prostaglandins; Receptors, Dopamine; Renin; Thromboxane A2; Vasodilation

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Platelets; Carotid Artery Thrombosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Membrane Proteins; Mice; Mice, Knockout; Platelet Activation; Platelet Aggregation Inhibitors; Prostaglandin D2; Receptors, G-Protein-Coupled; Receptors, Immunologic; Receptors, LDL; Receptors, Nicotinic; Receptors, Prostaglandin; Thromboxane A2

Acute vigorous exercise, associated with increased release of plasma catecholamines, transiently increases the risk of primary cardiac arrest. We tested the effect of acute submaximal exercise on vasoactive substances and their combined result on platelet function.. Healthy volunteers, hypertensive patients and patients with coronary artery disease (CAD) performed a modified treadmill exercise test. We determined plasma catecholamines, thromboxane A2, prostacyclin, endothelin-1 and platelet aggregation induced by adenosine diphosphate (ADP) and collagen at rest and during exercise.. Our results during exercise showed a) platelet activation (increased thromboxane B2, TXB2), b) increased prostacyclin release from endothelium and c) decreased platelet aggregation in all groups, significantly more in healthy volunteers than in patients with CAD (with hypertensives lying in between these two groups).. Despite the pronounced activation of Sympathetic Nervous System (SNS) and increased TXB2 levels during acute exercise platelet aggregation decreases, possibly to counterbalance the prothrombotic state. Since this effect seems to be mediated by the normal endothelium (through prostacyclin and nitric oxide), in conditions characterized by endothelial dysfunction (hypertension, CAD) reduced platelet aggregation is attenuated, thus posing such patients in increased risk for thrombotic complications.

Topics: Adult; Catecholamines; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epoprostenol; Exercise; Female; Humans; Hypertension; Male; Platelet Activation; Platelet Aggregation; Thromboxane A2

We evaluated whether renin-angiotensin system (RAS) blockade attenuates cardiovascular events.. Because inflammation and enhanced thrombogenesis are hallmarks of atherosclerosis, we assessed whether RAS inhibition elicits anti-inflammatory and anti-aggregatory effects.. Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), metalloprotease 9 (MMP-9), and interleukin 10 (IL-10) were determined in patients with coronary artery disease (CAD) and arterial hypertension six to eight weeks after coronary angioplasty (low-density lipoprotein serum levels <150 mg/dl). Patients were randomized double-blind to either 20 mg enalapril (ENAL, n = 27) or 300 mg irbesartan (IRB, n = 21) for 3 months. Blood samples were drawn at baseline and at three months. Thromboxane A2-induced platelet aggregation was determined turbidimetrically; urine bicyclo-prostaglandin E2 (PGE(2)) and inflammatory markers were measured by enzyme-linked immunosorbent assay technique.. Both treatment regimens enhanced serum IL-10 levels (IRB p < 0.001, ENAL p < 0.03) and reduced serum MMP-9 protein (IRB p < 0.001, ENAL p < 0.05) and MMP-9 activity (IRB p < 0.005, ENAL p < 0.05). Only IRB reduced serum IL-6 and hsCRP levels significantly compared with baseline (p < 0.01), whereas ENAL did not (hsCRP p < 0.02 IRB vs. ENAL, p < 0.01 IRB vs. ENAL). Platelet aggregation was only reduced by IRB (p < 0.001, ENAL p < 0.06, IRB vs. ENAL p < 0.001) while urine PGE(2) levels remained unchanged.. Angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) blockade reduced serum MMP-9 protein/activity to a similar extent, and only AT1 blockade reduced hsCRP, IL-6, and platelet aggregation in patients with CAD. Thus, AT1-blockade appears to exert stronger systemic anti-inflammatory and anti-aggregatory effects compared with ACE inhibition.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Biphenyl Compounds; C-Reactive Protein; Coronary Artery Disease; Dinoprostone; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Inflammation; Interleukin-10; Interleukin-6; Irbesartan; Male; Matrix Metalloproteinase 9; Middle Aged; Platelet Aggregation; Tetrazoles; Thromboxane A2

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Arachidonic Acid; Biotransformation; Cells, Cultured; Cyclooxygenase 2; Dinoprost; Drug Design; Endothelium, Vascular; Enzyme Activation; Female; Humans; Hypertension; Imidazoles; Inflammation; Intercellular Adhesion Molecule-1; Isoenzymes; Lipopolysaccharides; Losartan; Male; Membrane Proteins; Middle Aged; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Thromboxane A2; Up-Regulation; Vasoconstrictor Agents

Smoking potentiates the enhanced cardiovascular risk of hypertensive patients. Although nicotine replacement therapy is safe when used by healthy individuals to quit smoking, there is no evidence that nicotine replacement therapy is safe in hypertensive smokers. In this crossover, single-blinded, placebo-controlled study, we compared for 4 h the acute effects of transdermal nicotine on the mean arterial pressure (MAP) and heart rate (HR) of mildly hypertensive smokers treated with hydrochlorothiazide with the responses in normotensive smokers and nonsmokers monitored with Finapres and ambulatory blood pressure systems. The plasma concentrations of thromboxane B2 (TXB2, the stable breakdown product of TXA2) were also measured by ELISA to assess whether transdermal nicotine acutely affects TXA2 production. The use of 21-mg nicotine patches increased the MAP and HR in nonsmokers (from 94+/-4 mm Hg and 69+/-3 beats/min to 117+/-7 mm Hg and 83+/-3 beats/min, respectively; P < .05) as well as the MAP in normotensive smokers (from 83+/-4 to 106+/-7 mm Hg; P < .05). However, MAP and HR remained unaltered in hypertensive smokers after transdermal nicotine. Higher basal TXB2 levels were observed in hypertensive smokers compared with normotensive smokers and nonsmokers (2019+/-402 v 670+/-167 and 556+/-68 pg/mL, respectively; P < .05). Transdermal nicotine increased the TXB2 levels only in nonsmokers (P < .05). These data indicate that the use of transdermal nicotine in mildly hypertensive smokers is probably safe. Further studies involving other classes of hypertensive patients are warranted.

Topics: Administration, Cutaneous; Adult; Blood Pressure; Cross-Over Studies; Female; Heart Rate; Humans; Hypertension; Male; Nicotine; Nicotinic Agonists; Single-Blind Method; Smoking Cessation; Thromboxane A2

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

To determine the dose of acetylsalicylic acid (ASA), that inhibits the production of the vasoconstrictive, aggregatory thromboxane A2 while sparing the production of the vasodilatory antiaggregatory prostacyclin.. A controlled study comparing the effects of three doses of ASA on the production of thromboxane A2 and prostacyclin.. Seven pregnant hypertensive patients and five non-pregnant healthy women received 0.5, 1.0 and 2.0 mg/kg/day of ASA, each dose for 10-12 days, the treatment periods following each other immediately. Seven normotensive pregnant women served as controls and were given no ASA. Blood and urine samples were taken at baseline and after the treatment periods to determine serum thromboxane B2 and the urinary 2.3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxaneB2, the major stable metabolites of prostacyclin and thromboxane A2, respectively.. The urinary excretion of 11-dehydrothromboxaneB2 was significantly higher in both hypertensive (34.9+/-18.3 pg/micromol creatinine) and normotensive (39.3+/-14.4 pg/micromol creatinine) pregnant women than in non-pregnant women (14.8+/-6.4 pg/micromol creatinine). The urinary excretion of 2.3-dinor-6-ketoprostaglandinF1alpha was also higher in normotensive pregnant women (93.9+/-50.9 pg/micromol creatinine) than in non-pregnant women (18.2+/-11.3 pg/micromol creatinine). The excretion rate of 2.3-dinor-6-ketoprostaglandinF1alpha in hypertensive patients was lower than in normotensive pregnant women (44.7+/-24.2 pg/micromol creatinine). At baseline the urinary 2.3-dinor-6-ketoprostaglandin F1alpha/11-dehydrothromboxaneB2 ratio was almost the same in the hypertensive patients (1.6) and in the non-pregnant women (1.2). The ratio was 2.6 in normotensive pregnant women. In the hypertensive group, already the lowest dose of ASA inhibited urinary 11-dehydrothromboxaneB2 excretion significantly. Because none of the doses of ASA inhibited 2.3-dinor-6-ketoprostaglandinF1alpha production, the 2.3-dinor-6-ketoprostaglandinF1alpha/11-dehydrothromboxaneB2 ratio was shifted in the favor of prostacyclin at all dose levels. In the non-pregnant women, even the highest dose level of ASA failed to affect the ratio.. In the dose range of 0.5-2.0 mg/kg/day, ASA has a favorable effect on the ratio of prostacyclin to thromboxane A2 in hypertensive pregnancies.

Topics: Aspirin; Epoprostenol; Female; Humans; Hypertension; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

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

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

Platelet aggregation and thromboxane A2 generation were studied in hypertensive pregnant women using normotensive non-pregnant and pregnant controls. In hypertensive pregnancy, adrenaline- and adenosine diphosphate-induced platelet aggregation was at the non-pregnant level and lower than in normotensive pregnancy. Collagen-induced aggregation was at a lower level in hypertensive pregnancy than in both control groups. Thromboxane generation during spontaneous clotting and in platelet-rich plasma did not differ between the three groups. However, thromboxane generation was low during aggregation induced by small collagen concentrations in hypertensive pregnancy, but at higher collagen concentrations the difference between the groups disappeared. During nifedipine treatment (10 mg t.i.d.), aggregation and thromboxane production in platelet-rich plasma induced by the three stimuli remained unaltered in hypertensive pregnancy, while thromboxane synthesis during spontaneous clotting was reduced. In nifedipine-treated non-pregnant controls, only EC80 for adrenaline-induced aggregation decreased. In vitro, pharmacological concentrations of nifedipine inhibited platelet aggregation and thromboxane production. In conclusion, nifedipine reduces thromboxane generation in spontaneous clotting, without inhibiting platelet aggregation and thromboxane production in platelet-rich plasma in hypertensive pregnancy. Reduced aggregability of platelet ex vivo may reflect their continuous activation and desensitization in vivo in hypertensive pregnancy.

Topics: Adult; Antihypertensive Agents; Blood Platelets; Blood Pressure; Female; Humans; Hypertension; In Vitro Techniques; Male; Nifedipine; Platelet Aggregation; Platelet Count; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

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

1. The haemodynamic effects of calcium antagonists could depend at least in part on the activity of vasoactive prostanoids. 2. We set out to study the effect of the cyclo-oxygenase inhibitor ibuprofen, 400 mg three times daily for 3 days, by a randomised cross-over study vs placebo in 12 mild to moderate essential hypertensive patients who had been treated for 1 month with amlodipine. 3. Blood pressure, heart rate and vascular resistances in the upper limb (Doppler ultrasound) were measured. Plasma renin activity and urinary aldosterone, as well as indices of renal function, were evaluated. Urinary 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2, as well as 6-keto-PGF1 alpha and TXB2, were measured as indices of systemic and renal PGI2 and TXA2 synthesis. 4. Amlodipine normalised blood pressure and reduced upper limb vascular resistances; it did not affect urinary prostanoid excretion. Short-term combined administration of ibuprofen resulted in, by comparison with placebo, inhibition of systemic PGI2 (-80.5 ng 24 h-1, 95% CI -99.2, -61.4; P < 0.001) and TXA2 (-216.1 ng 24 h-1, 95% CI -276.5, -155.8; P < 0.001), together with an increase in systolic (+7.8 mm Hg, 95% CI +3.1, +12.3; P < 0.01) and diastolic (+3.9 mm Hg, 95% CI +1.2, +6.6; P < 0.01) blood pressure; it had no significant effect on regional vascular resistances (+4.7 mm Hg ml-1 s, 95% CI -5.6, +15.0). Effects of ibuprofen on renal prostanoid synthesis were less marked, and there was no change in indices of renal function or hydro-electrolytic balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Amlodipine; Biomarkers; Blood Pressure; Creatinine; Cross-Over Studies; Cyclooxygenase Inhibitors; Epoprostenol; Heart Rate; Hemodynamics; Humans; Hypertension; Ibuprofen; Male; Middle Aged; Outpatients; Renin; Single-Blind Method; Thromboxane A2; Ultrasonography; Vascular Resistance; Vasodilator Agents

To study the effect of daily treatment with 50 mg of aspirin (ASA) on the hypertensive pregnancy complications and on the production prostacyclin (PGI2) and thromboxane A2 (TxA2) in high risk pregnant women and their infants.. Placebo controlled prospective study.. Departments of Obstetrics and Gynaecology, University of Helsinki, University of Oulu and Central Hospital of Middle Finland, Finland.. Two hundred and eight pregnant women with pre-existing hypertension or a history of severe preeclampsia in their previous pregnancy. Prostanoids were studied in a subgroup of 18 women.. The women were randomised to receive ASA (50 mg/day, n = 103) or placebo (n = 105) from the mean of 15 weeks gestational age to delivery. The exacerbation of pre-existing hypertension or the appearance of hypertension in previously normotensive women, the appearance of proteinuria and fetal growth were the main end points, but some other clinical characteristics were also recorded. Urinary excretion of PGI2 and TxA2 metabolites by mothers and infants and their production in umbilical arteries in vitro were also studied.. Two women (one in both groups) had miscarriages, and one pregnancy was terminated for fetal anencephaly (ASA group). In addition, seven women discontinued the treatment due to urticaria (two women in ASA group), increased activity of aspartate amino transferase in serum (one woman in both groups), or increased bleeding time (one woman in ASA group, two women in placebo group), and one woman in the placebo group was lost from follow-up. Thus the end points could be assessed in 97 women taking ASA and 100 women taking placebo. ASA did not diminish the rate of the rise of blood pressure without (12 vs 14, respectively) or with proteinuria (9 vs 11), but fetal haemodynamic disturbances as assessed by Doppler equipment (1/44 vs 6/45 women studied, P = 0.05) and need for treatment in neonatal intensive care unit (10 vs 21, P = 0.04) were more rare in ASA group. ASA tended to increase the birthweight of the newborn (3348 +/- 707 g vs 3170 +/- 665 g, mean +/- SD, P = 0.07), but two perinatal deaths occurred in ASA group. ASA prolonged the bleeding time of the mother (435 s, 210-998 s (geometric mean, range) vs 349 s, 210-690 s, P = 0.02), but caused no extra blood loss during delivery, nor affected neonatal hemostasis. In a subgroup of mothers (ASA, n = 10; placebo, n = 8), ASA inhibited more than 90% of platelet TxA2-production, and caused a 65 to 80% decrease in the urinary excretion of TxA2 metabolites, but no decrease in the urinary excretion of PGI2 metabolites.. ASA did not prevent the rise of maternal hypertension, but improved fetal haemodynamic performance and reduced the need of intensive neonatal care. It inhibited strongly maternal thromboxane A2 but not PGI2 production and thus shifted the balance between PGI2/TxA2 to the dominance of the vasodilatory, anti-aggregatory side.

Topics: Adult; Aspirin; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Thromboxane A2; Time Factors

The purpose of this study was to determine if acetaminophen decreased prostacyclin production by endothelial cells in culture and by pregnant women.. The effect of acetaminophen on endothelial cells in culture was determined by the addition of acetaminophen in concentrations of 10 and 100 micrograms/ml with comparison to control and indomethacin at 10 micrograms/ml. Prostacyclin production was estimated in 24 and thromboxane A2 production in six third-trimester pregnant women by measurement of excretion of urinary metabolites before and after ingestion of either 1000 mg of acetaminophen or placebo.. Compared with control (549 +/- 61 pg/well, mean +/- SD), production of prostacyclin in vitro was significantly inhibited by acetaminophen at 10 micrograms/ml (321 +/- 25) and 100 micrograms/ml (257 +/- 14). This inhibition is similar to inhibition by 10 micrograms/ml of indomethacin (228 +/- 11). Excretion of prostacyclin metabolite was significantly lower after ingestion of acetaminophen (2233 +/- 446 vs 1246 +/- 199 pg/mg creatinine, mean +/- SEM) but unchanged after ingestion of placebo (1745 +/- 304 vs 1712 +/- 211). There was no difference in response between normal and hypertensive women, and there was no effect of acetaminophen on thromboxane metabolite excretion.. Acetaminophen in typical oral doses results in reduced production of prostacyclin by endothelial cells in culture and in a reduction in prostacyclin, but not thromboxane, production in pregnant women.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Adult; Cells, Cultured; Double-Blind Method; Endothelium; Epoprostenol; Female; Humans; Hypertension; Indomethacin; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Thromboxane A2

We carried out a prospective, randomized, double-blind, placebo-controlled study to investigate the capacity of aspirin to prevent pregnancy-induced hypertension and to alter prostaglandin metabolism. A total of 791 pregnant women with various risk factors for pre-eclamptic toxemia were screened with use of the rollover test (a comparison of blood pressure before and after the woman rolls from her left side to her back) during week 28 or 29 of gestation. Of 69 women with abnormal results (an increase in blood pressure during the rollover test), 65 entered the study and were treated with a daily dose of either aspirin (100 mg; 34 women) or placebo (31 women) during the third trimester of pregnancy. The number of women in whom pregnancy-induced hypertension developed was significantly lower among the aspirin-treated than among the placebo-treated women (4 [11.8 percent] vs. 11 [35.5 percent]; P = 0.024); the same was true for the incidence of preeclamptic toxemia (1 [2.9 percent] vs 7 [22.6 percent]; P = 0.019). The mean ratio of serum levels of thromboxane A2 to serum levels of prostacyclin metabolites after three weeks of treatment decreased by 34.7 percent in the aspirin-treated group but increased by 51.2 percent in the placebo-treated group. No serious maternal or neonatal side effects of treatment occurred in either group. We conclude that low daily doses of aspirin taken during the third trimester of pregnancy significantly reduce the incidence of pregnancy-induced hypertension and pre-eclamptic toxemia in women at high risk for these disorders, possibly through the correction of an imbalance between levels of thromboxane and prostacyclin.

Topics: Adult; Aspirin; Clinical Trials as Topic; Double-Blind Method; Epoprostenol; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies; Random Allocation; Thromboxane A2

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

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.

Topics: Adult; Blood Pressure; Captopril; Female; Humans; Hypertension; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase

The effect of sulindac on renal function and blood pressure was compared with those of placebo, piroxicam, and naproxen in 20 patients with primary hypertension being treated with a diuretic and a beta-blocker. Although the three non-steroidal anti-inflammatory drugs (NSAIDs) did not differ in their effect on renal function (weight, glomerular filtration rate, creatinine clearance) or on serum thromboxane and plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), blood pressure was significantly lower with sulindac than with placebo, piroxicam, or naproxen. These differences were associated with less renal cyclooxygenase inhibition by sulindac (reflected by urinary thromboxane B2 and 6-keto PGF1 alpha) than by other NSAIDs. The findings suggest that the blood pressure differences reflect vasodilation due to differences in the balance between systemic and renal effects of the NSAIDs.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Adult; Amiloride; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Clinical Trials as Topic; Diuretics; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indenes; Male; Middle Aged; Naproxen; Piroxicam; Random Allocation; Sulindac; Thiazines; Thromboxane A2; Timolol

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

Cardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery.. Coronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10. TXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups.. Poorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Atrial Fibrillation; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Coronary Vessels; Humans; Hypertension; Thromboxane A2

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances，and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Disease Models, Animal; Humans; Hypertension; Male; Rats; Receptors, Thromboxane; Renal Insufficiency, Chronic; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

[Figure: see text].

Topics: Angiotensin II; Animals; Cytochrome P-450 CYP1B1; Cytokines; Dinoprostone; Group IV Phospholipases A2; Hydroxytestosterones; Hypertension; Mice; Mice, Inbred C57BL; Reactive Oxygen Species; Thromboxane A2

We examined the potential contributions of oxidative stress and thromboxane A

Topics: Animals; Blood Pressure; Heme Oxygenase-1; Hypertension; Kidney Glomerulus; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane-A Synthase

: The aim of this study was to analyse the signalling pathways involved in H2O2 vascular responses in hypertension.. Vascular function, thromboxane A2 (TXA2) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRAs) from hypertensive (spontaneously hypertensive rats, SHR) and normotensive Wistar Kyoto (WKY) rats.. H2O2 and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY. Moreover, H2O2 increased TXA2 production more in SHR than in WKY. The c-Src inhibitor PP1 reduced H2O2 and U46619-induced contraction and TXA2 release in both strains. The ERK1/2 inhibitor PD98059 reduced H2O2 but not U46619-induced contraction only in SHR arteries. The Rho kinase inhibitor Y26372 reduced H2O2 and U46619-induced contractions only in SHR arteries. Basal c-Src, ERK1/2 and Rho kinase expression were greater in MRA from SHR than WKY. In SHR, the combination of PD98059 with the TP antagonist SQ29548 but not with Y27632 inhibited the H2O2 contraction more than each inhibitor alone. H2O2 and U46619 increased NAD(P)H oxidase activity and O2 production and decreased mitochondrial membrane potential in vessels from SHR. The effects induced by H2O2 were abolished by inhibitors of TXA2 synthase, ERK1/2 and c-Src. The mitochondrial antioxidant mitoTEMPO reduced H2O2-induced contraction and NAD(P)H oxidase activation.. In arteries from WKY, c-Src mediates H2O2 contractile responses by modulating TXA2 release and TXA2 effect. In SHR, H2O2 induces c-Src dependent TXA2 release that provokes vascular contractile responses through Rho kinase, c-Src and O2 from NAD(P)H Oxidase and mitochondria. Moreover, ERK1/2 activation contributes to H2O2 contraction in SHR through effects on mitochondria/NAD(P)H Oxidase.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; CSK Tyrosine-Protein Kinase; Endothelium, Vascular; Hydrogen Peroxide; Hypertension; Male; Membrane Potential, Mitochondrial; Mesenteric Arteries; Mitochondria; Muscle Contraction; Muscle, Smooth, Vascular; NADPH Oxidases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; rho-Associated Kinases; Signal Transduction; src-Family Kinases; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

A contributing factor to increased peripheral resistance seen during hypertension is an increased production of endothelium-derived contractile factors (EDCFs). The main EDCFs are vasoconstrictor prostanoids, metabolites of arachidonic acid (AA) produced by Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2) following phosphorylation (at Ser(505)) mediated by extracellular signal-regulated kinase (ERK1/2) and cyclooxygenase (COX) activations. Although endoplasmic reticulum (ER) stress has been shown to contribute to pathophysiological alterations in cardiovascular diseases, the relationship between ER stress and EDCF-mediated responses remains unclear. We tested the hypothesis that ER stress plays a role in EDCF-mediated responses via activation of the cPLA2/COX pathway in the aorta of the spontaneously hypertensive rat (SHR). Male SHR and Wistar-Kyoto rats (WKY) were treated with ER stress inhibitor, tauroursodeoxycholic acid or 4-phenlybutyric acid (TUDCA or PBA, respectively, 100 mg·kg(-1)·day(-1) ip) or PBS (control, 300 μl/day ip) for 1 wk. There was a decrease in systolic blood pressure in SHR treated with TUDCA or PBA compared with control SHR (176 ± 3 or 181 ± 5, respectively vs. 200 ± 2 mmHg). In the SHR, treatment with TUDCA or PBA normalized aortic (vs. control SHR) 1) contractions to acetylcholine (ACh), AA, and tert-butyl hydroperoxide, 2) ACh-stimulated releases of prostanoids (thromboxane A2, PGF2α, and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA2 and ERK1/2, and 5) production of H2O2. Our findings demonstrate a novel interplay between ER stress and EDCF-mediated responses in the aorta of the SHR. Moreover, ER stress inhibition normalizes such responses by suppressing the cPLA2/COX pathway.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Aorta; Arachidonic Acid; bcl-2-Associated X Protein; Blood Pressure; Cells, Cultured; Cyclooxygenase 1; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Endothelium, Vascular; Epoprostenol; Hydrogen Peroxide; Hypertension; Male; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenylbutyrates; Phospholipases A2, Cytosolic; Phosphorylation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Taurochenodeoxycholic Acid; tert-Butylhydroperoxide; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

The role of wild blueberries (WB) on key signaling steps of nitric oxide (NO) and cyclooxygenase (COX) pathways was examined in spontaneously hypertensive rats (SHRs) after eight weeks on a control (C) or an 8% w/w WB diet. Aortic rings from SHRs were stimulated with phenylephrine (Phe) in the absence or presence of inhibitors of: soluble guanylyl cyclase (sGC), phosphodiesterase-5 (PDE(5)), prostaglandin I(2) (PGI(2)) synthase and thromboxane A(2) (TXA(2)) synthase. Additionally, enzymatic activities in these pathways were determined by the concentration of NO, cyclic guanosine monophosphate (cGMP), PGI(2) and TXA(2). In the WB-fed SHR, attenuation of Phe-induced vasoconstriction was mediated by an increased synthesis or preservation of cGMP. Despite an increased release of PGI(2) in the WB group, neither inhibition of PGI(2) or TXA(2) synthase resulted in a different response to Phe between the control and the WB rings. Hence, in the SHR, WB decrease Phe-mediated vasoconstriction under basal conditions by enhancing NO-cGMP signaling without a significant involvement of the COX pathway.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Aorta; Blueberry Plants; Cyclic GMP; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diet; Enzyme Inhibitors; Epoprostenol; Fruit; Hypertension; Intramolecular Oxidoreductases; Male; Nitric Oxide; Nitric Oxide Synthase; Phenylephrine; Plant Preparations; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred SHR; Signal Transduction; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasodilator Agents

Hypertension is associated with the impairment of renal cyclooxygenase (COX) activity, which regulates vascular tone, salt and water balance and renin release. We aimed to evaluate the functional role of COX isoforms in kidneys isolated from spontaneously hypertensive rats (SHR) after α1-adrenoceptor (α1-AR) stimulation.. Male six-month-old SHR and normotensive Wistar-Kyoto rats (WKY) were used. The kidneys were isolated to measure perfusion pressure and COX-1- or COX-2-derived prostanoids in response to α1-AR activation.. The basal perfusion pressure was higher in SHR kidneys compared with WKY kidneys (95 ± 11 vs. 68 ± 6 mmHg, P<0.05). Phenylephrine induced a greater vasopressor response in SHR kidneys (EC50 of 1.89 ± 0.58 nmol) than WKY kidneys (EC50 of 3.30 ± 0.54 nmol, P<0.05 vs. SHR). COX-1 inhibition decreased the α1-AR-induced vasoconstrictor response in WKY but did not affect SHR response, while COX-2 inhibition diminished the response in SHR. Both basal prostacyclin (PGI2) and thromboxane A2 (TxA2) values were higher in SHR kidney perfusates (P<0.05) and were reduced by COX-1 and COX-2 inhibitors in both strains. Furthermore, phenylephrine increased PGI2 through COX-2 in WKY and through COX-1 in SHR, but the agonist did not significantly modify TxA2 in both strains.. The data suggest that COX-1 contributes to vasoconstrictor effects in WKY kidneys and that COX-2 has the same effect in SHR kidneys. The results also suggest that basal release of COX-2-derived vasoconstrictor prostanoids is involved in renal vascular hypersensitivity in SHR.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Blood Pressure; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Epoprostenol; Hypertension; In Vitro Techniques; Kidney; Male; Phenylephrine; Rats; Signal Transduction; Thromboxane A2; Vasoconstriction

Obesity and arterial hypertension, important risk factors for atherosclerosis and coronary artery disease, are characterized by an increase in vascular tone. While obesity is known to augment vasoconstrictor prostanoid activity in endothelial cells, less is known about factors released from fat tissue surrounding arteries (perivascular adipose). Using lean controls and mice with either monogenic or diet-induced obesity, we set out to determine whether and through which pathways perivascular adipose affects vascular tone. We unexpectedly found that in the aorta of obese mice, perivascular adipose potentiates vascular contractility to serotonin and phenylephrine, indicating activity of a factor generated by perivascular adipose, which we designated "adipose-derived contracting factor" (ADCF). Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective. By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity. Perivascular adipose as a source of COX-derived ADCF was further confirmed by detecting increased thromboxane A2 formation from perivascular adipose-replete aortae from obese mice. Taken together, this study identifies perivascular adipose as a novel regulator of arterial vasoconstriction through the release of COX-derived ADCF. Excessive ADCF activity in perivascular fat under obese conditions likely contributes to increased vascular tone by antagonizing vasodilation. ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.

Topics: Adipose Tissue; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Hypertension; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Obesity; Thromboxane A2; Vasodilation

The prostanoid thromboxane A2 has been implicated to contribute to the pathogenesis of many cardiovascular diseases, including hypertension. To study the role of vascular thromboxane-prostanoid (TP) receptors in blood pressure regulation, we generated mice with cell-specific deletion of TP receptors in smooth muscle using Cre/Loxp technology. We crossed the KISM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Tbxa2r gene (Tp(flox)). In KISM22α-Cre(+)Tp(flox/flox) (TP-SMKO) mice, TP receptors were efficiently deleted from vascular smooth muscle cells. In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were attenuated to a similar extent in both the peripheral and renal circulations. Yet, acute vascular responses to angiotensin II were unaffected at baseline and after chronic angiotensin II administration. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice but had negligible hemodynamic effects in TP-SMKOs, which were completely protected from U46619-induced sudden death. Baseline blood pressures were normal in TP-SMKOs. However, the absence of TP receptors in vascular smooth muscle cells was associated with significant attenuation of angiotensin II-induced hypertension and diminished vascular remodeling. This was also associated with reduced urinary thromboxane production after chronic angiotensin II. Thus, TP receptors in vascular smooth muscle cells play a major role in mediating the actions of thromboxane A(2) in TP agonist-induced shock, hypertension, and vascular remodeling of the aorta.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Blood Pressure; Death, Sudden; Hypertension; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, Thromboxane; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 μg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.

Topics: Animals; Arteries; Blood Pressure; Cyclooxygenase 1; Cyclooxygenase 2; Epoprostenol; Gene Expression Regulation; Hemodynamics; Hypertension; Immunity, Innate; Interleukin-6; Male; Membrane Proteins; Mesenteric Arteries; Rats; Rats, Inbred SHR; Rats, Wistar; Thromboxane A2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vasoconstriction

FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases BP. We previously showed that inhibition of sphingosine kinase increases vascular tone and BP in hypertensive, but not normotensive rats. Since FTY720 is reported to have inhibitory effects on sphingosine kinase, we investigated whether FTY720 increases vascular tone and BP only in hypertensive rats via this mechanism.. The contractile and BP modulating effects of FTY720 were studied in vivo and ex vivo (wire myography) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs).. Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in BP was observed in WKY rats, as measured 24 h after administration. Similar to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced large contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions were inhibited by endothelium denudation, COX and thromboxane synthase inhibitors, and by thromboxane receptor antagonism, indicating that (like DMS-induced contractions) they were endothelium-dependent and mediated by thromboxane A₂.. These data demonstrate that FTY720 increases vascular tone and BP only in hypertensive rats, most likely as a result of its inhibitory effect on sphingosine kinase.

Topics: Animals; Blood Pressure; Carotid Arteries; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Fingolimod Hydrochloride; Hypertension; Immunosuppressive Agents; Isoenzymes; Male; Muscle, Smooth, Vascular; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sphingosine; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function.. In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10), that were virtually absent in WKY vessels (DMS: 0.0±0.0 and SMase: 0.6±0.1 mN/mm; n = 9, p<0.05). Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA(2), cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42±4%; n = 7), but not in WKY (-12±10%; n = 6). Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691±42 vs. 419±27 pmol, n = 3-5 respectively, p<0.05). These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513±19 pmol WKY vs. 645±25 pmol SHR, n = 6-12, p<0.05). Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade) in plasma from humans with essential hypertension (185±8 pmol vs. 252±23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05).. Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.

Topics: Adult; Anesthesia; Animals; Arachidonic Acid; Blood Pressure; Carotid Arteries; Ceramides; Chromatography, Liquid; Coronary Vessels; Cyclooxygenase 1; Female; Humans; Hypertension; Immunohistochemistry; In Vitro Techniques; Male; Mass Spectrometry; Middle Aged; Phospholipases A2, Calcium-Independent; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sphingomyelin Phosphodiesterase; Sphingosine; Thromboxane A2; Vasoconstriction

Glitazones exhibit beneficial effects in the vascular system, both on large vessels and at a microcirculatory level. We previously reported the effects of glitazones in the aorta of spontaneously hypertensive rats (SHR). We focus now on the acute and long-term actions of these drugs on mesenteric resistance arteries of the SHR. Incubation with pioglitazone or rosiglitazone (10⁻⁵ mol/l) improved endothelium-dependent relaxations to acetylcholine and the endothelial modulation of phenylephrine contractions. Acetylcholine relaxations that were abolished by N(G)-nitro-L-arginine methylester were partly recovered by the glitazones, but no effects of these drugs were observed in the presence of indomethacin or indomethacin + L-NAME. Glitazones did not change the contractions to U46619 or the endothelium-independent relaxation to sodium nitroprusside. Three-week oral pioglitazone or rosiglitazone treatment (3 and 10 mg/kg/day, respectively) confirmed the acute experiments. Thus, in microvessels, glitazones improve endothelial function in such a way that they do not alter endothelial nitric oxide release but reduce the production of vasoconstrictor prostanoids from endothelial cells.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelium, Vascular; Epinephrine; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Hypoglycemic Agents; Indomethacin; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitroprusside; Pioglitazone; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rosiglitazone; Thiazolidinediones; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Preeclampsia is a complex obstetrical syndrome characterized by hypertension and proteinuria. This syndrome is associated with oxidative stress, antioxidant imbalance and impaired production of vasoactive eicosanoids such as thromboxane A(2) (TXA(2)), a potent vasoconstrictor, and prostacyclin (PGI(2)), a well-known vasodilator. We hypothesized that there was a relationship between antioxidant vitamins, such as vitamin E and coenzyme Q(10) (CoQ(10)), and the production of vasoactive eicosanoids- PGI(2) and TXA(2)-potentially regulated by pro-oxidants and antioxidants in preeclampsia.. Therefore, the plasma levels of vitamin E, CoQ(10), TXA(2) and PGI(2) in normotensive (n = 30) and preeclamptic (n = 29) pregnancies were evaluated. Reduced and oxidized forms of vitamin E and CoQ(10) in blood were measured using a HPLC coupled to electrochemical detection. The levels of TXB(2) and 6-keto-PGF(1alpha), stable metabolites of TXA(2) and PGI(2) respectively, were measured by ELISA.. The CoQ(10) oxidized/reduced ratio was significantly higher in preeclamptic compared to normotensive pregnancies (p = 0.04). A strong correlation between plasma levels of reduced vitamin E and CoQ(10), corrected for apolipoprotein B, was observed only in preeclampsia (r = 0.69, p < 0.0001). The 6-keto-PGF(1alpha)/TXB(2) ratio was higher in preeclampsia than in controls (p = 0.02), and this ratio was correlated to the oxidized/reduced ratio of both, vitamin E and CoQ(10) in all pregnancies (p <0.023).. The data indicated that CoQ(10) is a sensitive marker of oxidative stress in preeclampsia. The correlation between vitamin E and CoQ(10) suggested a coordinated defense mechanism against oxidation. Furthermore, the higher 6-keto-PGF(1alpha)/TXB(2) ratio that strongly correlated with oxidative stress markers, suggests a mechanism developed by the maternal cardiovascular system to counteract hypertension during preeclampsia.

Topics: Adult; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Fatty Acids; Female; Humans; Hypertension; Oxidative Stress; Patient Selection; Pre-Eclampsia; Pregnancy; Thromboxane A2; Ubiquinone; Vitamin E

This study investigated the mechanisms underlying the response to hydrogen peroxide (H(2)O(2)) in mesenteric resistance arteries from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) rats. Arteries were mounted in microvascular myographs for isometric tension recording and for simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)](i)), superoxide anion (O(2)(.)) production was evaluated by dihydroethidium fluorescence and confocal microscopy, and thromboxane A(2) (TXA(2)) production was evaluated by enzyme immunoassay. H(2)O(2) (1-100 microM) induced biphasic responses characterized by a transient endothelium-dependent contraction followed by relaxation. Simultaneous measurements of tension and Ca(2+) showed a greater effect of H(2)O(2) in arteries from hypertensive than normotensive rats. The cyclooxygenase (cox) inhibitor, indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid] (1 microM); the COX-1 inhibitor, SC-58560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole] (1 microM); the thromboxane (TXA(2)) synthase inhibitor, furegrelate [5-(3-pyridinylmethyl)-2-benzofurancarboxylic acid, sodium salt] (10 microM); and the TXA(2)/prostaglandin H(2) receptor antagonist, SQ 29,548 ([1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.]]-7-[3-[[2-[(phenylamino) carbonyl] hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid)) (1 microM) abolished H(2)O(2) contraction in arteries from WKY rats but only reduced it in SHRs. The O(2)(.) scavenger, tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt) (1 mM), and the NADPH oxidase inhibitor, apocynin (4'-hydroxy-3'-methoxyacetophenone) (0.3 mM), decreased H(2)O(2) contraction in arteries from SHRs but not in WKY rats. H(2)O(2) induced TXA(2) and O(2)(.) production that was greater in SHRs than in WKY rats. The TXA(2) analog, U46619 [9,11-di-deoxy-11 alpha,9 alpha-epoxymethano prostaglandin F(2 alpha) (0.1 nM-1 microM)], also increased O(2)(.) production in SHR vessels. H(2)O(2)-induced TXA(2) production was decreased by SC-58560. H(2)O(2)-induced O(2)(.) production was decreased by tiron, apocynin, and SQ 29,548. In conclusion, the enhanced H(2)O(2) contraction in resistance arteries from SHRs seems to be mediated by increased TXA(2) release from COX-1 followed by elevations in vascular smooth muscle [Ca(2+)](i) levels and O(2)(.) production. This reveals a new mechanism of oxidative stress-induced vascular damage in h

Topics: Animals; Benzofurans; Calcium; Endothelium, Vascular; Enzyme Inhibitors; Hydrogen Peroxide; Hypertension; Indomethacin; Male; Mesenteric Arteries; Myocardial Contraction; Organic Chemicals; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides; Thromboxane A2; Thromboxane-A Synthase

In order to explore the changes and the roles of TXA2 and PGI2 during postoperative hypertensive crisis in patients with hypertensive intracerebral hemorrhage, 31 cases subject to craniotomy were divided into three groups: group A, 9 patients with postoperative hypertensive crisis; group B, 13 patients without postoperative hypertensive crisis; and group C, 9 patients without history of hypertension and hypertensive intracerebral hemorrhage. TXA2, TXB2, 6-keto-PGF1 alpha and PGI2 were measured after operation in the three groups respectively. The postoperative blood pressure in group A, including SBP and DBP, was elevated more obviously than that in the other two groups. TXA2 and PGI2 in group A were significantly higher than those in other two groups (P<0.01). Moreover, the ratio of TXB2 to 6-keto-PGF1 alpha in group A was significantly higher than that in other two groups (P<0.05). The increase of TXA2 and the relative inadequacy of prostacyclin, especially 6-keto-PGF1 alpha, may play roles in the postoperative hypertensive crisis. And the increased value of TXB2 to 6-keto-PGF1 alpha could provide the basis for diagnosis of postoperative hypertensive crisis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Epoprostenol; Female; Humans; Hypertension; Intracranial Hemorrhage, Hypertensive; Male; Middle Aged; Postoperative Period; Thromboxane A2

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

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

Patients with hypertension take antihypertensive agents and cholesterol-lowering drugs; however, few studies describe the effects of the interaction of antihypertensive agents with statins. Therefore, the purpose of this study was to characterize the effects of losartan, simvastatin, and their combination on the progression of hypertension in the spontaneously hypertensive rats (SHRs). Also, we determined whether diet influenced the drug responses. Rats were fed three different diets - low-salt (LS), high-salt (HS), and lipid-rich (LR) - and treated with either no drug (control), losartan (LOS, 10 mg/kg/day), simvastatin (SIM, 2 mg/kg/day) or LOS combined with SIM for four weeks. After four weeks on the diets, systolic blood pressure rose in all groups and remained elevated. Treatment with LOS alone or in combination with SIM reduced BP in the rats fed the LS and HS diet, respectively. Furthermore, LOS alone increased NO in the LS and LR groups; however, LOS combined with SIM completely abolished this rise in NO in LS group. Plasma PGI2 and TXA2 levels were increased in the presence of SIM alone; however LOS combined with SIM completely blocked SIM-induced increases in PGI2 and TXA2. Kidney levels of angiotensin II were higher in the LS group and significantly increased in the HS group following treatment with LOS alone. However, kidney aldosterone levels were significantly reduced in the presence of LOS in the HS group. Total cholesterol, LDL cholesterol, and triglycerides were significantly higher in the LR group. Together, these data suggest a contribution of endogenous NO and PGs in the antihypertensive effect of LOS and SIM that may be affected by the type of diet.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Diet; Diet, Sodium-Restricted; Dietary Fats; Endothelium, Vascular; Epoprostenol; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney; Lipids; Losartan; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Simvastatin; Sodium, Dietary; Superoxides; Thromboxane A2

The present study sought to evaluate the prevention and reversion effects of isosorbide-5-mononitrate (Is-5-Mn) on the development of hypertension (HT) and on the underlying vascular and platelet morphofunctional disturbances, using an animal model of cyclosporine (CsA)-induced HT. The following rat groups (n = 8) were tested: (1) a control group (orange juice, for 7 weeks); (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the prevention group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA and following thereafter with both drugs for 5 weeks. Blood pressure, lipid profile, vascular lesion, platelet aggregation and morphology, and platelet thromboxane A(2)/vascular prostacyclin equilibrium were evaluated. Is-5-Mn + CsA therapy prevented (systolic blood pressure [SBP]: 114.3 +/- 1.9 mm Hg, P < .001; diastolic blood pressure [DBP]: 97.0 +/- 3.3 mm Hg, P < .001) the CsA-induced HT (SBP: 146.2 +/- 4.5 mm Hg, P < .001; DBP: 124.9 +/- 4.5 mm Hg, P < .001 vs control: SBP: 111.6 +/- 0.7 mm Hg; DBP: 94.6 +/- 1.0 mm Hg), as well as the vascular lesion and the platelet morphofunctional disturbances. The curative group did not show attenuated CsA-induced BP increase; it showed further enhancement of the HT effect (SBP: 159.7 +/- 5.5 mm Hg, P < .05; DBP: 132.8 +/- 2.8 mm Hg), as well as worsened vascular lesions and platelet function, namely a disruption in the TXA(2)/PGI(2) equilibrium. Our data suggested that Is-5-Mn therapy may be a valid choice to prevent the morphofunctional changes associated with CsA-induced HT, when used as a preventive therapy. A careful evaluation of the impact of nitrate therapy should be considered, particularly the negative effect on cardiovascular hemodynamics, when considering its use after previous CsA disturbances have been established.

Topics: Adenosine Diphosphate; Animals; Aorta; Blood Platelets; Blood Pressure; Cyclosporine; Epoprostenol; Hypertension; Lipids; Male; Models, Animal; Nitrates; Platelet Aggregation; Rats; Rats, Wistar; Thromboxane A2

1.-- In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2.-- Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3.-- The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4.-- Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5.-- In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI(2)) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6.-- In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI(2) and PGE(2), while fructose treatment only diminished the PGE(2) release. On the contrary, the production of the vasoconstrictor thromboxane A(2) (TXA(2)) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI(2) release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF(2alpha) and TXA(2). 7.-- In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increa

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Aorta, Thoracic; Blood Pressure; Dinoprostone; Disease Models, Animal; Fructose; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Mesenteric Veins; Metabolic Syndrome; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboxane A2

In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H(2), whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A(2), PGF(2alpha), PGE(2), and possibly PGH(2) (PGI(2) >> thromboxane A(2) = PGF(2alpha) = PGE(2)). In SHR aortas, the release of prostacyclin and thromboxane A(2) was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane A(2) was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A(2) and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2) spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A(2) and prostacyclin with a most likely concomitant contribution of PGH(2).

Topics: Animals; Aorta, Thoracic; Calcimycin; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Hypertension; In Vitro Techniques; Ionophores; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasoconstriction

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

L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. Their effect on endothelial dysfunction in hypertension was studied after treatment with either 200 mg/kg of L-carnitine or propionyl-L-carnitine during 8 weeks of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Endothelial function was assessed in aortic rings by carbachol-induced relaxation (CCh 10(-8) to 10(-4) M) and factors involved were characterized in the presence of the inhibitors: L-NAME, indomethacin, the TXA2/PGH2 Tp receptor antagonist ICI-192,605 and the thromboxane synthetase inhibitor-Tp receptor antagonist, Ro-68,070. The effect on phenylephrine-induced contractions was also observed. To identify the nature of vasoactive COX-derived products, enzyme-immunoassay of incubation media was assessed. Involvement of reactive oxygen species was evaluated by incubating with superoxide dismutase and catalase. Nitric oxide production was evaluated by serum concentration of NO2+NO3.Treatment with both compounds improved endothelial function of rings from SHR without blood pressure change. Propionyl-L-carnitine increased NO participation in WKY and SHR. L-carnitine reduced endothelium-dependent responses to CCh in WKY due to an increase of TXA2 production. In both SHR and WKY, L-carnitine enhanced concentration of PGI2 and increased participation of NO. Results in the presence of SOD plus catalase show that it might be related to antioxidant properties of L-carnitine and propionyl-L-carnitine. Comparison between the effect of both compounds shows that both may reduce reactive oxygen species and increase NO participation in endothelium-dependent relaxations in SHR. However, only L-carnitine was able to increase the release of the vasodilator PGI2 and even enhanced TXA2 production in normotensive rats.

Topics: Administration, Oral; Animals; Antioxidants; Aorta, Thoracic; Blood Pressure; Body Weight; Carnitine; Cyclooxygenase Inhibitors; Endothelium, Vascular; Epoprostenol; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasodilation

The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17beta-estradiol on endothelial function in isolated aortic rings from male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Relaxation to acetylcholine on precontracted rings was impaired and endothelium-dependent contraction to acetylcholine in aortic rings was increased in SHR compared with WKY. Aortic NADPH-stimulated O(2)(-) release and prostaglandin (PG)H(2) production evoked by acetylcholine were increased, whereas nitric-oxide synthase activity was reduced in SHR versus WKY. Genistein, daidzein, or 17beta-estradiol enhanced the relaxant response to acetylcholine and decreased the endothelium-dependent vasoconstrictor responses to acetylcholine in SHR, but not in WKY, and these effects were not modified by the estrogen receptor antagonist ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Moreover, isoflavones enhanced nitric-oxide (NO) synthase activity and inhibited NADPH-stimulated O(2)(-) roduction and endothelial release of PGH(2). The contractions induced by the TP receptor agonist U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)) in denuded aortic rings were inhibited by genistein, daidzein, and 17beta-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17beta-estradiol restore endothelial function in male SHR through estrogen receptor-independent mechanisms. Increased NO production and protection of NO from O(2)(-)-driven inactivation might be involved in the improvement of vascular relaxation to acetylcholine in aortic rings from SHR. Moreover, isoflavones and 17beta-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH(2) release and its vasoconstrictor response.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Endothelial Cells; Estradiol; Genistein; Hypertension; Isoflavones; Male; Nitric Oxide Synthase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides; Thromboxane A2; Vasodilation

1. The aim of the present study was to evaluate the effect of preventive and curative isosorbide-5-mononitrate (Is-5-Mn) treatment on the development of hypertension, cGMP content, thromboxane (TX) A(2)/prostaglandin (PG) I2 balance, the peripheral serotonergic system, platelet activation, lipid peroxidation and plasma lipids in cyclosporine A (CsA)-induced hypertensive rats. 2. Control, CsA (5 mg/kg per day) and Is-5-Mn (150 mg/kg per day, b.i.d.) rat groups were treated orally over a period of 7 weeks. The preventive Is-5-Mn group (Is-5-Mn + CsA) was first treated for 2 weeks with Is-5-Mn, followed by 7 weeks with both drugs; the curative Is-5-Mn group (CsA + Is-5-Mn) was treated for a period of 7 weeks with CsA and with both drugs for an additional 5 weeks. The control group received oral vehicle. 3. Whereas in the group undergoing preventive treatment the CsA-induced increase in blood pressure (BP), compared with the control group, was avoided, in the group undergoing curative treatment, the increase in BP was even higher. The decreased arterial cGMP content in the CsA group was prevented and reverted when Is-Mn was administered either preventatively or curatively with CsA. Platelet TXA2 production, although unaffected in the Is-5-Mn + CsA group, was significantly higher in the CsA + Is-5-Mn group compared with the group receiving CsA alone. Furthermore, plasma TXA2 was reduced following preventive Is-5-Mn treatment, but was worsened in the group undergoing curative therapy. Aortic PGI2 synthesis was identical in all groups. Consequently, the TXA2/PGI2 ratio was only altered in the CsA + Is-5-Mn group, demonstrating a markedly higher value. In both groups treated simultaneously with CsA and Is-5-Mn, a higher platelet 5-hydroxytryptamine (5-HT) content was obtained compared with CsA treatment alone, but only preventive treatment with Is-5-Mn resulted in a significant reduction in plasma 5-HT. Changes in ADP and collagen-induced platelet aggregation paralleled those of plasma 5-HT and TXA2: the hyperaggregation profile of the CsA group, although partially prevented, was not reverted by simultaneous treatment with Is-5-Mn and CsA. Lipid peroxidation and lipid profile values also worsened in the CsA + Is-5-Mn group compared with the group administered CsA alone. 4. In conclusion, the beneficial effects of concomitant Is-5-Mn and CsA treatment were demonstrated when Is-5-Mn was administered preventatively because not only was arterial hypertension prevente

Topics: Animals; Aorta; Blood Platelets; Cyclic GMP; Cyclosporine; Epoprostenol; Hypertension; Isosorbide Dinitrate; Lipid Peroxidation; Platelet Activation; Rats; Rats, Wistar; Thromboxane A2; Vasoconstriction

In the spontaneously hypertensive rat (SHR) and aging Wistar-Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine. In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H2, PGF2alpha, PGE2, PGD2, prostacyclin (PGI2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619>>8-isoprostane=PGF2alpha=PGH2>PGE2=PGD2>PGI2). The contractions produced by PGH2 and PGI2 were fast and transient, mimicking endothelium-dependent contractions. PGI2 did not relax isolated aortic rings of WKY and SHR. Acetylcholine evoked the endothelium-dependent release of thromboxane A2, PGF2alpha, PGE2, PGI2 and most likely PGH2 (PGI2>>PGF2alpha>or=PGE2>TXA2>8-isoprostane, PGD2). Dazoxiben abolished the production of thromboxane A2, but did not influence the endothelium-dependent contractions to acetylcholine. The release of PGI2 was significantly larger in the aorta of SHR than in WKY, and the former was more sensitive to the contractile effect of PGI2 than the latter. The inhibition of PGI-synthase was associated with an increase in PGH2 spillover and the enhancement of acetylcholine-induced endothelium-dependent contractions. Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI2 with a concomitant contribution of PGH2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta, Thoracic; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; Imidazoles; In Vitro Techniques; Indomethacin; Nitrobenzenes; Prostaglandins; Prostaglandins I; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Salicylates; Sulfonamides; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

The renin-angiotensin-aldosterone system and oxidative stress play a major role in the pathogenesis of hypertension.. We examined the effects of simvastatin, an HMG-CoA inhibitor, and losartan, an angiotensin type 1 receptor antagonist, in Dahl rats fed a high salt diet (8% NaCl), and treated with either simvastatin (3 mg/kg/d), losartan (10 mg/kg/d), or their combination using the drinking water as vehicle, for 3 weeks. Mean blood pressure (MAP) was measured by tail-cuff plethysmography. Plasma levels of nitric oxide (NO) and prostanoids, as well as plasma and tissue angiotensin II (Ang II) and aldosterone (ALDO) were analyzed by enzyme immunoassay. Renal and aortic superoxide production was determined by fluorescence spectrometry. Vascular reactivity of second-order mesenteric arteries was assessed in vitro.. Simvastatin, losartan, and the drug combination attenuated the salt-induced increase in MAP. Plasma NO was elevated by simvastatin, losartan, and the combination, whereas plasma thromboxane was reduced by losartan. Simvastatin, losartan, and the combination reduced renal Ang II, but only the combination reduced cardiac Ang II. Heart and renal ALDO were reduced by simvastatin, losartan, and the combination. Aortic and renal NADPH-dependent superoxide production was reduced by simvastatin, losartan, and the combination. The response to acetylcholine, in mesenteric arteries preconstricted with norepinephrine, was greater in the losartan group.. Thus, treatment with simvastatin and losartan lowered oxidative stress and improved endothelial function. Simvastatin significantly reduced the effect of losartan on vascular reactivity in mesenteric arteries, suggesting that their combination may be contraindicated.

Topics: Acetylcholine; Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Blood Pressure; Body Weight; Drug Therapy, Combination; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; In Vitro Techniques; Kidney; Losartan; Male; Mesenteric Arteries; Myocardium; Nitric Oxide; Organ Size; Oxidative Stress; Prostaglandins; Rats; Rats, Inbred Dahl; Simvastatin; Sodium Chloride, Dietary; Superoxides; Thromboxane A2; Treatment Outcome; Vasoconstriction; Vasodilator Agents

The pathogenesis of hypertension has been associated with endothelial dysfunction and oxidative stress. We have previously shown that palm oil (PO), with an unsaturated-to-saturated fatty acid ratio close to one and rich in antioxidants vitamins, reduces oxidative stress-induced hypertension in normal rats. Here, we investigated the cardiovascular effects of natural vitamin-rich PO using the Dahl Salt-sensitive hypertension model. Male rats were fed either a high salt (8%NaCl, HS) or low salt (0.3% NaCl, LS) diet with or without PO (Carotino, 5 g/kg daily) for four weeks. Mean arterial pressure (MAP), heart rate, blood flow and vascular resistance, vascular reactivity in vitro as well as remodelling of second-order mesenteric arteries were measured. Plasma levels of nitric oxide (NO), prostacyclin, thromboxane A(2) (TXA(2)) and isoprostane (ISO), were determined by enzyme immunoassay. Plasma, heart and kidney GSH and GSSG levels were analyzed by HPLC and aortic superoxide ((.)O(2)-) production by fluorescence spectrometry. High salt induced an elevation in MAP that was associated with decreased NO, prostacyclin and GSH: GSSG ratio. Plasma ISO and TXA(2), aortic and renal vascular resistance as well as aortic (.)O(2)- were increased. Palm oil reduced MAP, plasma TXA(2) and vascular resistance of the renal and aortic arteries, and increased the GSH: GSSG ratio and NO in the LS group. The HS-induced elevation in ISO and (.)O(2)- production and the reductions in kidney GSH: GSSG ratio, were attenuated by PO. The effect of PO was also associated with a reduced vessel wall-thickness: lumen diameter ratio and a greater relaxant effect of mesenteric arteries to acetylcholine, in the LS group. The mortality associated with HS was reduced by PO. Thus, palm oil attenuates the progression of salt-induced hypertension and mortality, via mechanisms involving modulation of endothelial function and reduction in oxidative stress.

Topics: Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Glutathione; Hypertension; Immunoenzyme Techniques; Isoprostanes; Male; Nitric Oxide; Oxidative Stress; Palm Oil; Plant Oils; Prostaglandins I; Random Allocation; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Thromboxane A2; Vascular Resistance

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiovascular System; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension; Lactones; Sulfones; Thromboxane A2

Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.. Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.. BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).. ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension; Kidney Cortex; Kidney Medulla; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Piperidines; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Thromboxane A2

Hypertension is associated with functional and morphological alterations of the endothelium, which disturbs delicate balance of endothelium-derived factors resulting in endothelial dysfunction. The endothelial dysfunction could then facilitate the maintenance of elevated peripheral resistance, which would favor the occurrence of atherosclerosis.. The aim of the present study was to determine the circulating levels of vasodilators [nitric oxide (NO) and prostacyclin (PGI2)] and vasoconstrictors [endothelin I (ET-I) and thromboxane (TX)A2)], which reflect endothelial cell dysfunction.. Nitric oxide as nitrites and nitrates (NOx) were measured spectrophotometrically; ET-I, TXA2 (as TXB2) and PGI2 (as 6 keto PGFIalpha) were measured using enzyme immunoassay methods in 54 male subjects having predominantly untreated, mild hypertension and compared with age-matched 75 healthy controls.. Significantly higher levels of ET-I (p<0.001) and TXB2 (p<0.001) were found in essential hypertension subjects (EHT) as compared to controls. No significant difference was observed in NOx and 6 keto PGFIalpha between the two groups. There was significant increase (p = 0.005) in the ratio of TXB2/6 keto PGFIalpha in EHT subjects as compared to controls.. Elevated levels of vasoconstrictors in untreated essential hypertension subjects as compared to controls confirmed the presence of endothelial dysfunction, even in mild cases of hypertension. Early detection of endothelial dysfunction may be a useful measure to guide therapy before the damaging effects of hypertension manifests.

Topics: Case-Control Studies; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Hypertension; Immunoenzyme Techniques; Male; Middle Aged; Nitric Oxide; Thromboxane A2

Chronic treatment with cyclosporine A (CsA), a potent immunosuppressive agent, is associated with the development of arterial hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and rat aortic rings. Male rats weighing 250-300 g were given either CsA (25mg/kg/day) in olive oil or vehicle by intraperitoneal (ip) injection for 7 days. CsA administration produced a 42% increase (P<0.001) in mean arterial pressure (MAP) which reached a plateau after 3 days. The level of both nitrate/nitrite (NO(2)/NO(3)), metabolites of nitric oxide (NO), decreased by 50% (P<0.001), but the level of thromboxane A2 (TBXA2) increased by 75% (P<0.001), in the urine. When 10(-9)M of CsA was added acutely to intact aortic rings from untreated rats, NO(2)/NO(3) production decreased by 83% (P<0.011), but TBXA2 production increased by 86% (P<0.001). The effects of CsA were reversed both in vivo and in vitro by pretreatment with metoprolol (15 mg/kg/day ip), B1-adrenoceptor antagonist. There were no changes in MAP and tension in rats treated with metoprolol alone. In addition, in aorta of rats that were treated with CsA ip for 7 days, CsA significantly activated protein kinase C (PKC) translocation. This suggests that PKC mediate, in part, CsA-induced hypertension. In summary, CsA inhibits endothelial NO formation, activate PKC, and increase TBXA2 production, with resulting increase in MAP, and this changes can be overcome by pretreatment with metoprolol.

Topics: Adrenergic beta-Antagonists; Animals; Aorta, Thoracic; Cyclosporine; Enzyme Activation; Hypertension; Immunosuppressive Agents; In Vitro Techniques; Male; Metoprolol; Nitric Oxide; Protein Kinase C; Rats; Rats, Sprague-Dawley; Thromboxane A2

Hypertension induced by oxidative stress has been demonstrated in normal rats. In the current study, we investigated the effect of the oral AT(1) receptor blocker losartan (10 mmol/kg/day) on oxidative stress, induced by glutathione (GSH) depletion (using buthionine-sulfoximine, BSO, 30 mmol/L/day in the drinking water), in Sprague-Dawley rats.. Mean arterial pressure (MAP) was measured by tail-cuff plethysmography and the plasma levels of total 8-isoprostane, nitric oxide, prostacyclin, thromboxane A(2), angiotensin II, aldosterone, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, heart, and kidney GSH were analyzed by high-performance liquid chromatography. Aortic and renal superoxide production was determined by fluorescence spectrometry.. In the BSO-treated group, MAP, angiotensin II, isoprostane, thromboxane A(2), and superoxide were elevated; whereas prostacyclin, GSH, cAMP, and cGMP were reduced, compared to control. Losartan alone reduced MAP, and increased renal GSH, plasma nitric oxide, angiotensin II, aldosterone, and aortic cGMP. When administered concurrently with BSO, losartan reversed the BSO-induced elevation of MAP, superoxide, and thromboxane A(2) as well as the reduction in prostacyclin and aortic cAMP levels, but did not significantly alter the reduction in GSH or the elevation in angiotensin II and aldosterone.. Losartan attenuates BSO-induced hypertension, which appears to be mediated, in part, by angiotensin II and the prostanoid endothelium-derived factors.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Aorta; Biomarkers; Blood Pressure; Buthionine Sulfoximine; Cyclic AMP; Cyclic GMP; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; F2-Isoprostanes; Glutathione; Heart Rate; Hypertension; Kidney; Losartan; Male; Models, Cardiovascular; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxides; Thromboxane A2; Treatment Outcome

The effects of chronic nitric oxide deficiency on prostacyclin and thromboxane A(2) production in vivo are unknown. Therefore, we treated rats with N(G)-nitro-L-arginine methyl ester (L-NAME), and used losartan and high calcium diet as antihypertensive treatments. Forty eight Wistar rats were divided into six groups: control; losartan (20mgkg(-1)day(-1)); high calcium diet (dietary calcium elevated from 1.1% to 3%); L-NAME (20mgkg(-1)day(-1)); losartan+L-NAME and high calcium diet+L-NAME. Prostacyclin and thromboxane A(2) production were measured after eight weeks as urinary 2,3-dinor-6-keto-PGF(1alpha) and 11-dehydro-TXB(2), respectively. Both the high calcium diet and losartan reduced blood pressure in L-NAME hypertension. Chronic nitric oxide deficiency did not modulate prostacyclin production but it nearly doubled thromboxane A(2) production in vivo. This effect was not influenced by lowering of blood pressure by blockade of angiotensin II type 1 receptors. Independent of the level of blood pressure and blockade of nitric oxide synthesis the high calcium diet decreased prostacyclin production by one third and increased thromboxane A(2) production almost two-fold in vivo.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Calcium, Dietary; Enzyme Inhibitors; Epoprostenol; Hypertension; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Receptors, Angiotensin; Thromboxane A2

Oxidative stress, associated with increased plasma isoprostane (ISO) and reductions in plasma glutathione (GSH), has been shown to cause severe hypertension in normal rats. Palm oil (PO), with an unsaturated-to-saturated fatty acid ratio close to one and rich in antioxidant vitamins, has been investigated for its beneficial effects on arterial thrombosis and atherosclerosis. In this study, the effect of PO on oxidative stress induced by inhibition of GSH synthesis (using buthionine sulfoximine [BSO]) was examined.. Sprague-Dawley rats were separated into two groups and received either natural vitamin-rich PO (Carotino, 5 g/kg daily) or water by gavage. After 4 weeks, they were further divided between receiving either BSO (30 mmol/L/day in the drinking water) or drug-free water for an additional week. Mean arterial pressure (MAP), heart rate (HR), and body weight (BW) were measured before and weekly during the experiment. The levels of plasma ISO, nitric oxide (NO), prostacyclin (PGI2), and thromboxane A2 (TXA2) were determined by enzyme immunoassay, and plasma, heart, and kidney GSH by high-performance liquid chromatography.. The PO reduced the age-dependent increase in MAP, and the pressor response to BSO, without changing the HR or BW compared to the BSO and control groups. It also elevated PGI2, NO, and aortic cGMP, but decreased TXA2 and aortic cAMP. In addition, the BSO-induced increase in ISO and TXA2, and the reduction in kidney GSH were attenuated by PO. However, the PO effect on NO, PGI2, cGMP, and TXA2 was partly counteracted by BSO.. Palm oil reduces BSO-induced oxidative stress and attenuates hypertension by mechanisms involving changes in endothelium-derived factors.

Topics: Animals; Buthionine Sulfoximine; Computer Graphics; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Glutathione; Hypertension; Immunoenzyme Techniques; Isoprostanes; Nitric Oxide; Oxidative Stress; Palm Oil; Plant Oils; Rats; Rats, Sprague-Dawley; Thromboxane A2

The involvement of cyclooxygenase-2 (COX-2)-derived products and superoxide anion in the effect of lipopolysaccharide in noradrenaline (NA)-induced contraction was investigated in small mesenteric arteries (SMA) from normotensive, Wistar Kyoto (WKY), and spontaneously hypertensive (SHR) rats. In WKY, lipopolysaccharide (10 microg/ml, 1 and 5 h) only inhibited the NA response (0.1-30 microM) in the presence of dexamethasone (1 microM), indomethacin (10 microM), the selective COX-2 inhibitor, NS 398 (10 microM), and the TXA(2)/PGH(2) receptor antagonist, SQ 29,548 (10 microM) but not of superoxide dismutase (SOD, 100 U/ml). In SHR, lipopolysaccharide inhibited the NA response by itself; this inhibition was potentiated by dexamethasone, indomethacin, NS 398, SQ 29,548 and SOD. The effect of lipopolysaccharide plus indomethacin, NS 398 or SQ 29,548 was higher in SMA from WKY than SHR only after 1 h lipopolysaccharide incubation. N(G)-nitro-L-arginine methyl ester (100 microM) and endothelium removal abolished the indomethacin-induced potentiatory effect of lipopolysaccharide in both strains. Endothelium removal also abolished the SOD potentiatory effect in SMA from SHR. Lipopolysaccharide increases COX-2 expression to a similar level in both strains and iNOS expression in a greater extent in SHR; these increases were reduced by dexamethasone. These results indicate: 1) lipopolysaccharide induces the endothelial production of contractile prostanoids from COX-2 in SMA, probably to compensate the increase in NO from iNOS; 2) the production of prostanoids in the presence of lipopolysaccharide seems to be greater in normotensive than hypertensive rats only after lipopolysaccharide short incubation times; 3) endothelial production of O(2)(.-) contributes to counteract depression of NA contraction caused by lipopolysaccharide only in SHR.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase 2; Dexamethasone; Dose-Response Relationship, Drug; Drug Combinations; Fatty Acids, Unsaturated; Hydrazines; Hypertension; In Vitro Techniques; Indomethacin; Isoenzymes; Lipopolysaccharides; Male; Mesenteric Arteries; Mice; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrobenzenes; Norepinephrine; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Thromboxane; Sulfonamides; Superoxide Dismutase; Thromboxane A2

The purpose of this study was to determine the role of thromboxane A2 (TXA2) in a conscious, chronically instrumented rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP).. Mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and 24-h urinary excretion of TXB2 (metabolite of TXA2) were determined in normal pregnant rats and RUPP pregnant rats.. At day 20 of pregnancy, RUPP rats showed a significantly (P < .05) higher MAP (125 +/- 3 mm Hg v 100 +/- 2 mm Hg) as compared with normal pregnant controls. The elevation in arterial pressure in RUPP group was associated with a marked increase (P < .05) in the urinary concentration of TXB2 compared with normal pregnant group (3663 +/- 488 v 2646 +/- 257 pg/24 h). Baseline GFR (1.74 +/- 0.13 v 2.40 +/- 0.20 mL/min, respectively, P < .05) and ERPF (5.13 +/- 0.44 v 6.44 +/- 0.58 mL/min, respectively) were decreased in RUPP rats relative to pregnant controls. Infusion of a TX receptor antagonist, SQ 29,548 (2 mg/kg bolus plus 2 mg/kg per h infusion) had no significant effect on increased MAP in RUPP pregnant rats. Similarly, ERPF and GFR did not change during acute blockade of TXA2 receptors in this group.. These findings suggest that enhanced production of TXA2 does not play a major role in mediating the hypertension and renal vasoconstriction produced by chronic RUPP in pregnant rats.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Hydrazines; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Renal Circulation; Thromboxane A2; Uterus

Interactions among angiotensin II (Ang II), endothelin-1 (ET-1) and thromboxane A2 (TXA2) may play an important role in the regulation of renal function. The present study investigated the participation of TXA2 and ET-1 in the increase in renal vascular resistances (RVR) induced by Ang II, as well as the consequences of diabetes, hypertension, and the combination of both on this response.. Isolated kidneys from male normoglycemic or streptozotocin-induced diabetic Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were used. The increase in perfusion pressure (PP) produced by Ang II was studied in the absence or presence of the TXA2 receptor antagonist, ifetroban, or the ETA/ETB receptor antagonist, PD145065.. Systolic arterial pressure (SAP) was higher in SHR than in WKY, but diabetic rats (D) from each strain showed lower SAP values than their respective non-diabetic rats. Basal renal PP was higher in WKY and SHR than in WKY-D and SHR-D. Increases in renal PP produced by Ang II were comparable in the kidneys from all groups. Either ifetroban or PD145065 reduced the maximal Ang II response in all animals. The maximal inhibitory effect of ifetroban was higher (P<0.05) in WKY than in the other groups. However, the maximal inhibitory effect of PD145065 was lower in SHR than in the other groups.. This study supports a role for ET-1 and TXA2 as mediators of the increase in renal vascular resistance produced by Ang II. These results indicate that the participation of ET-1 in the renal vasoconstriction produced by Ang II was reduced under hypertensive conditions, and that of TXA2 was reduced by both diabetes and hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Kidney; Male; Oligopeptides; Oxazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Endothelin; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Thromboxane A2; Vascular Resistance; Vasoconstriction

Injections of the thromboxane A(2) mimetic U-46619 (10 and 20 microg) into the left atrium of anesthetized rabbits evoked decreases in heart rate (HR) and arterial blood pressure (ABP) followed by an increase in ABP. Bilateral, cervical vagotomy abolished the U-46619-induced bradycardia and attenuated the hypotension. Injections of U-46619 into the ascending aorta did not evoke the bradycardia and hypotension but did cause arterial hypertension. To further define the origin of the vagal reflex, recordings of nerve impulses were made from 11 chemosensitive cardiac vagal afferent nerves. Impulse frequency increased in all 11 fibers in response to left atrial injections of phenylbiguanide (20-30 microg) and U-46619 (5-10 microg). Onset time of nerve activity induced by U-46619 correlated with the onset time of bradycardia. We conclude that U-46619 injections into the left heart elicit decreases in HR and ABP via a vagal reflex that originates from the heart similar to the coronary chemoreflex described for other agents.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia; Animals; Biguanides; Blood Pressure; Bradycardia; Chemoreceptor Cells; Female; Heart Atria; Heart Rate; Hypertension; Hypotension; Male; Neurons, Afferent; Rabbits; Reflex; Serotonin Receptor Agonists; Thromboxane A2; Vagotomy; Vagus Nerve; Vasoconstrictor Agents

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

We have investigated the effects of moderate global undernutrition during gestation in the rat on the blood pressure of male and female offspring, and on the development of systemic vascular function. Pregnant Wistar rats were nutritionally restricted (R) by feeding with 70% of the normal gestation-matched dietary intake from 0 to 18 days gestation.R offspring were growth retarded at birth but of similar weight to controls (C) at 20 days. Systolic and/or diastolic and mean arterial blood pressures, measured directly by femoral artery catheter, were elevated from 60 days onward in male R offspring (mean arterial pressure: day 60, P < 0.01; day 100, P < 0.05; day 200, P < 0.005, R vs. C), and from 100 days onward in female R offspring (mean arterial pressure day 100 and day 200, P < 0.05; R vs. C). Maximal constriction to phenylephrine (PE) (P < 0.05) and to noradrenaline (NA) (P < 0.05) was reduced in isolated femoral arteries of day 20 R pups. These differences did not persist into adulthood. In male adult R offspring (200 days), maximal vasoconstriction to the thromboxane A2 mimetic, U46619 (P < 0.05) and sensitivity to potassium (P < 0.01) were enhanced. Moderate maternal undernutrition in rat gestation adversely affects cardiovascular function in the offspring. These abnormalities increase with age and are more pronounced in males.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Birth Weight; Blood Pressure; Diet; Energy Intake; Female; Gestational Age; Hypertension; Male; Muscle, Smooth, Vascular; Norepinephrine; Organ Size; Phenylephrine; Potassium; Pregnancy; Rats; Rats, Wistar; Thromboxane A2; Vascular Diseases; Vasoconstrictor Agents

To clarify whether endothelium-derived contracting factor (EDCF) is developed in renal artery of hypertensive Dahl rats and whether prolonged oral L-arginine treatments prevent development of EDCF and hypertension.. The effect of prolonged salt treatment with or without L-arginine on the renal artery was examined.. Dahl salt-sensitive and -resistant rats were fed a 0.4 or an 8% NaCl diet for 4 weeks. High sodium intake increased arterial pressure in Dahl salt-sensitive rats. The rings of renal arteries were suspended for isometric tension recording. Only in the hypertensive rats, more than 1 micromol/l acetylcholine induced an endothelium-dependent contraction response. The contraction was completely inhibited by indomethacin or ONO-3708 [prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptor antagonist], and partially inhibited by OKY-046 (TXA2 synthetase inhibitor). Acetylcholine-induced relaxation was significantly depressed in hypertensive rats, which was partially improved by SQ29548 (PGH2/TXA2 receptor antagonist). Oral L-arginine, but not ONO-8809 (orally active PGH2/TXA2 receptor antagonist) treatment, inhibited the contraction and amended the relaxation. The endothelium-independent contraction to TXA2 receptor agonist U46619 and relaxation to nitroprusside were not altered by L-arginine treatment The L-Arginine treatment reduced blood pressure and sodium retention with increases in urinary NO2-/NO3- and cGMP excretion. Hydralazine treatment also inhibited development of EDCF.. The present results suggest that impaired endothelium-dependent relaxation to acetylcholine is caused in part by induction of EDCF synthesis/release in renal arteries of hypertensive Dahl rats. L-arginine can attenuate sodium retention and development of hypertension, which lead to a decrease in EDCF synthesis in renal arteries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arginine; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cyclic GMP; Endothelins; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydralazine; Hydrazines; Hypertension; In Vitro Techniques; Indomethacin; Male; Methacrylates; Natriuresis; Nitrates; Nitrites; Nitroprusside; Rats; Rats, Inbred Dahl; Renal Artery; Thromboxane A2; Vasoconstriction

In vitro studies have suggested that losartan interacts with the thromboxane (TxA2)/ prostaglandin H2 (PGH2) receptor in human platelets, reducing TxA2-dependent platelet activation. The aim of this study was to evaluate the effect of different angiotensin II type 1 receptor antagonists in stroke-prone spontaneously hypertensive rats (SHRSP). The level of platelet activation was assessed by determining P-selectin expression in platelets by flow cytometry. The ex vivo adhesion of platelets was also analyzed. The number of platelets that expressed P-selectin in SPSHR was significantly increased (% P-selectin expression: WKY 4 +/- 0, 4%; SHRSP 15.5 +/- 0, 8% [n = 8], p < 0.05). In SHRSP receiving losartan (20 mg/kg body weight per day) the percentage of platelets expressing P-selectin fell to levels close to that observed in WKY. The number of platelets from SHRSP treated with valsartan and candesartan (20 mg/kg body weight per day for 14 days) that expressed P-selectin was not significantly different from those from untreated SPRHR. Only losartan treatment reduced ex vivo platelet adhesion to a synthetic surface. The antiplatelet effect of losartan does not appear to be related to the level of blood pressure reduction. In ex vivo experiments, losartan significantly reduced the binding of the radiolabeled TxA2 agonist U46619 to platelets obtained from SHRSP in a dose-dependent manner. Treatment with losartan reduced the number of activated platelets in SHRSP independently of its blood pressure effects. TxA2-receptor blockade is proposed as a mechanism by which losartan can prevent platelet activation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Platelets; Blood Pressure; Humans; Hypertension; Losartan; P-Selectin; Platelet Activation; Platelet Adhesiveness; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Tetrazoles; Thromboxane A2; Valine; Valsartan

Vasoconstrictor and vasodilator release from vascular endothelial cells not only regulates vascular tone but also induces vascular smooth muscle cell proliferation.. In order to understand the role of vasoconstrictor and vasodilator release in the development of hypertension in spontaneously hypertensive rats (SHR), aortic endothelial cells were isolated and cultured from 4-week-old and 24-week-old SHR (SHR-4 and SHR-24) and age-matched Wistar-Kyoto rats (WKY-4 and WKY-24) used as control. Prostacyclin (PGI2), endothelin-1 (ET-1) and thromboxane A2 (TXA2) release from cultured endothelial cells in the culture medium, were measured after 30 min with or without treatment with acetylcholine, calcium ionophore A23187 or thrombin.. The results showed that there was no significant difference in ET-1 secretion between SHR-4 and age-matched WKY rats, but ET-1 secretion was about twice as high in SHR-24 as in WKY-24. TXA2 secretion was significantly higher in SHR-4 than in WKY-4 and was also higher than in SHR-24, but there was no significant difference between SHR-24 and WKY-24. The secretion of PGI2 was higher in SHR-24 than in WKY-24 and also higher than in SHR-4 and WKY-4. The prostaglandin PGI2 and TXB2 secretions from all groups of cultured VECs treated with various reagents, acetylcholine, calcium ionophore A23187 or thrombin were increased in similar patterns. However, there was no significantly different response between SHR and WKY VECs.. Similar levels of ET-1 secreted from endothelial cells between SHR-4 and WKY-4 indicated that ET-1 secretion seems not a crucial factor in early hypertension development in SHR. The high level of TXA2 secretion in SHR-4 may involve in early hypertension development in SHR.

Topics: Animals; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Epoprostenol; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2

The influence of the endothelium on aortic contractility to KCl 100 mM was studied during maturation and aging in normotensive Wistar and spontaneously hypertensive rats (SHR). In Wistar rats, there was no significant difference in maximal responses in the course of aging whether the endothelium was present (E+) or not (E-). A similar result was obtained in SHR E- rings. However, contraction was significantly higher in E+ rings of young (9 weeks) compared to adult and old SHR (18, 25, 36 and 72 weeks) (in mN/mm2: 34.8 +/- 3.1 versus 24.8 +/- 1.8, 16.0 +/- 2.5, 17.4 +/- 2.0 and 12.9 +/- 1.8, p<0.01). This increase remained significant in 18- compared to that of 25-, 36- and 72-week-old rats (p<0.01). No change appeared with age in noradrenaline-induced contractions of E+ rings neither in Wistar nor in SHR. A dose-dependent decrease in response to KCl was observed after an in vivo pretreatment of the young SHR with acetylsalicylic acid. Finally, blocking the TXA2/PGH2 receptor by addition of GR 32191B or ONO-3708 led to a decrease in the response of young SHR aortic rings to KCl. This study points out a decrease in the response of SHR aortic rings to a depolarizing agent during maturation. The enhanced contraction observed in young SHR seems to be the result of an increased participation of an endothelium-derived, cyclooxygenase-dependent contracting factor(s), most likely either TXA2 or PGH2. This factor might play a key role in the onset of hypertension in the spontaneously hypertensive strain.

Topics: Aging; Animals; Aorta; Aspirin; Biphenyl Compounds; Body Weight; Endothelium, Vascular; Heptanoic Acids; Hypertension; In Vitro Techniques; Muscle Contraction; Norepinephrine; Potassium Chloride; Prostaglandin Antagonists; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

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

The purpose of this study was to determine whether activation of prostaglandin H(2)-thromboxane A(2) (PGH(2)-TxA(2)) receptors impedes vasodilation in the in situ peripheral microcirculation of spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Using intravital microscopy, we found that vasodilation elicited by suffusion of acetylcholine and vasoactive intestinal peptide (VIP), two neurotransmitters localized in perivascular nerves in the peripheral circulation, on the in situ cheek pouch was significantly attenuated in spontaneously hypertensive hamsters relative to age- and genetically matched normotensive hamsters (P < 0.05). However, nitroglycerin-induced vasodilation was similar in both groups. Pretreatment with SQ-29548, a selective and potent PGH(2)-TxA(2)-receptor antagonist, restored acetylcholine- and VIP-induced vasodilation in spontaneously hypertensive hamsters. SQ-29548 had no significant effects on resting arteriolar diameter and on nitroglycerin-induced vasodilation in both groups. SQ-29548 slightly but significantly potentiated VIP- but not acetylcholine-induced vasodilation in normotensive hamsters. Collectively, these data indicate that activation of PGH(2)-TxA(2) receptors impedes agonist-induced vasodilation in the in situ cheek pouch of spontaneously hypertensive hamsters. We suggest that this model is suitable for studying the role of prostanoids in mediating vasomotor dysfunction observed in genetic hypertension.

Topics: Acetylcholine; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cheek; Cricetinae; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Male; Nitroglycerin; Prostaglandin H2; Prostaglandins H; Thromboxane A2; Vasoactive Intestinal Peptide; Vasodilation; Vasodilator Agents; Vasomotor System

One of the most severe side effects of the immunosuppressive agent, cyclosporin A (CsA), is increased risk of thromboembolic complications and drug-related hypertension. Because platelets might be involved in these processes, we tested the possibility of CsA affecting platelet activation, which might contribute to these adverse drug reactions. The experiments were done using Wistar rats, treated or not (control) with CsA (Sandimmun Neoral), 5 and 30 mg/kg/day, for 7 weeks. Systolic, diastolic, and mean blood pressures, intracellular free calcium concentration ([Ca2+]i), platelet serotonin (5-HT) contents, and aggregation were determined, at weeks 0, 2, and 7 of treatment. Inositol phosphates (InsP) production, platelet thromboxane A2 (TXA2) generation, and morphology of platelets, through electron microscopy studies, also were compared. It was demonstrated that blood pressures increased in the CsA-treated groups, when compared with the control group, after 2 and 7 weeks of administration. CsA at both "attack" and "maintenance" doses increased basal, 5-HT, and thrombin-evoked [Ca2+]i after 2 and 7 weeks versus the control group. However, basal and evoked InsP production was stimulated by 5 mg/kg of CsA, but inhibited by 30 mg/kg, when compared with the control. Platelet 5-HT contents decreased significantly after 2 and 7 weeks in the CsA-treated groups, when compared with the control group. Collagen-induced whole blood platelet aggregation increased drastically in the "attack" CsA-treated group, whereas adenosine diphosphate (ADP)-induced platelet aggregation did not reach statistical significance. Finally, in vitro basal, collagen-, and ADP-evoked platelet TXA2 generation increased in both CsA concentrations, versus the control. In conclusion, our study demonstrates that both CsA doses alter platelet calcium homeostasis (even affecting the calcium fluxes differently), 5-HT and TXA2 contents and aggregation, which might contribute to the development and/or maintenance of high blood pressures and increased risk of thromboembolic complications.

Topics: Animals; Calcium; Cyclosporine; Hypertension; Immunosuppressive Agents; Inositol Phosphates; Male; Platelet Activation; Rats; Rats, Wistar; Serotonin; Thromboxane A2

The myogenic response of skeletal muscle arterioles is enhanced in hypertension because of the release of endothelin (ET) and prostaglandin H(2) (PGH(2))/thromboxane A(2) (TxA(2)) from the endothelium. We hypothesized that ET and PGH(2)/TxA(2) modulate Ca(2+) signaling in arteriolar smooth muscle and thereby enhance myogenic constriction. Thus, simultaneous changes in intracellular Ca(2+) concentration in smooth muscle ([Ca(2+)](i)), measured by fura 2 microfluorometry (expressed as Ca(2+) fluorescence ratio [R(Ca)]), and diameter were obtained as a function of intraluminal pressure (P(i)) in isolated cannulated gracilis muscle arterioles (diameter approximately 120 micrometer) of normotensive Wistar rats (WR) and spontaneously hypertensive rats (SHR). In the absence of extracellular Ca(2+), increases in P(i) from 20 to 160 mm Hg increased the passive diameter of arterioles without changes in R(Ca). In the presence of extracellular Ca(2+) and endothelium, increases in P(i) elicited similar increases in R(Ca) (30+/-7% for control and 33+/-8% for SHR at 160 mm Hg) but a significantly (P<0.05) greater constriction of SHR arterioles compared with WR arterioles (at 160 mm Hg, 55+/-4% versus 38+/-2%, respectively, of passive diameter). In the absence of the endothelium, P(i)-induced changes in the R(Ca) and diameter of SHR and WR arterioles did not differ significantly. Also, a step increase in P(i) (from 80 to 140 mm Hg) elicited a similar increase in R(Ca) but greater constrictions in SHR versus WR arterioles. In the presence of the TxA(2) receptor inhibitor SQ29,548 and the ET(A) receptor inhibitor BQ123, there was no difference between responses of SHR and WR arterioles. In WR arterioles, increasing concentrations of KCl elicited a significant increase in R(Ca) (38+/-7% at 80 mmol/L) and completely constricted the arterioles. In contrast, constrictions to ET (52+/-7% at 3x10(-12) mol/L) and the TxA(2) agonist U46619 (40+/-8% at 3x10(-9) mol/L) were not accompanied by increases in R(Ca) at submaximal concentrations. Collectively, these findings suggest that in hypertension, endothelium-derived ET and PGH(2)/TxA(2) increase the Ca(2+) sensitivity of the contractile apparatus of arteriolar smooth muscle; thus, the similar increases in [Ca(2+)](i) in response to the elevation of intraluminal pressure elicit greater myogenic constriction.

Topics: Animals; Arterioles; Calcium; Constriction, Pathologic; Cytophotometry; Disease Models, Animal; Endothelins; Endothelium; Hypertension; Microscopy, Video; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Rats, Wistar; Thromboxane A2; Vascular Resistance

The arteries of aged spontaneously hypertensive rats (SHR) exhibit spontaneous electrical activity together with membrane depolarization. Vascular eicosanoid production is increased in SHR, which is further accelerated with aging. We tested the hypothesis that eicosanoids are involved in spontaneous electrical activity, membrane depolarization or both in mesenteric arteries of aged SHR.. Membrane potentials were recorded with microelectrodes from the mesenteric arteries of aged (24 months and older) SHR, aged Wistar-Kyoto (WKY) rats and adult (6- to 8-month-old) SHR.. The membrane potential was less negative in aged SHR (-38.5 +/- 0.9 mV) than in either aged WKY rats or adult SHR (-49.8 +/- 0.5 and -47.2 +/- 0.6 mV, respectively; P < 0.05 for both). Spontaneous electrical activity (5-20 mV, 1-7/min) was present only in arteries of aged SHR. Spontaneous electrical activity was not affected by phentolamine, atropine or tetrodotoxin, but was abolished by indomethacin, a cyclooxygenase inhibitor, and ONO-3708, a thromboxane A2/prostaglandin H2 receptor antagonist. Furthermore, indomethacin and ONO-3708 hyperpolarized the membrane by about 5 mV in aged SHR but not in the other two groups. Spontaneous electrical activity was enhanced by a thromboxane A2 analog and prostaglandin H2, and was abolished by a Ca2+ antagonist, nicardipine, and Ca(2+)-free solution.. These findings suggest that cyclooxygenase-dependent eicosanoids contribute importantly to both spontaneous electrical activity and membrane depolarization, presumably through activation of the thromboxane A2/prostaglandin H2 receptor, in mesenteric arteries of aged SHR, and that spontaneous electrical activity is mediated by a Ca2+ influx through voltage-dependent Ca2+ channels.

Topics: Aging; Animals; Atropine; Blood Pressure; Calcium Channels; Cyclooxygenase Inhibitors; Eicosanoids; Hypertension; Indomethacin; Male; Membrane Potentials; Mesenteric Artery, Superior; Microelectrodes; Muscle, Smooth, Vascular; Phentolamine; Platelet Aggregation Inhibitors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrodotoxin; Thromboxane A2

This study was performed to clarify the mechanism of vasoconstriction induced by oxygen-derived free radicals in spontaneously hypertensive rats. The isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats was measured in Krebs-Henseleit solution. Oxygen-derived free radicals were generated by mixing xanthine and xanthine oxidase. The removal of endothelium enhanced the contractions induced by oxygen-derived free radicals. The inhibition of nitric oxide production with NG-nitro-L-arginine methyl ester (10(-4) M) enhanced the contractions. Treatment with the thromboxane A2 (TXA2) synthetase inhibitor OKY-046 (10(-4) M) or RS-5186 (10(-4) M) markedly reduced the contractions. Treatment with the cyclooxygenase inhibitor indomethacin (10(-5) M) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist, ONO-3708 (10(-6) M), completely abolished the oxygen-derived free radical-induced contractions. In contrast, treatment with the PGI2 synthetase inhibitor tranylcypromine (10(-4) M) did not attenuate the oxygen-derived free radical-induced contractions. Whether endothelium was present or not, the release of TXB2, PGE2, and 6-keto-PGF1alpha, but not PGF2alpha, was increased by the production of oxygen-derived free radicals. Catalase and the hydroxyl radical scavenger deferoxamine plus mannitol markedly inhibited the oxygen-derived free radical-induced contractions. These results suggest that oxygen-derived free radical-induced vasoconstriction in spontaneously hypertensive rat aorta is caused by TXA2 and PGH2 released in smooth muscle.

Topics: Animals; Aorta; Cyclooxygenase Inhibitors; Endothelium, Vascular; Free Radical Scavengers; Free Radicals; Hypertension; Male; Nitric Oxide; Oxygen; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

We have previously shown that in the rat a diet high in cholesterol and deficient in vitamin E and selenium results in hypercholesterolaemia and increased lipid oxidation. We utilized this model to determine whether rats given this diet develop impaired endothelium-dependent relaxation mediated by nitric oxide (NO) in mesenteric and in renal vessels. In addition, we tested whether the impairment is due to (i) decreased endothelial NO synthase activity, (ii) increased NO inactivation and/or (iii) increased production of the endothelium-derived constricting factors thromboxane A2/prostaglandin H2 and endothelin-1. We also investigated whether endothelial dysfunction induced by dyslipidaemia increases the sensitivity for the development of hypertension in response to high dietary salt.. Male Dahl salt-sensitive (DSS) rats were divided into three groups and received a standard diet (control group), a high (4%) cholesterol diet (HChol), or a high cholesterol diet deficient in the anti-oxidants vitamin E and selenium (HChol-Def). The NaCl content of these diets was 0.5%. After 18 weeks we studied endothelium-dependent relaxation in response to acetylcholine (ACh) in aortas and in isolated perfused preparations of mesenteric arteries and kidneys. In some experiments, ifetroban, a thromboxane A2/prostaglandin H2 receptor antagonist, was added to the organ bath or the perfusion buffer. Vascular responses to endothelin-1 as well as to BQ-123, an endothelin A receptor blocker, were studied in the isolated perfused kidneys. In addition, two extra groups of rats were fed a diet high in sodium chloride (2%): one of the groups received the normal cholesterol diet whereas the other group received the diet high in cholesterol and deficient in vitamin E and selenium.. Compared to normocholesterolemic rats, responses to ACh were significantly impaired in aortas, mesenteric arteries and kidneys of HChol-Def rats (P < 0.01). Endothelial NO synthase activity (conversion of [14C]L-arginine to [14C]L-citrulline) was similar in aortas of control, HChol and HChol-Def rats; thus suggesting that impaired endothelium-dependent relaxation in the HChol-Def rats was not due to decreased cNOS catalytic activity. Ifetroban improved the impaired endothelium-dependent relaxation in mesenteric vessels, but not in aortas and kidneys. Endothelin-1 (ET-1: 10(-13)-10(-11) mol/l) elicited NO-mediated relaxations in kidneys of control rats but not in kidneys of HChol-Def; blockade of ET-1 with BQ-123, an ET(A) receptor blocker, did not improve NO-mediated relaxation of HChol-Def. Despite impaired endothelium-dependent relaxation in renal and mesenteric vessels, HChol-Def DSS rats failed to develop hypertension (systolic blood pressure 144 +/- 1 in control and 150 +/- 2 mmHg in HChol-Def) but manifested a significant increase in sensitivity to the pressor effects of a high (2% NaCl) dietary salt content during the initial 10 weeks of the study, although the final blood pressure at 18 weeks was similar in both groups.. These studies support the notion that (i) products of lipid oxidation may reduce NO bioactivity without affecting endothelial NO synthase mass or catalytic activity, (ii) the mechanisms involved in the endothelial dysfunction induced by hypercholesterolaemia and oxidized lipids may differ among vascular beds, and (iii) decreased NO bioavailability does not necessarily result in systemic hypertension, but it may enhance the sensitivity to the hypertensinogenic effect of dietary salt.

Topics: Acetylcholine; Animals; Aorta; Blood Pressure; Body Weight; Diet; Disease Models, Animal; Endothelin-1; Endothelins; Endothelium, Vascular; Hypercholesterolemia; Hypertension; Kidney; Male; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Synthase; Perfusion; Prostaglandin H2; Prostaglandins H; Rats; Thromboxane A2

Prostacyclin (PGI2), thromboxane A2 (TXA2) and F2-isoprostanes, prostaglandin F2-like compounds, have wide and contrasting spectrum of biological activities and may influence blood pressure and atherogenesis. To investigate the dynamics of PGI2, TXA2 and F2-isoprostanes in patients with hypertension and hyperlipidemia (HH group), we measured the major urinary metabolites of PGI2: 6-keto PGF1alpha (Keto) and 2,3-dinor-6-keto PGF1alpha, (Dinor), those of TXA2:TXB2 and 11-dehydro TXB2 (Dehydro), and urinary 8-isoprostane (Iso) in 34 patients. Urinary excretion of Dinor was significantly lower in patients than in controls and that of Dehydro was significantly higher in patients than in controls. Keto, TXB2 and Iso were not significantly different between them. Antiplatelet agents decreased not only TXA2 metabolites but also PGI2 metabolites. Urinary C-peptide immunoreactivity was correlated with Dinor and Dehydro. After administration of eicosapentaenoic acid (EPA), total cholesterol (T-cho) and triglycerides (TG) significantly decreased. Although prostanoids did not show significant change, changes in T-cho were correlated with changes in Dinor and changes in Iso. These results suggest that PGI2 and TXA2 of systemic origin might be related to the pathophysiology of hypertension and hyperlipidemia and that the dynamics of PGI2, TXA2 and F2-isoprostanes might be related to not only blood pressure regulation but also lipid and glucose metabolism.

Topics: Aspirin; Dinoprost; Dipyridamole; Eicosapentaenoic Acid; Epoprostenol; Humans; Hyperlipidemias; Hypertension; Platelet Aggregation Inhibitors; Thromboxane A2; Ticlopidine

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

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

Ridogrel is a dual acting thromboxane synthase inhibitor/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B2 or 6-keto-prostaglandin F1alpha, although ex vivo serum thromboxane B2 was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200+/-6.1 to 173+/-6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B2 and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B2 excretion (from 103+/-7 ng/day to 49+/-10 ng/day, P<0.01) while preserving 6-keto-prostaglandin F1alpha excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F1alpha in addition to attenuating serum and urine thromboxane B2. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hypertension; Male; Pentanoic Acids; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Thromboxane; Systole; Thromboxane A2; Thromboxane-A Synthase

Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252, on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35 +/- 5 mm Hg; tail-cuff method) compared with placebo (P < .05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase (P < .05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group (P < .05 versus placebo) and improved by concomitant chronic LU135252 treatment (P < .05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine (r = -.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment (P < .05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 (P < .05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P < .05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.

Topics: Acetylcholine; Angiotensin II; Animals; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Rats; Rats, Inbred WKY; Thromboxane A2; Vasoconstrictor Agents

We examined the hypothesis that activity of Ca2+-dependent K+ channels is increased in the basilar artery during chronic hypertension. Diameter of the basilar artery was measured using a cranial window in anesthetized normotensive Wistar-Kyoto rats (WKY, arterial pressure = 109 +/- 3 mmHg, mean +/- SE) and stroke-prone spontaneously hypertensive rats (SHRSP, arterial pressure = 179 +/- 4 mmHg). Responses of the basilar artery to topical application of tetraethylammonium ion (TEA), an inhibitor of Ca2+-dependent K+ channels, were examined in WKY and SHRSP. Vessel diameter decreased by 2 +/- 1 and 4 +/- 0.1% in WKY and by 7 +/- 2 and 18 +/- 1% in SHRSP (P < 0.05 vs. WKY) in response to 10(-4) and 10(-3) M TEA, respectively. Similar results were obtained using iberiotoxin (10(-8) and 10(-7) M), a highly selective inhibitor of Ca2+-dependent K+ channels. In contrast to constrictor responses to TEA and iberiotoxin, constrictor responses of the basilar artery in response to serotonin and U-46619 were similar in WKY and SHRSP. In WKY rats that were made chronically hypertensive (arterial pressure = 172 +/- 6 mmHg) after treatment for 4 wk with N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, constriction of the basilar artery in response to TEA was also enhanced. These findings suggest that activity of Ca2+-dependent K+ channels is enhanced in the basilar artery in vivo in two models of chronic hypertension. Thus Ca2+-dependent K+ channels in the basilar artery may be activated during chronic hypertension, perhaps as a response to elevation of intracellular concentration of Ca2+.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Basilar Artery; Calcium; Hypertension; Muscle Contraction; Peptides; Potassium Channel Blockers; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Tetraethylammonium; Tetraethylammonium Compounds; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Wasp Venoms

Diabetes and hypertension are both associated with an increased risk of renal disease. The combination of these diseases produces marked acceleration of the problems.. To examine the reactivity in the renal vasculature of diabetic hypertensive rats.. We investigated the reactivity towards 5-hydroxytryptamine (5-HT) in Krebs solution-perfused kidneys of diabetic normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In addition, the interaction between the thromboxane A2 mimetic U46619 and 5-HT was examined.. Discrete dose-response curves were obtained for the response to 5-HT (0.1-30 micrograms/g kidney) in Krebs solution-perfused kidneys of control and diabetic WKY rats and SHR. The following order of reactivity was determined: control SHR > diabetic SHR > control WKY rats = diabetic WKY rats. The thromboxane A2 mimetic U46619 (10 ng/ml) potentiated responses to 5-HT significantly in kidneys of diabetic WKY rats and control SHR, but not in kidneys from control WKY rats and diabetic SHR.. The differential affected reactivity towards 5-HT kidneys from diabetic and hypertensive rats might be due to previously documented differences in receptor number. The marked effect of U46619 on the reactivity towards 5-HT in kidneys of diabetic and control rats indicates that this interaction might be important given the increased levels of thromboxane A2 reported to occur in these diseases. The reason for the lack of effect of thromboxane/prostaglandin receptor stimulation on responses to 5-HT in the combined model (i.e. diabetic hypertensive rats) needs to be determined.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Synergism; Hypertension; In Vitro Techniques; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

We have recently reported in normal isolated-perfused rat lungs that low basal tone appears to be regulated by nitric oxide (NO)-dependent and -independent mechanisms of soluble guanylate cyclase activation. In this study, we examined the role of NO in the regulation of pulmonary artery (PA) tone from rats with renin-dependent hypertension. Rats were made hypertensive by ligating the abdominal aorta above the left and below the right renal artery (aortic coarctation, AC). Mean arterial pressure significantly increased from 119 +/- 8.4 mmHg in control animals to 156 +/- 15 mmHg 7-14 days after AC surgery. PA pressures, however, remained unchanged (8.5 +/- 3.4 mmHg in control animals vs. 11 +/- 3.3 mmHg in AC animals). Hypoxic contractions in U-46619 precontracted isolated small PA (160-260 microns diameter) were significantly increased from 51 +/- 13 mg in the control group to 142 +/- 38 mg (P < or = 0.05) in AC animals. Nitro-L-arginine (NLA; 100 microM) contractions were also enhanced in the AC animal. The enhanced NLA response may correlate with an increase in endothelial cell NO synthase (NOS) as detected by Western blotting (132 +/- 28% of control; P < 0.05). These data suggest that, in this renin-dependent model of systemic hypertension, there is increased endothelial cell NOS activity that maintains low PA tone, preventing the lung from developing increased pressures.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Abdominal; Aortic Coarctation; Blood Pressure; Endothelium, Vascular; Guanylate Cyclase; Hypertension; Hypoxia; In Vitro Techniques; Male; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Regression Analysis; Renin; Thromboxane A2; Vasoconstrictor Agents

The thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptor mimetic U-46619 (0.6 microgram.kg-1.min-1) was infused into conscious rats receiving a high-salt diet. U-46619 increased the mean arterial pressure (MAP) over 13 days by 25 +/- 2 mmHg, whereas the MAP of vehicle-infused controls did not change (-2 +/- 2 mmHg). In subgroups infused with U-46619, cardiac output was unchanged, whereas renal blood flow was reduced (before: 8.5 +/- 0.8; day 4: 5.7 +/- 0.7 ml/min; P < 0.01). Ifetroban (a specific TxA2/PGH2 receptor antagonist) reduced MAP to basal levels in the group receiving U-46619 when infused intravenously (1-100 micrograms/kg) but not intracerebroventricularly (1-100 ng/kg). Hexamethonium (10 mg/kg i.v., a ganglionic blocking agent) and prazosin (0.1 mg/kg, an alpha-adrenergic antagonist) decreased MAP significantly (P < 0.05) more in the experimental group (hexamethonium, U-46619: -55 +/- 3 vs. vehicle: -43 +/- 4 mmHg; and prazosin, U-46619: 28 +/- 3 vs. vehicle: 17 +/- 2 mmHg). In conclusion, hypertension during prolonged infusions of U-46619 into conscious, salt-loaded rats is accompanied by an increase in total and renal vascular resistance and is dependent on peripheral but not central TxA2/PGH2 receptors and on the autonomic and alpha 1-adrenergic peripheral sympathetic nervous systems.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Heart Rate; Hexamethonium; Hypertension; Male; Oxazoles; Prazosin; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Sympathetic Nervous System; Thromboxane A2; Time Factors; Vasoconstrictor Agents

Our study was designed to investigate whether angiotensin II subtype 1 (AT1) receptors are involved in the constrictor responses evoked by endothelin-1 and the thromboxane A2 analogue U46619 in aortic rings from spontaneously hypertensive rats (SHR), by studying the effect of the AT1 receptor antagonist losartan. In addition, since nitric oxide seems to participate in the mechanism of action of losartan, we studied the effect of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on the action of losartan.. Dose-response curves of either endothelin-1 (10(-10) to 10(-7) mol/l) or U46619 (10(-10) to 10(-6) mol/l) were studied in the presence or absence of losartan (10(-5) mol/l) in aortic rings from SHR. Likewise, similar experiments were done in aortic rings pretreated with the nitric oxide synthesis inhibitor, L-NAME (10(-4) mol/l).. Pre-incubation with losartan significantly reduced the contractile response to endothelin-1 compared with control rings, without modifying the value represented by 50% of the maximal response (pD2). The concentration-response curve to U46619 was shifted to the right in the presence of losartan, reducing the pD2 compared with control rings. The presence of captopril (10(-5) mol/l) in the incubation media did not alter the response to either endothelin-1 or U46619. The diminished response to both endothelin-1 and U46619 in the presence of losartan was reversed in L-NAME-pretreated rings.. Angiotensin II seems to participate in the vasoconstriction induced by both endothelin-1 and the thromboxane A2 analogue through the stimulation of AT1 receptors in SHR aortic rings, because losartan inhibited this effect. Moreover, nitric oxide appears to be involved in this action of losartan.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Aorta, Thoracic; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Hypertension; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

To determine whether opening of coronary vascular adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels is involved in the maintenance of resting coronary flow in hypertrophied hearts.. We examined the effects of glibenclamide, a selective inhibitor of KATP channels, on basal coronary vascular tone in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Using a Langendorff system, the hearts from WKY rats and SHRs were isolated and perfused with oxygenated Krebs-Henseleit solution at a constant perfusion pressure of 60 and 100 mmHg respectively.. Basal coronary flow and myocardial oxygen consumption (MV02) were similar in SHRs and WKY rats. The percentage decreases in coronary flow with glibenclamide at graded doses were greater (P < 0.01) in SHRs than in WKY rats (n = 8), whereas the percentage decreases in MV02 with glibenclamide were similar in the two groups. The decreases in coronary flow caused by U46619 (a thromboxane A2-mimetic agent) were similar in SHRs and WKY rats (n = 4). The increase in coronary flow caused by pinacidil (a KATP opener) was greater in SHRs than in WKY rats; glibenclamide prevented the pinacidil-induced increase in coronary flow in both SHRs and WKY rats. There was a significant positive correlation between the glibenclamide-induced decrease in coronary flow and the degree of left ventricular hypertrophy (r = 0.54, P < 0.05).. Our results suggest that the basal opening state of coronary vascular KATP channels is activated to a greater extent in SHRs than WKY rats, which may contribute to the maintenance of basal myocardial perfusion in hypertrophied hearts.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Vessels; Glyburide; Guanidines; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Organ Size; Oxygen Consumption; Pinacidil; Potassium Channel Blockers; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Drug Administration Schedule; Hypertension; Hypertension, Pulmonary; Hypoxia; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Sheep; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

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

Whether the alterations in the synthesis of thromboxane A2 (TXA2) is the direct mechanism underlying the blood pressure-lowering effect of fish oil was investigated in this study. Six groups of 11 male spontaneously hypertensive rats were fed semipurified diets containing corn or fish oils and graded levels (50, 5000 or 15,000 ppm) of dietary vitamin E for 8 weeks. Plasma TXA2, assayed by RIA, was significantly greater in the corn oil group than in the fish oil group (P < 0.05). Compared to 50 ppm dietary vitamin E, 5000 and 15 000 ppm dietary vitamin E, respectively, significantly decreased plasma TXA2 (P < 0.05). Systolic, mean or diastolic blood pressure, evaluated by the tail cuff method, were significantly higher in the corn oil group than in the fish oil group (P < 0.05). However, vitamin E had no effect on blood pressure. No relationship between TXA2 and blood pressure was found. Experimental results indicated that the alterations in the synthesis of TXA2 were not the direct antihypertensive effect of fish oil.

Topics: Animals; Blood Pressure; Corn Oil; Diet; Disease Models, Animal; Fatty Acids; Fatty Acids, Unsaturated; Fish Oils; Hypertension; Lipid Peroxidation; Male; Peroxides; Rats; Rats, Inbred Strains; tert-Butylhydroperoxide; Thromboxane A2; Vitamin E

Differences in alpha(2)-adrenoceptor-induced relaxation of the aorta between stroke-prone spontaneously hypertensive rats (SHRSP) and control normotensive Wistar Kyoto rats (WKY) were studied. Changes in the tension of ring preparations of the aortas were measured isometrically. Relaxation was observed in the preparations precontracted in the presence of ONO-11113, a thromboxane A(2) analogue. The alpha(2)-agonist clonidine and UK-14304 induced dose-dependent relaxation in both the WKY and SHRSP preparations. The relaxation was impaired in the SHRSP preparation. A modified sandwich experiment showed that the relaxing substance from the SHRSP endothelium was decreased. Acetylcholine (ACh) also induced dose-dependent relaxation, and the relaxation was impaired in the SHRSP preparations. alpha(2)-Agonists induced a greater degree of impairment in the relaxation than did ACh. The relaxation induced by alpha(2)-agonists and by ACh was blocked by N G-nitro-L-arginine (L-NNA). Indomethacin improved the relaxation induced by ACh but not that induced by alpha(2)-agonists in the SHRSP aortas. These results suggest that the impairment of relaxation by alpha(2)-agonists in SHRSP is not caused by the increase in the release of endothelium-derived contracting factor (EDCF) but by the reduction in the release of nitric oxide (NO). Alteration of the alpha(2)-adrenoceptors and/or the intracellular mechanism through which NO is synthesized by stimulation of the alpha(2)-adrenoceptors may be the cause of the reduction in relaxation.

Topics: Acetylcholine; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Aorta; Brimonidine Tartrate; Endothelium, Vascular; Hypertension; Indomethacin; Nitroarginine; Quinoxalines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasodilation

To explore the mechanism(s) by which antiestrogens may protect against the development of cardiovascular disorders, we measured the production of vasodilatory, antiaggregatory prostacyclin (PGI2) and that of vasoconstrictive, proaggregatory thromboxane A2 (TxA2) before and after 6 months' use of antiestrogens in postmenopausal patients after operation for stage II breast cancer (n = 38). Urine samples were assayed by high performance liquid chromatography and radio-immunoassays for 2,3-dinor-6-ketoprostaglandin F1 alpha (= metabolite of PGI2, dinor-6-keto) and for 2,3-dinor-thromboxane B2 (= metabolite of TxA2, dinor-TxB2). In addition, in 35 of these 38 patients we assayed the capacity of platelets to produce thromboxane A2 during standardized blood clotting. The 4 patients using low-dose aspirin had low thromboxane production, and were excluded from further analysis of the data. An antiestrogen regimen consisting either of tamoxifen (n = 15) or of toremifene (n = 19) caused no changes in production of PGI2 or TxA2, or in their ratio, and in this regard, these antiestrogens behaved similarly. Hypertensive patients (n = 7) using different anti-hypertensive agents were characterized by reduced urinary out-put of dinor-6-keto (18.5 +/- 6.1 vs 35.5 +/- 18.5 ng/mmol, mean +/- SD, p < 0.05) and reduced platelet capacity to produce TxA2 (62.6 +/- 67.8 vs 134.6 +/- 75.6 ng/mL, p < 0.05). The patients (n = 15) who had used estrogen replacement therapy (ERT) up until diagnosis of breast cancer showed reduced dinor-TxB2 excretion (15.5 +/- 12.7 vs 29.9 +/- 20.9 ng/mmol, p < 0.05) before initiation of antiestrogens, and elevated dinor-6-keto output during the antiestrogen regimen (32.4 +/- 21.2 vs 22.7 +/- 8.7 ng/mmol, p = 0.07). Smokers (n = 6) had elevated dinor-TxB2 output before and during antiestrogen use. Thus we conclude that the cardiovascular protection provided by an antiestrogen regimen is unlikely to be mediated through vaso- and platelet active PGI2 and TxA2.

Topics: Aged; Breast Neoplasms; Epoprostenol; Estrogen Antagonists; Estrogens; Female; Humans; Hypertension; Menopause; Middle Aged; Molecular Structure; Smoking; Tamoxifen; Thromboxane A2; Toremifene

Chronic nitric oxide inhibition promotes hypertension, renal dysfunction, and renal injury by unclear mechanisms. We examined the effects in this model of concomitant treatment with the calcium channel blocker nifedipine. Six adult male Munich-Wistar rats received 0.025% nifedipine in chow. Six untreated rats served as controls. Fifteen days later, renal function was evaluated in anesthetized rats before and after a bolus injection of the nitric oxide inhibitor N omega-nitro-L-arginine methyl ester at 3 mg/kg IV. Renal vasoconstriction and systemic hypertension induced by the inhibitor were similar in untreated and nifedipine-treated rats. In a second protocol, eight rats received the nitric oxide inhibitor in their drinking water at 2.6 mmol/L. Eight additional rats also received nifedipine as above. At day 15, rats given the nitric oxide inhibitor exhibited systemic hypertension and renal vasoconstriction. Simultaneous nifedipine lowered blood pressure slightly without ameliorating renal hemodynamics. Tail-cuff pressure rose continuously in rats receiving the nitric oxide blocker, reaching 171 +/- 7 mm Hg at 30 days, but remained at 143 +/- 3 mm Hg in rats also given nifedipine. At this stage, rats treated with the nitric oxide inhibitor exhibited extremely variable plasma renin activity, tuft collapse in 10.1 +/- 2.2% of the glomeruli, and renal interstitial fibrosis. Simultaneous nifedipine treatment normalized the dispersion of plasma renin levels, while preventing renal morphological abnormalities. These results suggest that in the chronic nitric oxide inhibition model, sustained operation of voltage-sensitive calcium channels is not essential for renal vasoconstriction but contributes to systemic hypertension and plays a pivotal role in the development of renal structural injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Arginine; Blood Pressure; Calcium Channel Blockers; Hemodynamics; Hypertension; In Vitro Techniques; Kidney; Kidney Glomerulus; Male; Nephritis, Interstitial; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide; Norepinephrine; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Thromboxane A2; Time Factors; Vasoconstrictor Agents

Recent studies have reported elevated prostaglandin levels in patients with renal artery stenosis and hypertension. To investigate whether a distinction between essential hypertension and hypertension with renal artery stenosis is possible by measuring eicosanoid excretion, we studied the excretion of these compounds in patients with essential hypertension and in hypertensives with concomitant renal artery stenosis.. The 24-h urinary excretion of metabolites of prostaglandin I2, prostaglandin E2 and metabolites of thromboxane A2 was sampled under standardised conditions, in 15 patients with essential hypertension and in 15 patients with unilateral renal artery stenosis with hypertension. Also clinical and biochemical characteristics of the subjects were analysed.. The patients with renal artery stenosis had significantly lower excretion of prostaglandin I2 than did the essential hypertensive patients. However, the overlap in the values was large, thus not allowing a diagnostic differentiation according to urinary prostaglandin I2 levels. The excretion of prostaglandin E2 and of metabolites of thromboxane A2 showed no significant differences among the groups.. Measurement of urinary prostaglandin or prostaglandin metabolite excretion did not contribute to the non-invasive detection of the presence of a renal artery stenosis in the patients in this study.

Topics: Adult; Aged; Dinoprostone; Epoprostenol; Female; Humans; Hypertension; Hypertension, Renovascular; Logistic Models; Male; Middle Aged; Renal Artery Obstruction; Thromboxane A2

This study was designed to examine the impairment of endothelium-dependent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A2-prostaglandin endoperoxide (TP)-receptor blocker, and to establish whether endothelial dysfunction contributes to the elevated blood pressure. In isolated aortic rings from SHR, endothelium-dependent relaxations caused by acetylcholine, adenosine diphosphate, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contractions were significantly enhanced in aorta from SHR. In contrast, relaxations caused by direct smooth muscle vasodilators, nitroprusside and cromakalim, and contractions caused by U-46619 were not different between SHR and WKY rats. Treatment of SHR with the oral TP-receptor antagonist, ifetroban, at 20 and 50 mg.kg-1.day-1 fully restored endothelium-dependent relaxation toward normal. However, ifetroban produced no effect on blood pressure in SHR. In vitro incubation of aortic rings from SHR with ifetroban also normalized relaxations to acetylcholine but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acetylcholine-induced relaxations in aorta from SHR. The results demonstrate that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial cell dysfunction and TP-receptor activation may not significantly contribute to elevated systemic blood pressure in SHR.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Arachidonic Acid; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Endothelium, Vascular; Hypertension; Male; Oxazoles; Propionates; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Thromboxane; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

We investigated endothelium-dependent responses of thoracic aorta isolated from age-matched male and female spontaneously hypertensive rats (SHR) to explore gender differences in endothelial dysfunction that may contribute to the sexual dimorphism observed in the development of hypertension in this strain. Endothelium-dependent relaxation in response to acetylcholine (10(-9) to 10(-4) mol/L) was significantly greater in female rats than in male rats, although impaired responses were seen in both sexes compared with normotensive controls. Inhibition of cyclooxygenase by indomethacin (10(-5) mol/L) improved endothelium-dependent relaxation, but it did not abolish the gender difference. Relaxations in response to sodium nitroprusside were identical in denuded aortic rings from male and female SHR. Acetylcholine at higher concentrations (10(-6) to 10(-4) mol/L) induced endothelium-dependent contraction in intact, quiescent aortic rings from male SHR but not in those from female SHR. After incubation with NG-nitro-L-arginine (10(-4) mol/L), contraction in response to acetylcholine became apparent in rings from female SHR, but it was still significantly less pronounced than in similarly treated rings from male SHR. Endothelium-dependent contraction was prevented by indomethacin in both sexes, suggesting that a cyclooxygenase product such as endoperoxide may be mediating this effect. Because responses evoked by the thromboxane/endoperoxide receptor agonist U46619 (10(-10) to 10(-6) mol/L) were not greater in rings from male SHR than those from female SHR, increased smooth muscle responsiveness or higher thromboxane/endoperoxide receptor density in the males could not account for the differences in endothelium-dependent contraction. These results suggest that sex steroid hormones may control endothelium-dependent vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta; Body Weight; Endothelium, Vascular; Female; Hypertension; Male; Nitric Oxide; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Wistar; Sex Characteristics; Species Specificity; Thromboxane A2; Vasoconstrictor Agents

To determine if hyperinsulinemia, hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein (HDL) cholesterol are present in women with pregnancy-induced hypertension or preeclampsia.. Serum concentrations of insulin, uric acid, total and lipoprotein cholesterol, triglyceride, and apolipoproteins A-I and B were measured in 31 women with pregnancy-induced hypertension (eight with proteinuria) and in 21 healthy, pregnant, weight-matched controls at 30-39 weeks' gestation. The urinary excretion of the stable metabolites of prostacyclin (PGI2) (6-keto-prostaglandin [PG] F1 alpha and 2,3-dinor-6-keto-PGF1 alpha) and thromboxane A2 (TxA2) (thromboxane B2 and 2,3-dinor-thromboxane B2) was assessed in 17 women with pregnancy-induced hypertension and in eight controls.. Women with pregnancy-induced hypertension exhibited 18% lower mean serum HDL2 cholesterol levels (0.9 versus 1.1 mmol/L, P < .05) and 65% higher mean triglyceride levels (3.3 versus 2.0 mmol/L, P < .05) compared to controls, whereas other serum lipid and apolipoprotein values did not differ significantly in the two groups. Mean serum insulin levels (13.3 versus 6.5 mU/L, P < .01) and uric acid levels (339.7 versus 231.2 mumol/L, P < .01) in patients with pregnancy-induced hypertension were significantly higher than those in the controls. Urinary output of PGI2 metabolites was reduced by 35-45% in patients with pregnancy-induced hypertension, whereas no differences were seen in the excretion of TxA2 metabolites. Serum HDL2 cholesterol concentrations correlated positively with 2,3-dinor-6-keto-PGF1 alpha excretion, and serum triglyceride concentrations correlated positively with 2,3-dinor-thromboxane B2 excretion. In addition, insulin levels correlated positively with triglyceride levels but negatively with HDL2 cholesterol concentrations.. The metabolic characteristics (hypertriglyceridemia, hyperinsulinemia, hyperuricemia, low HDL2 cholesterol) in pregnancy-induced hypertension resemble the main features of the "insulin resistance syndrome." This may result in endothelial cell dysfunction as evidenced by PGI2 suppression.

Topics: Apolipoprotein A-I; Apolipoprotein A-II; Case-Control Studies; Cholesterol; Epoprostenol; Female; Humans; Hypertension; Insulin; Insulin Resistance; Lipids; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Triglycerides; Uric Acid

Our purpose was to determine the effect of oxidized lipids on the contractile activity of isolated human umbilical arteries.. Umbilical artery rings were prepared for isometric tension recording and exposed to cumulative concentrations of oxidized and nonoxidized lipid and control solutions. Rings were also incubated with the lipid or control solutions and then contracted with cumulative concentrations of U46619. A final set of rings in Ca(++)-free depolarized solution was incubated with the agents above, and then the Ca++ concentration was increased cumulatively.. The lipids had no direct contractile effect. Both lipids inhibited the response to U46619 and Ca++, with the oxidized lipids having the most significant effect.. Oxidized lipids lack a direct contractile effect on isolated human umbilical arteries and inhibit the contractile response to thromboxane and calcium.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Calcium; Dose-Response Relationship, Drug; Female; Humans; Hypertension; In Vitro Techniques; Isotonic Solutions; Lipid Peroxides; Muscle Contraction; Muscle, Smooth, Vascular; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Umbilical Arteries; Vasoconstrictor Agents

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

High potassium (K) diets are known to have a protective effect on the endothelium and the kidney against hypertensive injury independent of blood pressure change. Vasodepressor prostaglandins (PGs) have been shown to be cytoprotective in various tissues. This study investigated the effect of high K diets on the vascular and renal eicosanoid system in stroke-prone spontaneously hypertensive rats (SHRsp). Eicosanoid production by the aorta and eicosanoid content in the renal cortex were examined in SHRsp rats fed high NaCl diets containing either 0.5% K (normal) or 2.1% K (high). Although the high K diet did not affect the blood pressure, SHRsp on the high K diet had less thickening of the aortic wall than SHRsp on the normal K diet (-15%, p < 0.001). The aortic strip of the high K SHRsp produced less vasodepressor PG than that of the normal K SHRsp when they were incubated in a medium (PGI2 -45%, p < 0.003; PGE2 -34%, p < 0.001). Furthermore, when the aorta was perfused in a chamber at hypertensive pressure, again the high K aorta showed reduced PGI2 production as compared with the normal K aorta (intravascular side -52%, p < 0.01). Eicosanoid content in the renal cortex was not significantly different between the normal K and the high K SHRsp (PGI2 79 vs 87 ng/g dry weight; PGE2 214 vs 233 ng/g dry weight). Thus, the high K diet reduced vascular eicosanoid production but did not alter eicosanoid content in the renal cortex. The reduced vascular eicosanoid production in the high K SHRsp may reflect the reduced necessity for cytoprotective vasodepressor PG against vascular injuries.

Topics: Administration, Oral; Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Body Weight; Cerebrovascular Disorders; Diet; Dinoprostone; Epoprostenol; Hypertension; Kidney Cortex; Male; Organ Size; Perfusion; Potassium; Prostaglandins; Rats; Rats, Inbred SHR; Thromboxane A2

In the present study, we successfully established a "tissue explant technique" to obtain high yield and purity of endothelial cells from the aorta of hypertensive and normotensive rats (SHR and WKY). Small pieces of aorta were placed on fibronectin precoated petri dishes. The effects of oxygenation in the tissue preparation stage, tilting of the petri dish during the explanting period and timing of the removal of tissue blocks from petri dishes were evaluated. These procedures appeared to be critical for cell survival, tissue adhesion and minimizing of non-endothelial cell contamination. The cultured endothelial cells were characterized by morphological, immunohistochemical and biochemical examination. The cultured cells from both SHR and WKY rats showed similar endothelial cell character, positive immunofluorescence staining for the von Willebrand factor, and uptake of acetylated low-density lipoprotein (DiI-ac-LDL). The secretory function of prostacylcin I2 (PGI2), thromboxane A2 and endothelin of cultured endothelial cells was measured. The results showed that the secretion of both PGI2 and endothelin was greater in SHR than in WKY rats, but that there was no difference in thromboxane A2 secretion. Therefore, our "tissue explant technique" can provide high yield and purity of endothelial cells with their specific biological function in vitro. It will permit us to further study the role of endothelial cells in the development of hypertension.

Topics: Animals; Aorta, Thoracic; Cell Division; Cells, Cultured; Culture Techniques; Endothelins; Endothelium, Vascular; Epoprostenol; Factor VIII; Fluorescent Antibody Technique; Hypertension; Indicators and Reagents; Lipoproteins, LDL; Male; Microscopy, Electron, Scanning; Organ Culture Techniques; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Tunica Intima; von Willebrand Factor

Cardiorespiratory variables were measured continuously in five conscious goats before and after the infusion of U-46619 at a dose of either 2, 4, or 6 micrograms.kg-1.5 min-1. Infusion of U-46619 led to immediate increases in pulmonary arterial blood pressure (ABP) that were sustained for up to 15 min after the end of the infusion. Systemic ABP also increased, but the relative increase from control was less than the pulmonary pressor response. At the highest dose, U-46619 elicited a delayed tachypneic response that was greatest several minutes after the infusion was stopped. U-46619 was also infused simultaneously with sodium nitroprusside to clamp ABP pressure at baseline levels to determine whether stimulation of baroreceptors might contribute to the latency of the tachypneic response. Although sodium nitroprusside infusion prevented the increase in ABP, the increase in breathing frequency was still delayed 3-4 min from the start of the infusion. We conclude that U-46619 elicits pulmonary and systemic arterial hypertension in the conscious goat. At the higher dose U-46619 also elicits a delayed tachypnea that remains delayed even if ABP is normal.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Gas Analysis; Blood Pressure; Female; Goats; Hypertension; Hypertension, Pulmonary; Nitroprusside; Phenylephrine; Pressoreceptors; Prostaglandin Endoperoxides, Synthetic; Respiration Disorders; Respiratory Mechanics; Thromboxane A2; Vasoconstrictor Agents

To study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats.. Vehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks.. Systolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out.. NKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta.. NKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.

Topics: Animals; Aorta, Thoracic; Arteries; Blood Pressure; Calcium Channel Blockers; Cerebral Arteries; Dihydropyridines; Epoprostenol; Hypertension; Kidney; Male; Nicardipine; Rats; Renal Artery; Thromboxane A2

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

In blood pressure (BP) reduction induced by gallopamil, hydralazine and prazosin in patients with essential hypertension a common trend was found in renal prostanoid production which included increased TxB2 excretion and/or augmented TxB2/6-keto-PGF1alfa ratio and, with the exception of response to prazosin, enhanced PGF2alfa excretion. Role of direct biochemical actions by the drugs in these responses was excluded by in vitro experiments with kidney slices from rats. The clinical and in vitro experimental findings suggested a mediator role of sympathetic activation but not that of the increased renin release in the urinary eicosanoid responses. Significant correlation was observed between the changes in reabsorbed amounts of sodium and excreted amounts of TxB2 and PGF2alfa. The results suggest that the reactivity of pressure type prostanoids in the kidney could be considered as part of a more complex renal counteraction to BP decrease.

Topics: Adolescent; Adult; Blood Pressure; Dinoprost; Epoprostenol; Female; Gallopamil; Glomerular Filtration Rate; Humans; Hydralazine; Hypertension; Kidney; Male; Middle Aged; Prazosin; Prostaglandins; Sodium; Thromboxane A2; Vasodilator Agents; Venous Pressure

Although platelets from patients with moderate hypertension are abnormally sensitive to agonist-induced aggregation, their sensitivity to antagonists is not known. Nitric oxide (NO) is an endogenous antagonist of platelet function. The objective of this study was to determine whether platelet sensitivity to the inhibitory activity of sodium nitroprusside, a donor of NO, is abnormal in hypertension.. Untreated patients with uncomplicated essential hypertension (mean arterial pressure > 120 mmHg) were studied. The rise in cytosolic calcium in response to 9,11-deoxy-11 alpha, 9 alpha-epoxymethanoprostaglandin F2 alpha (U46619, a thromboxane mimetic) was measured in fura-2-loaded platelets from 20 patients and 15 normotensive healthy subjects. Inhibition by sodium nitroprusside was measured in a further group of 14 patients and 20 normotensive subjects.. Basal cytosolic calcium concentration and the rise in this parameter induced by U46619 were significantly greater in platelets from hypertensive patients than in those from normotensive controls. The mean half-maximal inhibitory concentration of nitroprusside to calcium mobilization induced by 3 mumol/l U46619 was 3.1-fold greater in platelets from hypertensive patients than in those from controls (95% confidence interval 1.6-6.0).. The sensitivity of platelets to nitroprusside is reduced in essential hypertension. This reduced sensitivity to NO might influence the risk of arterial thrombosis in hypertensives.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Blood Platelets; Calcium; Cytosol; Drug Resistance; Female; Humans; Hypertension; In Vitro Techniques; Ion Transport; Male; Middle Aged; Nitric Oxide; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2

This study examined the role of endothelin (ET), the thromboxane A2 (TXA2)-prostacyclin (PGI2) ratio (TXA2/PGI2), plasma renin activity (PRA) and urinary aldosterone excretion (ALDO) in urban hypertensive patients and in the sodium pressor response in normotensives. Twenty-seven urban hypertensive patients and the same number of normotensive controls were studied on baseline diet, after 5 days of sodium restriction and after 5 days of sodium loading. Mean arterial blood pressure, plasma and ET values, PRA, TXA2/PGI2 and ALDO were assessed on each diet. The results showed that baseline PRA was suppressed in the hypertensive patients; this indicates that urbanisation-related hypertension is of the low renin type. ET levels and TXA2/PGI2 were higher in hypertensive than in normotensive subjects, suggesting an association between high blood pressure and these factors. Although the baseline PRA in hypertensives was suppressed, urinary ALDO was no different from that in the normotensive controls where PRA was normal. In addition, sodium restriction did not increase PRA in hypertensive subjects while it more than doubled it in the controls. However, ALDO in hypertensive patients increased to levels that were no different from those in the normotensive subjects. Sodium loading increased blood pressure, ET values and TXA2/PGI2 indicating an association between the latter two factors and the sodium pressor response in those with hypertension. ALDO decreased to similar levels on sodium loading in the two groups. This decrease in ALDO was accompanied by suppression of PRA only in normotensive subjects. In conclusion, the low-renin-activity urban hypertensives we studied had increased baseline ET levels and TXA2/PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Black People; Blood Pressure; Endothelins; Epoprostenol; Female; Humans; Hypertension; Male; Renin; Sodium, Dietary; Thromboxane A2; Urbanization; Zimbabwe

To elucidate the underlying reason or reasons for the increased peripheral resistance in hypertension, we investigated the pressure-diameter relation--the myogenic response--of isolated, cannulated arterioles (approximately 50 microns) of cremaster muscle of 12-week-old Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and normal Wistar (NW) rats. All arterioles constricted in response to step increases in perfusion pressure from 20 to 160 mm Hg. This constriction was, however, significantly enhanced from 60 to 160 mm Hg in arterioles of SHR compared with NW or WKY rats. For example, at 80 and 140 mm Hg, respectively, the normalized diameter (expressed as a percentage of the corresponding passive diameter of arterioles of SHR) was 11.8% and 27.6% (P < .05) less compared with those of WKY rats. Endothelium removal eliminated the enhanced pressure-induced tone in SHR. Similarly, indomethacin (10(-5) mol/L, sufficient to block prostaglandin synthesis) or SQ 29,548 (10(-6) mol/L), a thromboxane A2-prostaglandin H2 receptor blocker that inhibited vasoconstriction to the thromboxane agonist U46619, attenuated the enhanced pressure-diameter curve and reversed the blunted dilation to arachidonic acid in SHR. In contrast, the thromboxane A2 synthesis inhibitor CGS 13,080 (5 x 10(-6) mol/L) did not affect the increased pressure-induced tone or the reduced dilation to arachidonic acid in SHR. Thus, the present findings suggest that in early hypertension pressure-induced arteriolar constriction is increased. This seems to be due to an enhanced production of endothelium-derived constrictor factors, primarily prostaglandin H2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arachidonic Acid; Arterioles; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; In Vitro Techniques; Indomethacin; Male; Muscles; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins; Prostaglandins H; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents

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

Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-beta-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10(-4) M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Diphosphate; Animals; Aorta, Thoracic; Endothelium, Vascular; Hypertension; In Vitro Techniques; Indapamide; Kinetics; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Receptors, Thromboxane; Thromboxane A2

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

We investigated the ability of the vasodilator prostaglandins E2 (PGE2) and I2 (PGI2) to counterbalance the vasoconstrictor action of thromboxane A2 (TxA2) in the rat renal vasculature during hypertension. In vivo measurements of renal blood flow (RBF) were made in 6-wk-old anesthetized spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats pretreated with indomethacin. The stable TxA2 agonist U-46619 was injected into the renal artery, and the magnitude and the kinetic parameters of the renal response were evaluated before and after continuous intrarenal infusion of a low dose of PGE2, viprostol (PGE2 analogue), PGI2, and iloprost (PGI2 analogue). The selected dose of vasodilator PGs did not affect arterial pressure and RBF. In the control period, the TxA2 agonist reduced RBF by 30% with a 90-s half time of recovery in both strains. Infusion of vasodilator PGs in young WKY significantly blunted the maximum vasoconstrictor effect of the TxA2 agonist and facilitated the recovery from vasoconstriction. In marked contrast, infusion of the vasodilator PGs in young SHR failed to affect the magnitude of the vasoconstrictor effect of the TxA2 agonist, although the recovery from vasoconstriction was facilitated as in WKY. On the other hand, infusion of bradykinin or dibutyryladenosine 3',5'-cyclic monophosphate (dibutyryl cAMP) blunted the TxA2-induced vasoconstriction to a similar degree in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Vessels; Bradykinin; Bucladesine; Hypertension; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Species Specificity; Thromboxane A2; Vasoconstriction

Chronic subcutaneous administration of heparin consistently lowers blood pressure in hypertensive rats. This antihypertensive effect is related at least in part to a concomitant decrease in hematocrit. Groups of spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats were treated with subcutaneous heparin (700 U/d) for 6 weeks. Weekly determinations of systolic blood pressure (tail-cuff) and hematocrit were done. Peripheral plasma renin activity, plasma aldosterone, plasma prostaglandins (PGs) (PGF2 alpha, PGI2), thromboxane A2, and urinary kallikrein were measured. Blood pressure responses of acute and chronic heparin treatment to vasoconstrictor substances, including angiotensin I, angiotensin II, and norepinephrine, were determined. As before, heparin produced a significant (P < .01) decrease in hematocrit in both SHRs and NWRs, but a parallel decrease in blood pressure was noted only in SHRs. A significant (P < .001) increase in plasma renin activity was found in heparin-treated SHRs and NWRs; however, a corresponding elevation of plasma aldosterone level was noted only in heparin-treated NWR. Plasma aldosterone level significantly (P < .01) decreased in heparin-treated SHRs. Plasma PGs and urinary kallikrein levels were not different among the groups. The blood pressure responses to vasoconstrictor substances were essentially similar among the heparin-treated and control groups. These findings suggest that PGs or kallikrein have a slight or no role in determining the antihypertensive effect of heparin. Conversely, the results suggest that a reduced aldosterone level contributes to the antihypertensive mechanism of heparin.

Topics: Aldosterone; Animals; Blood Pressure; Dinoprost; Epoprostenol; Hematocrit; Heparin; Hypertension; Injections, Subcutaneous; Kallikreins; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Wistar; Renin-Angiotensin System; Thromboxane A2

Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of endothelium-derived, cyclooxygenase-dependent contractile factors. The objectives of the present study were to determine whether alterations in endothelial function precede the development of hypertension in SHRs and to characterize the contractile factor(s) produced by SHR endothelial cells. Mean systolic blood pressures were minimally (6 mm Hg) higher at 4 weeks of age in SHRs than in Wistar-Kyoto (WKY) rats. Endothelium-mediated relaxations of mesenteric and renal resistance arteries from SHRs and WKY rats were compared in myographs and arteriographs in paired experiments. Acetylcholine (ACh, 10(-9) to 10(-7) M) induced endothelium-dependent relaxations in precontracted mesenteric and renal resistance arteries that were similar in SHRs and WKY rats. At higher concentrations of ACh (10(-6) to 10(-5) M), relaxations were replaced by contractile responses in SHR but not in WKY rat resistance arteries. The contractile responses were endothelium dependent and were inhibited by indomethacin in both mesenteric and renal arteries. Thus, endothelial dysfunction precedes and may contribute to the development of accelerated hypertension in SHRs. SQ 29548, a prostaglandin H2 (PGH2)-thromboxane A2 receptor antagonist, blocked the contractile responses in renal but not in mesenteric resistance arteries. The contractile responses in mesenteric arteries were inhibited by 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide production via the cyclooxygenase pathway. We conclude from these data that the endothelium-derived contracting factor (EDCF) produced in SHR renal arteries is most likely PGH2 whereas the contractile factor produced in mesenteric arteries is superoxide.

Topics: Acetylcholine; Amitrole; Animals; Bridged Bicyclo Compounds, Heterocyclic; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Indomethacin; Male; Mesenteric Arteries; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Renal Artery; Superoxides; Thromboxane A2; Vasodilation

The aim of the present study was to assess the mechanisms by which norepinephrine (NE) increased the synthesis of prostanoids and revealed a hyperactivity of the Thromboxane (Tx) A2 synthase in the Lyon genetically hypertensive (LH) rat kidney. To this purpose, the effects of NE (1.2 x 10(-8) to 9.6 x 10(-7) M) on renal function and prostanoid synthesis were assessed in isolated perfused kidneys following beta-adrenoceptor blockade by sotalol (10(-5)M) and compared to those of equipressor concentration of an alpha 2-adrenoceptor agonist, BHT 933 (3.5 x 10(-4) M) and angiotensin II (AII) (7.7 x 10(-9) M). Kidneys were isolated from eight week-old male LH rats and from their normotensive (LN) and low blood pressure (LL) controls and perfused in a single pass system. In baseline conditions, sotalol did not modify renal function or urinary prostanoids in any of the three strains. Following NE stimulation, it potentiated the increase in renal vascular resistance of LL and LN controls but not that of LH rats. The pressure-natriuresis and the urinary prostanoids remained unchanged. BHT 933 elicited a weak stimulation of prostanoid release while AII markedly increased it and revealed, as did NE, the hyperactivity of the TxA2 synthase. It is concluded that the NE-induced stimulation of prostanoid synthesis does not involve beta-adrenoceptors and is unrelated to the associated hemodynamic changes. These results also demonstrate that the increased renal synthesis of TxA2 observed in LH rat kidney is not a specific response to alpha-adrenoceptor stimulation and is likely to involve activation of the phosphoinositide pathway.

Topics: Adrenergic beta-Antagonists; Animals; Hypertension; Kidney; Male; Norepinephrine; Perfusion; Rats; Thromboxane A2

The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; beta-Thromboglobulin; Blood Platelets; Coronary Disease; Drug Interactions; Endothelium, Vascular; Epoprostenol; Female; Humans; Hypertension; Isosorbide Dinitrate; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Factor 4; Risk Factors; Smoking; Thromboxane A2

To evaluate platelet activation thromboxane A2 (TxA2) and beta-thromboglobulin (beta TG) were used as markers and in addition we studied the biosynthesis of prostacyclin. Synthesis of TxA2 and prostacyclin was assessed by measurement of urinary metabolites. Fifteen untreated hypertensive patients (HT) and 15 age-matched normotensive controls (NT) were investigated at rest, during and after exercise. HT patients were re-examined after 3 months on enalapril. During basal conditions there was no difference in the excretion of Tx-M, PGI-M or beta TG between the groups. During strenuous exercise HT exhibit a significantly higher increase in prostacyclin synthesis (162%) compared to NT (76%). The levels of beta TG increased with 82% in the HT and 24% in the NT group, Tx-M increased with 27% and 23% respectively. Treatment with the ACE-inhibitor enalapril did not significantly alter these findings. These results indicate that there is no evidence of basal platelet activation in early essential hypertension. Strenuous exercise leads to some increase in Tx-M in both groups, with no pronounced differences between the groups. Hypertensive patients exhibit a significantly increased prostacyclin response to exercise which could be due to differences in vessel-wall reactivity. Enalapril seems to exert no effect on platelet activation or on prostacyclin biosynthesis.

Topics: Adult; Basal Metabolism; beta-Thromboglobulin; Blood Pressure; Enalapril; Epoprostenol; Exercise; Humans; Hypertension; Male; Middle Aged; Platelet Activation; Thromboxane A2

Fourteen normotensive and 14 hypertensive black men with mild essential low-renin hypertension were examined during two protocols producing sodium depletion (less than 40 mmol sodium diet per day) for 5 days, followed by sodium loading (300 mmol sodium diet per day) for another 5 days. Changes in plasma renin activity, urinary aldosterone excretion, and excretion rates of stable breakdown products of thromboxane A2 (thromboxane B2) and prostacyclin (6-keto PGF1 alpha) were simultaneously assessed by radioimmunoassay. On the basis of low-renin status and paradoxically normal aldosterone excretion in both normotensives and hypertensives, thromboxane B2 excretion was increased by 14% (not significant); 6-keto PGF1 alpha was significantly decreased by 47% in the hypertensives compared to the normotensives. As a result, thromboxane B2/6-keto PGF1 alpha ratio was significantly increased from 1.29 +/- 0.10 in the normotensives to 2.78 +/- 0.12 in the hypertensive patients. The same ratio increased significantly after sodium loading in both groups, but more distinctly in the hypertensives (40%). Prostacyclin is a vasodilator, a natriuretic, and a potent inhibitor of platelet aggregation. Thromboxane A2 has opposite effects. The impaired prostacyclin biosynthesis we found in the hypertensive patients could account for the increased vascular resistance and some complications typical for hypertensive state.

Topics: Adult; Aldosterone; Black People; Epoprostenol; Evaluation Studies as Topic; Humans; Hypertension; Male; Renin; Renin-Angiotensin System; Sodium, Dietary; Thromboxane A2; Zimbabwe

The goal of this study was to determine the role of prostaglandin H2-thromboxane A2 (PGH2-TxA2) in altered responses of cerebral arterioles during chronic hypertension. Diameter of pial arterioles was measured during suffusion with ADP, acetylcholine, and nitroglycerin using intravital microscopy in Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHR) (8-10 mo old). ADP (100 microM) increased pial arteriolar diameter by 21 +/- 3% (means +/- SE) in WKY and only by 7 +/- 3% in SHR. Acetylcholine (10 microM) increased diameter 10 +/- 2% in WKY and, in contrast, reduced diameter 7 +/- 3% in SHR. Nitroglycerin produced similar vasodilatation in WKY and SHR. We then examined whether impaired dilatation of cerebral arterioles in SHR to ADP and acetylcholine may be related to activation of the PGH2-TxA2 receptor. SQ 29548, a specific PGH2-TxA2 receptor antagonist, restored vasodilatation in response to ADP in SHR toward that observed in WKY and reversed vasoconstriction to vasodilatation in response to acetylcholine in SHR. SQ 29548 did not alter responses in WKY. Thus these findings suggest that impaired responses of cerebral arterioles to ADP and acetylcholine during chronic hypertension may be related to the activation of the PGH2-TxA2 receptor.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Arterioles; Brain; Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Male; Nitroglycerin; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasodilator Agents

The isolated and perfused kidney of the spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to serotonin (5-hydroxytryptamine) when compared with normotensive Wistar-Kyoto (WKY) rats. Experiments were designed to determine the involvement of products of cyclooxygenase in the augmented response and delayed tachyphylaxis to serotonin in the SHR kidney. Kidneys taken from male, 4-month-old SHR and WKY rats were studied in parallel and perfused with Tyrode's solution at constant, optimal flow rates. Vasoconstrictor responses were recorded as increases in perfusion pressure. The vasoconstrictor responses to serotonin, norepinephrine and angiotensin II were exaggerated in the SHR kidney compared with that of the WKY rat. Indomethacin did not affect the responsiveness to serotonin in the kidney of the SHR but increased the responses to the higher doses of the monoamine in the kidney of the WKY rats. Indomethacin accelerated the tachyphylaxis to serotonin in the SHR but delayed it in the WKY rats. Dazoxiben did not alter the responses to serotonin in the SHR. Responses to norepinephrine in the kidneys from both strains were not affected by indomethacin. The inhibitor of cyclooxygenase reduced the responses to angiotensin II in the kidneys from both hypertensive and normotensive animals. The basal and stimulated (serotonin, norepinephrine and angiotensin II) release of prostaglandins were measured by radioimmunoassay. The basal release of prostacyclin was lower, but that of thromboxane A2 higher, in the kidneys of SHR compared with those of WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Arachidonic Acids; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hypertension; In Vitro Techniques; Indomethacin; Kidney; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Tachyphylaxis; Thromboxane A2; Vasoconstriction

We designed experiments to reveal the antihypertensive properties of cicletanine, a novel antihypertensive drug, in Dahl salt-sensitive (Dahl-S) rats. Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet. This blood pressure reduction was associated with a decrease in heart weight and vascular wall thickness. Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure. Proteinuria and urinary excretion of n-acetyl-beta-D-glucosaminidase were decreased and glomerular filtration rate was increased with this treatment. Morphological investigation revealed an improvement in glomerulosclerosis, renal tubular damage and intrarenal arterial injury in the salt-induced hypertensive rats. In contrast, trichloromethiazide, which decreased blood pressure to the same extent as cicletanine, lowered urinary PGl2 excretion and generally did not ameliorate the deteriorated renal functions and morphological abnormalities. Thus, these data indicate that cicletanine ameliorates the development of hypertension in Dahl-S rats and protects the cardiovascular and renal systems against the injuries seen in the hypertension. The enhanced vasodepressor PGl2 synthesis probably participates, to some extent, in these beneficial properties of long-term cicletanine treatment.

Topics: Animals; Antihypertensive Agents; Dinoprostone; Diuretics; Eicosanoids; Epoprostenol; Glomerular Filtration Rate; Hypertension; Kidney; Myocardium; Organ Size; Pyridines; Rats; Rats, Inbred Strains; Sodium; Sodium Chloride; Thromboxane A2

1. This study was designed to examine the production of certain eicosanoids (prostaglandin E2), prostacyclin (as 6-keto-prostaglandin F1 alpha) and thromboxane A2 (as thromboxane B2) by glomeruli isolated from normotensive Wistar-Kyoto and spontaneously hypertensive rats both before and after the administration of one of three angiotensin-converting enzyme inhibitors, captopril, enalapril or fosinopril, for 10 days. 2. Measurements of glomerular eicosanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. The production of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 was greater by glomeruli from untreated spontaneous hypertensive rats (prostaglandin E2 2.24 +/- 0.41, 6-keto-prostaglandin F1 alpha 1.20 +/- 0.13 and thromboxane B2 2.75 +/- 0.43 ng 10 min-1 mg-1 of protein) than by those from Wistar-Kyoto rats (prostaglandin E2 1.41 +/- 0.28, 6-keto-prostaglandin F1 alpha 0.98 +/- 0.11 and thromboxane B2 1.29 +/- 0.24 ng 10 min-1 mg-1 of protein) under basal conditions. However, these differences only achieved statistical significance for thromboxane B2 (P less than 0.01). Similar strain-related differences were noted in the presence of arachidonic acid. 4. The ratio of glomerular (prostaglandin E2 + prostacyclin)/thromboxane A2 production was significantly lower in spontaneously hypertensive rats than in their normotensive counterparts under basal conditions with values of 1.3 +/- 0.18 and 2.2 +/- 0.20, respectively (P less than 0.01). 5. Angiotensin-converting enzyme inhibitors induced significant changes in the glomerular production of some eicosanoids, which differed both between strains and with the nature of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Culture Techniques; Dinoprostone; Eicosanoids; Enalapril; Fosinopril; Hypertension; Kidney Glomerulus; Male; Proline; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2

The objective of this study was to test whether angiotensin II (ANG II) and thromboxane A2 (TxA2) contribute to the increased renal vascular reactivity observed in genetic hypertension. Under control conditions, ANG II reduced renal blood flow 35% more in spontaneously hypertensive (SHR) than in Wistar-Kyoto (WKY) rats. This strain difference was abolished by inhibition of prostaglandin synthesis with indomethacin and thus may be due to a deficiency in the action of endogenous vasodilator prostaglandins. The stable TxA2-receptor agonist U 46619 produced equal reductions of renal blood flow in SHR and WKY under control conditions. However, after indomethacin, the agonist-induced vasoconstriction was 70% more in SHR than in WKY, suggesting that SHR kidneys have an increased vascular reactivity to TxA2, which is unmasked when indomethacin reduces elevated levels of endogenous TxA2. Radiolabeled ligand binding studies for ANG II and TxA2 were undertaken in glomeruli isolated from WKY and SHR at 6 and 12 wk of age. Scatchard analysis revealed a single high-affinity receptor site for ANG [dissociation constant (Kd) = 1.2 nM], which was similar in both strains and ages of rats. All groups also showed a single high-affinity TxA2 receptor site (Kd = 3.5 nM). No differences were observed in the ANG II receptor number between age-matched rats, although the density increased with age. The density of TxA2 receptors was threefold higher in young SHR and nearly twofold higher in 12-wk-old SHR than in age-matched WKY controls. These findings indicate that the exaggerated renal vascular reactivity of SHR to ANG II and TxA2 may be mediated by a shift in the balance between endogenous vasoactive prostanoids and increased density of renal TxA2 receptors.

Topics: Angiotensin II; Animals; Hypertension; Kidney; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Receptors, Prostaglandin; Receptors, Thromboxane; Renal Circulation; Thromboxane A2

This study investigated the release of prostacyclin (PGI2) and thromboxane A2 (TXA2) from the aortic walls of various experimental hypertensive rats, e.g. spontaneously hypertensive rats (SHR), Dahl salt-sensitive (Dahl S) rats, deoxycorticosterone (DOCA)-salt hypertensive rats and renovascular (2-kidney, 1-clip (2K1C) and 1-kidney, 1-clip (1K1C] hypertensive rats. The PGI2 generation was increased significantly in these hypertensive models, irrespective of the hypertensive mechanisms, when they developed established hypertension. Dahl S rats, having an impaired PGI2 production on a low salt diet, restored PGI2 generating capacity to the control level of Dahl salt-resistant rats when they were fed a high salt diet and developed salt-induced hypertension. On the other hand, the TXA2 generation in the vascular walls was enhanced particularly in rat models for genetic hypertension, and this system was unaltered in the models for secondary hypertension, e.g. DOCA-salt and renovascular hypertension. Thus, it is suggested that the elevation of blood pressure is associated with an increase in vascular PGI2 production, and that the increased vascular TXA2 production is a characteristic feature of genetic hypertension.

Topics: Animals; Aorta; Blood Pressure; Blood Vessels; Disease Models, Animal; Eicosanoids; Epoprostenol; Hypertension; Hypertension, Renovascular; In Vitro Techniques; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Thromboxane A2; Tritium

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

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

To clarify the role of renal thromboxane (TX)A2 in the development of deoxycorticosterone acetate (DOCA)-salt induced hypertension, relationship between systolic blood pressure and the synthesis of renal TXA2 was investigated in 18 rats without and with OKY-046 administration which suppressed the synthesis of renal TXA2. Systolic blood pressure was significantly higher in DOCA-salt group than in control and OKY groups. The synthesis of 6-keto-prostaglandin(PG)F1 alpha and TXB2 in both renal arteries and cortical slices were more enhanced in DOCA-salt and OKY groups than in control group, but there was no significant difference between DOCA-salt and OKY groups. In contrast, the synthesis of 6-keto-PGF1 alpha in renomedullary slices did not vary significantly among three groups, and that of TXB2 was more increased in DOCA-salt group than in control and OKY groups. The cumulative sodium retention was significantly greater in DOCA-salt group than in control group. Administration of OKY-046 reduced the cumulative sodium retention in DOCA-salt rats by 45% toward that of the control group. These results might suggest that the enhanced production of renomedullary TXB2 was important to the development of DOCA-salt induced hypertension.

Topics: Animals; Blood Pressure; Catecholamines; Desoxycorticosterone; Diet; Eicosanoids; Hypertension; Kidney Medulla; Male; Methacrylates; Rats; Rats, Inbred WKY; Renal Artery; Sodium; Sodium Chloride; Thromboxane A2; Thromboxane-A Synthase

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

Production of some lipoxygenase and cyclooxygenase derivatives of arachidonic acid was measured in placental tissue obtained from women with gestational hypertension and with normal pregnancies. The levels of leukotriene B4 were about five times higher in placentas from hypertensive women and also raised thromboxane A2 and reduced prostaglandin E2 levels were observed. Prostacyclin production was lowered only in women with more severe hypertension, in association with the highest measured levels of leukotriene B4 and thromboxane A2. It is suggested that increased placental levels of leukotriene B4 and thromboxane A2 appear already in mild gestational hypertension, while depression of prostacyclin may occur only at more severe stages of gestational hypertensive disease.

Topics: Adult; Dinoprostone; Epoprostenol; Female; Humans; Hypertension; Leukotriene B4; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

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

This study was designed to contrast the effects of prolonged treatment with a thromboxane (Tx) synthase inhibitor (UK 38485 or SC 41156) and a Tx receptor antagonist (SQ 29548) on the development of angiotensin II (Ang II)-salt-induced hypertension. Ang II infusion (125 ng/min i.p. for 12 days) in rats drinking 0.15 M NaCl resulted in severe hypertension accompanied by proteinuria, reduction of urinary creatinine excretion and augmentation of urinary TxB2 excretion and TxB2 release from aortic rings and renal cortex slices. In saline-drinking rats undergoing Ang II infusion, the concomitant administration by gavage of UK 38485 (100 mg/kg/day) or SC 41156 (25 mg/kg/day) reduced serum and urinary TxB2 and TxB2 release from aortic rings and/or renal cortex slices, but it was without effect on the development of hypertension. In contrast, concomitant infusion of SQ 29548 (4.2 mg/24 hr s.c.) significantly attenuated the increase of blood pressure produced by the infusion of Ang II in saline-drinking rats. This effect of SQ 29548 may be the consequence of blockade of the actions of one or more endogenous eicosanoids that increase blood pressure by a mechanism(s) involving interaction with TxA2 receptors. This implies that pressor eicosanoids play a contributory role in the development of severe Ang II-salt hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Male; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Sodium Chloride; Thromboxane A2; Thromboxane-A Synthase

To determine whether the increased renal biosynthesis of thromboxane A2 observed in young genetically hypertensive rats of the Lyon strain could be involved in the development of their hypertension, Lyon hypertensive female rats received either thromboxane synthetase inhibitors (Dazmegrel or OKY 046) or a thromboxane A2 receptor antagonist (AH 23848) during their prehypertensive stage. Treatment from 5 to 9 weeks of age with Dazmegrel failed to reduce systolic blood pressure. When given from 3 to 9 weeks of age, Dazmegrel and OKY 046 induced a similar progressive and specific reduction (60%) in the urinary excretion of thromboxane B2 that was associated with a transient decrease in blood pressure level with Dazmegrel and a longer lasting blood pressure-lowering effect with OKY 046. AH 23848, given according to the same schedule, normalized the blood pressure level. This effect persisted 1 week after the cessation of the treatment. Interestingly, active doses of thromboxane synthetase inhibitors or of thromboxane A2 receptor blocker required a 3-week delay to exhibit their antihypertensive properties. It is concluded that 1) the elevated production of thromboxane A2 observed in young Lyon hypertensive rats is likely to participate actively in their blood pressure regulation and 2) this effect may be independent of its direct vasoconstrictor properties.

Topics: Animals; Biphenyl Compounds; Female; Hypertension; Imidazoles; Methacrylates; Rats; Rats, Mutant Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

This study was designed to assess the contribution of thromboxane (Tx) A2 to the pathogenesis of renal dysfunction in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 mol/l NaCl by infusion of Ang II (125 ng/min, intraperitoneally) for 12 days. Relative to values in water- and saline-drinking rats without Ang II infusion, rats with Ang II-salt hypertension exhibited increased renal vascular resistance, decreased renal blood flow, and increased renal excretion and glomerular synthesis of TxB2. Treatment with an inhibitor of TxA2 synthesis, UK 38,485, had no effect on renal function in normotensive and hypertensive rats. Similarly, the TxA2 and prostaglandin endoperoxide antagonist SQ 29,548 did not affect renal function in normotensive rats. In contrast, in rats with Ang II-salt hypertension of 12 days' duration, SQ 29,548 caused a reduction in renal vascular resistance, allowing for maintenance of renal blood flow in the face of an accompanying reduction in blood pressure. A comparable reduction in renal perfusion pressure, produced by constriction of the abdominal aorta above the renal arteries, was not accompanied by a reduction in renal vascular resistance in Ang II-salt hypertensive rats. Therefore, the SQ 29,548-induced lowering of renal vascular resistance is attributable not to renal blood flow autoregulation, but to blockade of the renal vasoconstrictor actions of TxA2 and/or prostaglandin endoperoxides. This interpretation implies that pressor eicosanoids contribute to increase renal vascular resistance in rats with severe Ang II-salt hypertension.

Topics: Angiotensin II; Animals; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney; Male; Rats; Rats, Inbred Strains; Sodium, Dietary; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance

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

Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.

Topics: Animals; Glomerulosclerosis, Focal Segmental; Hyperlipidemias; Hypertension; Imidazoles; Kidney Glomerulus; Male; Naphthalenes; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase; Time Factors

The objective of this study was to test the hypothesis that angiotensin II and thromboxane A2 (TxA2) contribute to the elevated renal vascular resistance observed during the development of genetic hypertension. In 6-wk-old anesthetized spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats, renal blood flow (electromagnetic flowmetry) and carotid arterial pressure were measured during bolus injections of different doses of angiotensin II and U46619 (stable receptor agonist of TxA2) into the renal artery before and during inhibition of prostaglandin synthesis by indomethacin. In all cases, arterial pressure remained unchanged at the pre-injection levels. Under control conditions, angiotensin II reduced renal blood flow in SHR almost twice as much as in WKY. This strain difference was abolished by inhibition of prostaglandin synthesis, suggesting that a deficiency in the action of endogenous vasodilator prostaglandins is responsible for the enhanced response to angiotensin II in SHR. Under control conditions, the TxA2-receptor agonist produced similar reductions of renal blood flow in SHR and WKY. However, after indomethacin, the agonist-induced vasoconstriction was twice as large in SHR as in WKY, suggesting that SHR kidneys have an increased vascular reactivity to TxA2, which is unmasked when indomethacin reduces elevated levels of endogenous TxA2. These findings indicate important strain differences between young SHR and WKY in the renal vascular response to angiotensin II and TxA2 that may contribute to the renal vasoconstriction observed during the development of genetic hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Hypertension; Indomethacin; Kidney; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regression Analysis; Renal Circulation; Thromboxane A2; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation

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

The paper considers the significance of prostacyclin-thromboxane (PGI2/TxA2) balance for cardiovascular performance in health and in angina pectoris and myocardial infarction. The functional interaction between prostacyclin and thromboxane was examined in terms of a number of risk factors for coronary heart disease (CHD), such as ageing, atherosclerosis, arterial hypertension, diabetes mellitus, obesity, hypokinesia, smoking, alcoholism, sex differences, and predisposition to the disease. A unidirectional pattern of changes in the PGI2/TxA2 balance towards TxA2 was found in CHD and in the presence of all the aforementioned risk factors. The paper discusses possible mechanisms responsible for these changes, as well as their contribution to the pathogenesis and prevention of CHD.

Topics: Adult; Aged; Alcoholism; Coronary Disease; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Risk Factors; Smoking; Thromboxane A2

The influence of propranolol, nalorphine and haloperidol on the breathing pattern and on the blood levels of cyclooxygenase products of anaesthetized spontaneously-breathing normotensive Wistar rats (WR) and of spontaneously hypertensive rats (SHR) were investigated. The respiratory rate was higher and the effective lung resistance was smaller in the SHR than in the WR. Breathing frequency decreased after nalorphine in both groups, while only in SHR after haloperidol. Propranolol augmented the dynamic lung resistance in both groups. The blood 6-keto-PGF1 alpha level was higher and the TXB2 level was lower in the SHR than in the WR. The central inspiratory activity as well as the levels of peripherally acting substances involved in the regulation of respiration and in the control of bronchial smooth muscle tone are different in the SHR and WR.

Topics: Animals; Epoprostenol; Haloperidol; Hypertension; Inspiratory Capacity; Nalorphine; Propranolol; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Respiration; Respiratory Function Tests; Thromboxane A2

Increased platelet aggregation induced by ADP and arachidonic acid was observed in 12 patients with essential hypertension compared with 12 control subjects, but not after pretreatment with acetylsalicylic acid. The increase in intracellular calcium induced by ADP was also greater in the hypertensive patients, and again this difference disappeared after cyclo-oxygenase blockade. Urinary excretion of 2,3-dinor-thromboxane B2, the main metabolite of platelet thromboxane A2, was slightly, but not significantly increased in the hypertensive patients. These data suggest that thromboxane system activity is increased in the platelets of hypertensive patients.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Calcium; Cyclooxygenase Inhibitors; Female; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

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

In order to determine whether the increased renal biosynthesis of thromboxane A2, observed in young genetically hypertensive (LH) rats of the Lyon strain, could be involved in the development of their hypertension, 12 LH female rats were given a specific thromboxane A2 receptor antagonist, AH 23848 (Glaxo Group Research) orally (2 mg/kg twice a day) from 3 to 9 weeks of age. In addition, 12 LH and 12 normotensive (LN) rats were given vehicle only (sodium bicarbonate 8%). The thromboxane receptor antagonist AH 23848, which inhibited platelet aggregation by about 65%, did not modify the renal production of thromboxane A2, prostaglandin I2 (PGI2) or prostaglandin E2 (PGE2). It induced a progressive, potent and long lasting decrease in systolic blood pressure which was normalized in 6-, 7- and 8-week-old LH rats, thus demonstrating the involvement of thromboxane A2 in the onset of hypertension in this model. In contrast with thromboxane synthetase inhibitors, the AH 23848 antihypertensive effect persisted 1 week after the cessation of treatment, showing the superiority of thromboxane A2 receptor blockade over thromboxane synthetase inhibition.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Depression, Chemical; Drug Evaluation, Preclinical; Female; Hypertension; Platelet Aggregation; Rats; Rats, Inbred SHR; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

In order to assess the roles of vasoconstrictor thromboxane in the antihypertensive action of alpha 1 adrenoceptor antagonist, we explored the influences of OKY-046, a selective thromboxane inhibitor, on the antihypertensive effects of bunazosin in spontaneously hypertensive rats (SHR). 2-week antihypertensive treatment with bunazosin (0.5 mg/kg/day) did not produce a significant decrease of systolic blood pressure in SHR, as compared to untreated controls. The blood pressure reduction was associated with a decrease of PGI2/TXA2 in vascular eicosanoids generation (p less than 0.02) and an increase of TXA2 excretion in urine (p less than 0.05). A combination treatment with OKY-046 almost completely abolished the enhanced TXA2 generation in the vascular wall and kidney, which was strikingly associated with a potentiation of the blood pressure reduction by bunazosin treatment (176 vs 186 mmHg, p less than 0.01). Bunazosin directly stimulated TXA2 biosynthesis in vascular smooth muscle cells in culture in a dose-dependent manner. Thus, these data clearly indicate that bunazosin, a quinazoline derivative, enhances vasoconstrictor TXA2 system in the vascular wall and kidney possibly through direct actions, which would attenuate the antihypertensive effects of alpha 1 adrenoceptor antagonism by bunazosin treatment.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Vessels; Hypertension; Kidney; Male; Methacrylates; Quinazolines; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase

Uteroplacental ischemia causes hypertension in various species but the mechanisms involved are not known. These studies were designed to test the hypothesis that the systemic hypertension that occurs during reduced uteroplacental perfusion pressure is mediated by the prostaglandin system. Trained chronically instrumented pregnant dogs in the last third of gestation were studied. When uterine perfusion pressure was reduced to 60 mmHg for 60 min using an inflatable aortic occluder placed distal to the renal but proximal to the uterine and ovarian arteries, systemic arterial pressure increased from 95 +/- 5 to 110 +/- 7 mmHg. On another day in the same animals, the prostaglandin system was blocked with meclofenamate. Subsequent reduction of uterine arterial pressure caused no significant change in systemic pressure, from 96 +/- 4 to 99 +/- 6 mmHg, suggesting an important role for the prostaglandin system in mediating the normal response. In additional experiments, the thromboxane receptor antagonist SQ 29,548 was given. Arterial pressure averaged 94 +/- 5 mmHg after administration of SQ 29,548 and did not change significantly when uterine perfusion pressure was reduced during SQ 29,548. These data suggest that at least one component of the prostaglandin system, thromboxane, contributes to the rise in systemic arterial pressure during reduced uteroplacental perfusion pressure.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Hydrazines; Hypertension; Ischemia; Meclofenamic Acid; ortho-Aminobenzoates; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy, Animal; Prostaglandins; Reperfusion; Thromboxane A2; Uterus

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

To assess the participation of cardiovascular eicosanoids (prostaglandins and thromboxanes) system in the initiation of genetic hypertension, we examined eicosanoids metabolism in the heart, aortic wall and kidney in prehypertensive and hypertensive rat models for spontaneous hypertension (SHR). Vasoconstrictor thromboxane A2 (TXA2) generation in the aortic wall was significantly enhanced by 49% in the prehypertensive and by 18% in the hypertensive SHR when compared to the respective normotensive Wistar-Kyoto rats. Cardiac TXA2 content was significantly increased as well by 14% in the prehypertensive and by 30% in the hypertensive SHR. Moreover, vascular vasodepressor eicosanoids generation was decreased by 10% for PGI2 and by 29% for PGD2 in the prehypertensive SHR although the alterations were eliminated in the hypertensive SHR. In contrast to the cardiovascular eicosanoids system, there was no difference in renocortical TXA2 content in either young or adult SHR while vasodepressor prostaglandins contents were decreased by 29% for PGE2 and by 33% for PGD2 in SHR when they were in the prehypertensive stage. Thus, in the prehypertensive stage of SHR, the cardiovascular eicosanoids system exhibited enhanced vasoconstrictor TXA2 and decreased vasodepressor prostaglandins, thereby producing a vasoconstrictor state. These data indicate that the alterations in the cardiovascular eicosanoids system partially contribute to the initiation of hypertension in SHR.

Topics: Animals; Aorta, Thoracic; Dinoprostone; Epoprostenol; Hypertension; In Vitro Techniques; Kidney; Male; Myocardium; Prostaglandin D2; Prostaglandins; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Thromboxane A2

In young patients with borderline arterial hypertension the system of pressor and depressor prostaglandins (PG) is activated with maintenance of their physiological proportion. In patients with I stage essential hypertension a considerable rise in the level of PGF2 alpha and thromboxane determines the system imbalance in the direction of the predominance of pressor components. The platelet hemostatic link in I stage essential hypertension is characterized by an increase in platelet aggregation activity which is mediated by the imbalance of the prostacyclin-thromboxane system in the direction to thromboxane.

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Platelet Aggregation; Thromboxane A2; Time Factors

The effect of PAF has been examined in anaesthetized guinea-pigs. Intravenous (i.v.) administration of PAF (10 ng kg-1) did not modify the respiratory response but decreased the arterial blood pressure. A high dose of PAF (200 ng kg-1) caused marked bronchoconstriction and concomitant hypertension. The cyclooxygenase inhibitors aspirin (5 mg kg-1) and indomethacin (5 mg kg-1) and the thromboxane A2 (TXA2) receptor antagonist BM-13.177 (1 mg kg-1) failed to inhibit the peak bronchoconstrictive response but significantly inhibited the prolonged response following peak response. These inhibitors also attenuated PAF-induced hypertension. On the other hand, the lipoxygenase inhibitors phenidone (10 mg kg-1) and NDGA (5 mg kg-1) and the leukotriene (LT) receptor antagonist FPL-55712 (2 mg kg-1) affected neither bronchoconstriction nor hypertension induced by PAF. However, when aspirin was given in combination with NDGA, phenidone or FPL-55712, the peak and the following prolonged bronchoconstriction were significantly inhibited. The suppression of PAF-induced hypertension by aspirin was not further inhibited by the combination of these inhibitors. These results indicate that in anaesthetized guinea-pigs PAF-induced bronchoconstriction is composed of a dual response, a direct action (peak response) and an indirect action (prolonged response). The latter may be produced by the generation of TXA2 and lipoxygenase products, while PAF-induced hypertension is indirectly mediated by the generation of TXA2.

Topics: Animals; Blood Pressure; Bronchial Spasm; Cyclooxygenase Inhibitors; Guinea Pigs; Hypertension; In Vitro Techniques; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors; Male; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

The BP of 12 patients with essential hypertension was controlled with captopril over a period of three months. Cerebral blood flow, muscle blood flow (anterior tibialis muscle), platelet aggregation and platelet thromboxane A2 release were measured during a baseline drug-free period, and measurements repeated during the treatment phase on achieving BP control, after one and three months. Cerebral blood flow rose during the early phase of treatment and then dropped to baseline levels during chronic therapy. Muscle blood flow, both at rest and following maximal exercise, was unaffected by captopril therapy. Platelet aggregation was diminished during therapy, and this finding was paralleled by a reduction in platelet thromboxane A2 generation. Control of hypertension with maintenance of regional blood flow and beneficial changes in platelet function during treatment with captopril may improve the overall risk profile of hypertensive patients. Inhibition of platelet aggregation and thromboxane A2 release may contribute to the antihypertensive action of captopril and the maintenance of regional blood flow.

Topics: Aged; Blood Platelets; Blood Pressure; Captopril; Cerebrovascular Circulation; Humans; Hypertension; Middle Aged; Muscles; Platelet Aggregation; Regional Blood Flow; Risk Factors; Thromboxane A2

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

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

Osmotic minipumps containing OKY-046 (15-20 mg/kg per day), to inhibit thromboxane (TX) A2 synthase, were implanted into 43-day-old SHR and age-matched Wistar-Kyoto rats (WKY) to study the role of TXA2 in the development of hypertension in SHR. Inhibition of TXA2 synthase with OKY-046 did not affect urine volume, sodium excretion, potassium excretion, food and water intake or body weight in either WKY or SHR during the two weeks of study. In the first week systolic blood pressure (SBP) was significantly lower in SHR receiving OKY-046 in comparison to SHR which received no OKY-046 (127 +/- 3 vs. 110 +/- 4 mm Hg, P less than 0.01). OKY-046 did not affect SBP in WKY. By the second week SBP in SHR and WKY receiving OKY-046 did not differ from their respective controls despite an 85% reduction in serum immunoreactive TXB2 (iTXB2; the stable hydrolysis product of TXA2) and a 45% reduction in urinary iTXB2 excretion. These results support a possible role for TXA2 in the developmental stage of hypertension in SHR and other factors in the sustained elevation of blood pressure.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Pressure; Hypertension; Male; Methacrylates; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Thromboxane A2; Thromboxane-A Synthase

The vascular wall has the capacity to produce thromboxane A2. However, the role of vascular thromboxane A2 is still uncertain. In this study, we examined the relationship between vascular thromboxane A2 generation and vascular smooth muscle cell growth in spontaneously hypertensive rats (SHR). Vascular thromboxane A2 generation was significantly enhanced by 49% in 5-week-old and by 117% in 15-week-old SHR as compared with age-matched Wistar-Kyoto rats (WKY). Thromboxane A2 generation was also significantly enhanced by 59% in the cultured vascular smooth muscle cells of SHR when compared with production in WKY. Vascular smooth muscle cells of SHR exhibited a significantly shortened doubling time (by 32%) and greater [3H]thymidine uptake (by 56%), as compared with those of WKY. OKY 046 (10(-5) M), a thromboxane synthase inhibitor, significantly tempered the rapid vascular smooth muscle cell growth in SHR by 9% for doubling time and by 10% for [3H]thymidine uptake. OKY 046 did not influence the doubling time of WKY. Conversely, a stable analogue of thromboxane A2 dose-dependently stimulated the [3H]thymidine uptake by vascular smooth muscle cells of WKY, and, at a concentration of 10(-5) M, shortened the doubling time of vascular smooth muscle cells of WKY by 11%, whereas it showed slight effects on SHR. These data indicate that vascular thromboxane A2 is involved in the regulatory mechanism of vascular smooth muscle cell growth and that enhanced vascular thromboxane A2 generation is partly responsible for the rapid proliferation of vascular smooth muscle cells of SHR. The alterations of vascular thromboxane production may be a key trait for genetic hypertension.

Topics: Animals; Cell Division; DNA Replication; Dose-Response Relationship, Drug; Hypertension; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2

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

We examined vascular thromboxane A2 (TXA2) generation and its relation to a proliferation of vascular smooth muscle cells (VSMCs) in spontaneously hypertensive rats (SHRs). Aortic TXA2 release was significantly enhanced in 5-week-old SHRs, as compared with Wistar-Kyoto strain rats (WKY). The cultured VSMCs of SHRs exhibited a shorter doubling time and a greater [3H]thymidine uptake than those of WKY rats. OKY 046 a thromboxane synthetase inhibitor, tempered proliferation of VSMCs in SHRs, but not in WKY rats. STA2, a stable analog of TXA2, stimulated VSMC growth in WKY rats more than in SHRs. It is indicated that vascular TXA2 generation is enhanced, and partially participates in the rapid proliferation of VSMCs in SHRs.

Topics: Animals; Blood Vessels; Cell Division; Hypertension; In Vitro Techniques; Methacrylates; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane-A Synthase

Topics: Animals; Blood Pressure; Hypertension; Male; Phenylacetates; Rats; Rats, Inbred SHR; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI2), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI2 in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI2 was closely related to the height of blood pressure. The deterioration of vascular PGI2 was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A2 (TXA2) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI2 on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.

Topics: Aging; Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Epoprostenol; Hypertension; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2

Phospholipase A2 activity and prostaglandin synthesis were studied in the renal cortex and medulla of stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched normotensive Wistar-Kyoto rats (WKY) aged 10-50 weeks. Enhanced phospholipase A2 activity was found in both the cortical and the medullary microsomes of SHRSP kidneys. Phospholipase A2 activity progressively increased with age in SHRSP, but not in WKY. Prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) were the major prostaglandins found in the cortex, and PGE2 was the major prostaglandin found in the medulla. Prostaglandin l2 (PGI2) was synthesized in both the cortex and medulla, but cortical PGI2 synthesis was much lower than medullary synthesis. Enzymatic activity for all prostaglandin syntheses analysed here were higher in SHRSP. There was a greater age-related increase in prostaglandin synthesis in SHRSP kidneys than in WKY kidneys. In addition, the ratios of PGE2/TXB2 and 6-keto-prostaglandin F1 alpha (PGF1 alpha)/thromboxane B2 (TXB2) decreased in SHRSP. This may produce vasoconstriction and increase vascular resistance in SHRSP. These data suggest that increased prostaglandin synthesis and phospholipase A2 activity have an important role in the development and maintenance of hypertension in SHRSP.

Topics: Animals; Dinoprostone; Epoprostenol; Hypertension; In Vitro Techniques; Kidney; Male; Phospholipases; Phospholipases A; Phospholipases A2; Prostaglandins E; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Species Specificity; Thromboxane A2

As an experimental model, we used 6-week-old genetically obese-hypertensive rats (SHR-fa/fa) which were obtained by transferring the fatty/fa gene of hyperlipaemic obese rats into the genome of the SHR strain: the SHR-fa/fa were bigger and more hypertensive than their SHR littermates. Studying the capacity of the hearts, kidneys, spleens, brains and lungs to synthesize PGE2, PGF2 alpha and TXA2, enabled us to show that the hearts and lungs of SHR-fa/fa synthesized more PG than those of SHR; SHR-fa/fa brains generated less icosanoids than those of SHR; the amounts of PGE2 and TXA2 produced by the kidneys are similar in SHR and in SHR-fa/fa. From the experimental data we can infer that the introduction of the fatty/fa gene into the genome of SHR does not significantly alter the capacity of the kidneys to synthesize icosanoids; the more severe hypertension in the SHR-fa/fa would result from an increase in TXA2 biosynthesis by cardiac tissue which, at the same time, synthesized more PGE2, which could be a means of defence against hypertension. Moreover this genetical manipulation inhibited the icosanoid-synthesizing capacity of the brain which thus attenuated the central nervous system activity of the animals.

Topics: Animals; Brain; Dinoprost; Dinoprostone; Female; Hypertension; Kidney; Lung; Microsomes; Myocardium; Obesity; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred SHR; Spleen; Thromboxane A2

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 fetal and maternal morbidity and mortality from the hypertensive disease states of pregnancy is a major problem. While much is known about the syndrome, the cause has been elusive. The ewe was chosen to test a hypothesis that depletion of magnesium may be involved. Twelve Finnish ewes were subjected to low magnesium diets with half given magnesium in the water. Tests included measurement of blood pressure in the waking state and by noninvasive technique. Magnesium levels were measured by atomic absorption spectrophotometry in the plasma and tissue of the ear tips. Findings included significant elevation of arterial blood pressure, reduction in fetal weight with pathologic confirmation of placental and renal lesions which were similar to those seen in the human condition. Significant lowering of both plasma and tissue of magnesium was noted. The hypothesis was supported and extended to include possible interaction with prostacyclin and thromboxane as intermediaries in a hypomagnesic coagulative angiopathy. This entity would also explain the association of migraine in the eclamptic and preeclamptic syndrome reported by previous authors. The success of parenteral magnesium in the treatment of these human conditions is therefore more than purely empiric.

Topics: Animals; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Hypertension; Kidney; Magnesium; Magnesium Deficiency; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Sheep; Thromboxane A2

Three different levels of global forebrain ischemia were induced in rats and their plasma levels of Thromboxane B2 (TXB2) and 6 Keto PGF1 alpha were determined to investigate the relation between severity of ischemia and eicosanoid production. Ischemia stimulates the activity of cellular lipase whose actions cause deacylation of brain phospholipids and release of free fatty acids. Arachidonic acid (A.A.) is one of the predominant fatty acids which is liberated in brain after ischemia. A.A. is the primary substrate for the synthesis of prostaglandins (PGs), Thromboxane A2 (TXA2) and Prostacyclin (PGI2), which play an important role in regulation of platelet aggregation and vasotonus. Thromboxane is a potent platelet aggregator and vasoconstrictor. On the other hand, PGI2 has the opposite nature. Therefore it can be considered that PGs and moreover, the balance of TXA2 and PGI2 may have an intimate relation to the development of cerebral ischemia. Three different levels of ischemia were produced by bilateral carotid artery ligation (BLCL) using three kinds of rats with different blood pressure ranges, namely, SHRSP (Stroke-prone spontaneously hypertensive rats), SHRSR (Stroke-resistant spontaneously hypertensive rats) and WKY (Wistar kyoto rats). It is known that higher pressure groups suffer severe ischemia by BLCL procedure. Hypertensive rats (SHRSP, SHRSR) were originally produced from WKY. The experimental animals used were about 300 gr and 16 weeks old male rats. The plasma and brain TXB2 and 6 Keto-PGF1 alpha, stable metabolites of TXA2 and PGI2 were measured by radioimmunoassay. The chronological changes of brain and plasma PGs levels after ischemia using SHRSR were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Brain Chemistry; Brain Ischemia; Carotid Arteries; Cerebrovascular Circulation; Epoprostenol; Hypertension; Ligation; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2

Plasma from Dahl rats susceptible to salt-induced hypertension (Dahl S rats) contains inhibitory factors that reduce the release of thromboxane A2 from thrombin-activated platelets. Platelet-rich plasma from Dahl S rats on either low salt (0.11 or 0.3% NaCl) or high salt (4% NaCl) diets released about 50% less thromboxane A2 than comparable plasma from Dahl rats that are resistant to hypertension (Dahl R rats). This inhibitory activity was present even in the blood of 4-week-old completely normotensive Dahl S rats on a diet containing 0.11% low NaCl. The inhibitory activity could be transmitted to platelets of normal Sprague-Dawley rats by incubating these platelets in boiled and dialyzed plasma from Dahl S rats. Moreover, the inhibitory activity could be completely washed off the Dahl S platelets by incubation in Dahl R plasma. Thus, Dahl S plasma contains inhibitory factors that reduce platelet thromboxane A2 release. The factors are found in low concentrations even in Dahl R plasma; and in Dahl S or Dahl R plasma the factors are increased 25 to 32% by a 4% high NaCl diet. Digestion of Dahl S and Dahl R plasma with either trypsin or chymotrypsin destroyed the inhibitory factors, which have a molecular weight between 2,000 and 3,500. Twenty-four hours after bilateral nephrectomy, dialyzed plasma from both Dahl S and Dahl R rats was completely devoid of thromboxane A2 inhibitory activity. Thus, the factors appear to be heat-stable polypeptides either produced in the kidney or greatly influenced by the presence of renal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Blood Proteins; Hypertension; Molecular Weight; Nephrectomy; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2

As platelet and renal thromboxane (TX)A2 synthesis are increased in spontaneously hypertensive rats (SHR), we tested the hypothesis that increased renal TXA2 synthesis may cause the reduction in glomerular filtration rate (GFR), renal plasma flow (RPF), and the increase in arterial pressure in SHR of the Okamoto-Aoki strain. A selective inhibitor of TXA2 synthetase (UK 38485) was given acutely, with or without a TXA2 receptor antagonist (EP-092), to 6- to 8-wk-old SHR and age-matched Wistar-Kyoto rats (WKY) and chronically for 5.5 wk to 3.5-wk-old SHR. Inhibition of TXA2, measured by the stable metabolite TXB2, in the acute experiments was greater than 95% in serum and greater than 80% in glomeruli; in the chronic studies, it was greater than 65% in glomeruli. There was no endoperoxide shunting to vasodilatory and natriuretic prostaglandins (PGE2, PGI2) in glomeruli after TXA2 inhibition. Before drug administration, GFR and RPF were reduced and renal vascular resistance (RVR) was increased in SHR. During acute blockade of renal TXA2 synthesis, with or without a TXA2 receptor antagonist, there was no significant change in GFR, RPF, or RVR in WKY and SHR. Inhibition of TXA2 did not affect urine flow or sodium excretion in anesthetized or conscious WKY or SHR. Mean arterial pressure did not fall in treated SHR and WKY. Chronic TXA2 synthesis inhibition did not improve GFR or RPF in SHR, and systolic arterial pressure was not altered. These findings show that enhanced serum and glomerular TXA2 synthesis do not significantly contribute to the reduction in renal function and are not essential for the development of hypertension in young SHR.

Topics: Animals; Blood Pressure; Glomerular Filtration Rate; Hypertension; Imidazoles; Kidney; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxane A2; Time Factors; Vascular Resistance

The hemodynamic effects of intravenously infused dihydralazine (incremental doses up to 125 micrograms per minute during 60 minutes) were studied in ten women with acute or superimposed severe preeclampsia. The intervillous and umbilical vein blood flow were measured before and during dihydralazine infusion with 133Xenon method and with a combination of real-time and Doppler ultrasonic equipment, respectively. Maternal blood pressure decreased and pulse rate increased during the infusion. Dihydralazine did not change the intervillous blood flow but it increased the blood flow in umbilical vein. No effect on the 6-ketoprostaglandin F1 alpha in maternal plasma and urine or thromboxane B2 in maternal serum was observed. The results indicate that dihydralazine affects the placental and fetal circulations differently.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Dihydralazine; Female; Fetal Heart; Humans; Hydralazine; Hypertension; Infusions, Parenteral; Placenta; Pre-Eclampsia; Pregnancy; Pulse; Regional Blood Flow; Thromboxane A2; Umbilical Veins

To clarify the metabolism of PGE2, prostacyclin (PGI2) and thromboxane A2 (TxA2) in small vessels in spontaneously hypertensive rats (SHR), we removed superior mesenteric vascular beds from 10 week old SHR and age matched normotensive controls (WKY). The mesenteric artery was perfused with Krebs-Henseleit buffer and samples of effluent collected every 15 minutes during 3 hours perfusion for analysis of PGE2, 6-keto-PGF1 alpha (a stable metabolite of PGI2) and TxB2 (a stable metabolite of TxA2) by specific radioimmunoassays. Levels of all three arachidonic acid (AA) metabolites, PGE2, 6-keto-PGF1 alpha and TxB2, in the mesenteric effluent were significantly reduced in SHR as compared to WKY. TxB2 was detected in all samples throughout the perfusion. 6-keto-PGF1 alpha/PGE2 ratios and TxB2/PGE2 ratios were significantly increased in SHR. 6-keto-PGF1 alpha/TxB2 ratios in the first four samples were significantly decreased in SHR as compared to WKY. These data suggest that there may be reduced availability of PG precusor AA and unbalanced synthesis of PGs in small vessels in SHR. Both may have relevance to the development of hypertension in the animals.

Topics: Animals; Cross Reactions; Dinoprostone; Epoprostenol; Hypertension; Male; Perfusion; Prostaglandins E; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Splanchnic Circulation; Thromboxane A2; Thromboxanes

When CV-4151, a specific thromboxane (TX) A2 synthetase inhibitor, was given orally to 4 week old (4w) spontaneously hypertensive rats (SHR) daily for 3 weeks, the initiation of hypertension was delayed by about one week. The agent increased urinary excretion of water, sodium and creatinine, reduced that of TXA2 (as TXB2), increased that of PGI2 (as 6-keto-PGF1 alpha) and enhanced urinary PGI2/TXA2. In 4w Wistar-Kyoto rats (WKY) and 18w SHR was established hypertension, the agent had little effect on blood pressure and renal function. In isolated, perfused kidneys of 6w SHR, CV-4151 markedly inhibited both arachidonic acid-induced pressor action and production of TXA2. TXA2 synthetase activity in renal cortical microsomes of 5w SHR was approximately 1.5 times higher than that in age-matched WKY. CV-4151 inhibited TXA2 synthetase activity of medullary and cortical microsomes more effectively in 5w SHR than in age-matched WKY. Thus, in young SHR, the TXA2 synthetase inhibitor seemed to improve renal function by altering the balance of renal TXA2 and PGI2 biosynthesis and subsequently caused a delay in the initiation of hypertension. The present findings lend support to the idea that an imbalance in the renal TXA2-PGI2 biosynthesis may be involved in the initiation of hypertension in SHR.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Fatty Acids, Monounsaturated; Heart Rate; Hypertension; Kidney; Male; Oxidoreductases; Prostaglandins; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction

Topics: Adult; Epoprostenol; Female; Humans; Hypertension; Imidazoles; Oxidoreductases; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxane-A Synthase

The production of vasodilatory, antiaggregatory prostacyclin (PGI2) and vasoconstrictory, proaggregatory thromboxane A2 (TxA2) by the placenta was studied in the cases of hypertensive pregnancy complications by superfusing pieces from maternal and fetal sides of placentae of 9 pre-eclamptic, 6 hypertensive and 11 healthy women in vitro and measuring the release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), the breakdown products of PGI2 and TxA2 respectively, from the superfusate. Both sides of the placentae from the controls produced 6-keto-PGF1 alpha (maternal side 0.5 +/- 0.1 ng/g/min dry weight of tissue, mean +/- SEM; fetal side 0.7 +/- 0.2 ng/g/min) and TxB2 (maternal side 2.5 +/- 0.4 ng/g/min; fetal side 2.7 +/- 0.5 ng/g/min) with no correlation between the two. The 6-keto-PGF1 alpha production was normal in hypertensive complications whereas the TxB2 production was increased on the fetal side of the placentae obtained from the pre-eclamptic (3.7 +/- 0.3 ng/g/min: p less than 0.05) and hypertensive women (4.1 +/- 0.4 ng/g/min; p less than 0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxanes

Vipera russelli venom contains several isoenzymes of phospholipase A2 (PLA2) which were isolated by column chromatography. The effects of PLA2 fractions on blood pressure, plasma prostacyclin level and renin activity were studied in normotensive and renal hypertensive rats. PLA2 fractions II-5, II-7, III-3 and III-6 (0.1 mg/kg) injected i.v. into rats decreased the arterial blood pressure. The hypotensive action of PLA2 fractions was not affected by heat treatment (70-80 degrees C, 30 min, pH 6.8). After indomethacin (30 mg/kg, i.v.), the hypotensive response to PLA2 was markedly reduced. Plasma prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were measured by radioimmunoassays of their degradation products, 6-keto-PGF1 alpha and TXB2, respectively. PLA2 fractions (0.1 mg/kg) induced an increase in plasma PGI2 and TXA2 levels. There was a positive linear correlation between the PLA2-induced hypotensive effect and the ratio of increased 6-keto-PGF1 alpha to TXB2 (r = 0.83) in normotensive rats. In renal hypertensive rats, the increase in PGI2 level was larger than in normotensive rats. Plasma renin activity was also measured by the radioimmunoassay. Plasma renin activity was reduced by PLA2 fractions in renal hypertensive rats, but not in normotensive rats. These results suggest that the hypotensive effect of PLA2 fractions in normotensive rats may be partly due to the increase in plasma prostacyclin and thromboxane A2 levels. In addition to the larger increase in plasma PGI2 level, the reduction in plasma renin activity may also contribute to the greater hypotensive effect of PLA2 fractions in renal hypertensive rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Epoprostenol; Hot Temperature; Hypertension; Phospholipases; Phospholipases A; Phospholipases A2; Rats; Rats, Inbred Strains; Renin; Thromboxane A2; Time Factors; Viper Venoms

Topics: Adult; Epoprostenol; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxanes

Aggregation of washed platelets from stroke-prone spontaneously hypertensive rats(SHRSP) was markedly reduced with the development of hypertension in comparison with age-matched normotensive Wistar Kyoto rats(WKY) (Tomita et al. Stroke 15, 70-75, 1984). The mechanism of the hypoaggregability of SHRSP platelets was studied. Ca2+-dependence of thrombin-induced aggregation and MDA formation, and Ionophore A23187-induced aggregation of the platelets from SHRSP at a hypertensive age(16-weeks) was similar to that of the aggregation of platelets from age-matched WKY. Optimum Ca2+ concentration for aggregation and MDA formation was 1-2 mM. There was no difference in aggregation in Ca2+-free medium between the two strains. The enhancement by Ca2+ of both thrombin- and Ionophore A23187- induced aggregation, however, was markedly less in SHRSP than in WKY, whereas their MDA formation was equally enhanced by Ca2+. At a prehypertensive age (4-weeks) the degree of enhancement of aggregation by Ca2+ did not differ in the two strains. The magnitude of phospholipid(PI, PC, PE) degradation, and MDA formation IN SHRSP at early- and late- hypertensive ages(11- and 17-weeks) were either the same as or greater than that of age-matched WKY. A linear correlation line between the amount of MDA formed and the degree of platelet aggregation of SHRSP shifted to the right of WKY. In addition, thrombin-induced thromboxane B2 formation in SHRSP platelets was similar to that in WKY in the concentration range of 0.22 - 0.44 U/ml, and became significantly higher at 0.65 U/ml despite severe hypoaggregability of SHRSP platelets in all the concentrations examined. The overproduction of MDA or thromboxane B2 appears to be a compensatory mechanism. These results suggest that abnormalities of SHRSP platelets at hypertensive ages are due to an impaired function of thromboxane A2 and/or calcium concerned in aggregation and secretion but not due to a defect in cyclo-oxygenase and thromboxane synthetase pathway.

Topics: Animals; Blood Platelets; Calcium; Hypertension; Malondialdehyde; Phospholipids; Platelet Aggregation; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxanes

Blood pressure reduction induced by antihypertensive drugs with different mode of action approximated the pathological altered synthesis of TXB2 in spontaneously hypertensive rats to values of normotensive rats: in the kidney medulla by all drugs used, in the aorta only by the most efficient drugs (clonidine, dihydralazine) and in plasma and serum only in connection with a reduction in heart rate (clonidine, propranolol). The pathologically increased synthesis of 6-keto-PGF1 alpha was unchanged by drugs, therefore the ratio PGI2/TXA2 was directed towards the vasodilatory prostanoid. Unlike SHR in NTR an equieffective blood pressure reduction induced by the same drugs was without influence on TXB2 synthesis. From these results we can conclude, that the influence of antihypertensive drugs on TXB2 synthesis depends on the normotensive or hypertensive state of the animals and not on the drug per se. In hypertensive patients a blood pressure reduction by linseed oil was connected with a reduced TXB2 plasma level, too.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Clonidine; Dihydralazine; Hypertension; Kidney Medulla; Myocardium; Propranolol; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Thromboxane A2; Thromboxanes; Trapidil

Topics: Alprostadil; Angioplasty, Balloon; Anti-Bacterial Agents; Anticoagulants; Arterial Occlusive Diseases; Arteriosclerosis; Aspirin; Dipyridamole; Endarterectomy; Exercise Therapy; Fibrinolysis; Humans; Hyperlipidemias; Hypertension; Infusions, Intra-Arterial; Intermittent Claudication; Prostaglandins E; Serotonin Antagonists; Sympathectomy; Thromboxane A2

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 level of arterial blood pressure is set by complete interactions of several mechanisms which influence both blood flow in and resistance of the vascular system. An imbalance favouring elevation of vascular resistance or extracellular volume will result in hypertension. Such alterations may include increased activity of the sympathetic nervous system, of the renin-angiotensin system, or excessive secretion of mineralocorticoids. Of equal importance may be a reduced activity of blood pressure-lowering factors such as prostaglandins and the kallikrein-kinin system. This paper describes the possible significance of prostaglandins in the pathophysiology of hypertension and in degenerative vascular disease, based on their involvement in the control of vascular resistance, renal regulation of extracellular volume and platelet-vessel wall interactions. An abnormality in the biosyn-thesis of certain prostaglandin endoperoxide metabolites may lead to hypertension even without an increase in the activity of the classic blood-pressure-elevating systems. The contribution of prostaglandins for the development of hypertension and degenerative vascular disease may be based on an inherent abnormality of the prostaglandin system, as well as on the effects of major risk factors such as dietary intake of sodium and fat on prostaglandin synthesis. Specific blockade or stimulation of distinct biosynthetic pathways leading to antagonistically acting prostaglandins and nutritional manipulation of precursor fatty acids should lead to a better understanding of the pathomechanisms involved and may offer new strategies for therapy or prevention of these cardiovascular disorders.

Topics: Arachidonic Acids; Arteriosclerosis; Aspirin; Dinoprostone; Humans; Hypertension; Platelet Adhesiveness; Prostaglandins; Prostaglandins E; Thromboxane A2

In 6-week old spontaneously hypertensive rats (SHR), indomethacin (5 mg/kg i.v.) and pinane-thromboxane A2 (PTA2) (50 micrograms/kg per h i.v.) a thromboxane A2 (TXA2) antagonist as well as a TXA2 synthetase inhibitor, resulted in natriuresis accompanied by an increase in p-aminohippuric acid and inulin clearances. Indomethacin acted as an antidiuretic in 6 week Wistar-Kyoto rats (WKY). PTA2 did not alter renal functions in either 6 week WKY and 18 week SHR. Basal urinary excretion of TXB2 (UTXB2V) was greater in 6 week SHR than in 6 week WKY and 18 week SHR, and that of 6-keto-PGF1 alpha (U6-keto-PGF1 alpha V) did not differ among these strains. Thus, U6-keto-PGF1 alpha V/UTXB2V was lower in the 6 week SHR. Basal urinary excretion of PGE (UPGEV) was much greater in 18 week SHR than in the 2 other groups. In the 6 week SHR, PTA2 decreased UTXB2V and increased U6-keto-PGF1 alpha V without affecting UPGEV, and indomethacin reduced UTXB2V more markedly than did U6-keto-PGF1 alpha V and UPGEV. Thus, both PTA2 and indomethacin increased U6-keto-PGF1 alpha V/UTXB2V in the 6 week SHR. These findings indicate that a disequilibrium in the biosynthesis of vasoconstrictive TXA2 and of vasodilator PGI2 may be involved in water and sodium retention in SHR during the developmental phase of hypertension.

Topics: Animals; Bicyclic Monoterpenes; Blood Pressure; Diclofenac; Hypertension; Indomethacin; Kidney; Male; Potassium; Prostaglandins; Rats; Rats, Inbred Strains; Sodium; Thromboxane A2; Thromboxanes

Male SHR of young prehypertensive (5-6 weeks) and mature hypertensive (24-28 weeks) ages and age and sex matched control normotensive Wistar rats (NWR) were studied for aortic smooth muscle contractility in response to rabbit aorta contracting substance (RCS), serotonin, norepinephrine and potassium. Production of prostacyclin (PGI2) in SHR and NWR aortae of these two age groups was also compared. The contractility of young SHR in response to the agonists was all depressed as compared with the matched NWR. With age advances to 24-28 weeks, aortic responsiveness of NWR to all agonists were reduced and the contractility became the same for SHR and NWR except for the response to RCS which was now greater in SHR than in NWR. The PGI2-like substance released from young SHR aortae was the same as that from the matched NWR. The PGI2-like substance in mature aged rat aortae was much higher than that in young rat aortae and the activity in mature SHR was 1.8 times higher than that of the age matched NWR. The increased production of PGI2-like substance in aorta walls of the mature aged SHR may be a compensatory mechanism to reduce the elevated blood pressure.

Topics: Animals; Aorta, Thoracic; Epoprostenol; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Prostaglandins; Rats; Rats, Inbred Strains; Serotonin; Thromboxane A2; Thromboxanes

Arachidonic acid (AA)-induced pressor response and production of thromboxane YXB2, the stable metabolite of TXA2, prostaglandin (PG)-like substance (PLS) and 6-keto-PGF1 alpha the stable metabolite of prostacyclin (PGIs), were studied using isolated, perfused kidneys of 6- and 18-week old spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), two-kidney, one clip hypertensive rats (RHR) and DOCA/salt hypertensive rats (DOCA/salt HR). The AA-induced pressor response and release of TXB2 were highest in the 6-week old SHR, whereas, the release of PLS and 6-keto-PGF 1 alpha was marked in the 18-wek old SHR and the established hypertensive stages of both RHR and DOCA/salt HR. In the kidneys of SHR and WKy, exogenous TXA2 induced a severe vasoconstriction and there was a positive correlation between the AA-induced pressor response and the release of TXB2 or PLS. Thus, the initiation of hypertension in SHR may follow an accelerated synthesis of TXA2 against PGI2 in response to stimuli which induce a release of AA.

Topics: Animals; Hypertension; In Vitro Techniques; Kidney; Male; Perfusion; Prostaglandins; Prostaglandins, Synthetic; Rats; Thromboxane A2; Thromboxanes

Topics: Animals; Anti-Arrhythmia Agents; Aorta; Dipyridamole; Epoprostenol; Guinea Pigs; Heart; Humans; Hypertension; Platelet Aggregation; Prostaglandins; Rats; Regional Blood Flow; Thromboxane A2; Thromboxanes

Topics: Angiotensin II; Animals; Blood Pressure; Epoprostenol; Half-Life; Hypertension; In Vitro Techniques; Indomethacin; Kidney; Male; Platelet Aggregation; Prostaglandins; Rats; Thromboxane A2; Thromboxanes