thromboxane-a2 and Body-Weight

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

We assessed the effects of low-dose aspirin (0.5 and 15 mg/kg/d) on renal prostaglandin synthesis and action in healthy volunteers using intravenous furosemide as a stimulus. Inhibition of platelet cyclo-oxygenase was assessed by changes in serum thromboxane B2 (TXB2) level. After one week of treatment, ten healthy subjects did not show any change in weight, blood pressure, or diuretic and natriuretic responses to furosemide with either dose of aspirin. Serum TXB2 level was reduced to 3% of control by aspirin 0.5 mg/kg/d and to 0.1% by the higher dose. In contrast, urine excretion of TXB2 was only reduced to 68% and 51% of the placebo value, whereas 6-keto-prostaglandin F1 alpha (6kPGF1 alpha) excretion was not decreased by either dose. Furosemide produced a transient increase in excretion rates of TXB2 and 6kPGF1 alpha that was of lesser duration than the diuretic response. These transient increases were slightly reduced by aspirin. Baseline plasma renin activity was not affected by either dose of aspirin. The brisk increment in plasma renin activity seen ten minutes after furosemide, as well as later values (30 and 240 min) were not changed by aspirin. We conclude that chronic low-dose aspirin can profoundly affect platelet PG production without affecting stimulated renal PGI2 production or plasma renin activity. There is a modest reduction in urine TXB2 excretion that is consistent with a primarily renal source of this metabolite.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Blood Platelets; Body Weight; Eicosanoic Acids; Electrolytes; Female; Furosemide; Humans; Male; Radioimmunoassay; Renin; Thromboxane A2; Time Factors

The protective effect of aspirin against myocardial hypertrophy (MH) was studied. Model rats of pressure overload MH were prepared by abdominal aortic coarctation. Rats were randomly divided into the sham group (

Topics: Animals; Apoptosis; Aspirin; Blood Pressure; Body Weight; Cardiotonic Agents; Disease Models, Animal; Fibrillar Collagens; Heart Ventricles; Hypertrophy; Inflammation Mediators; Interleukin-10; Male; Myocardium; Myocytes, Cardiac; Organ Size; Prostaglandins; Rats, Wistar; Thromboxane A2; Tumor Necrosis Factor-alpha

Choline as a quaternary amine nutrient is metabolized to trimethylamine by gut microbiota and subsequently oxidized to circulating trimethylamine-N-oxide (TMAO), a gut-derived metabolite associated with liver toxicity and cardiovascular disease. The study was to probe the possible vasoprotective and hepatoprotective effects of total saponins of Gynostemma pentaphyllum (TSGP) in 3% high-choline water-feeding mice. The purified TSGP was obtained with content of 83.0% saponins, and its antioxidant activities were evaluated in vitro. Furthermore, the mice fed with high choline for 8 weeks significantly expressed vascular endothelial dysfunction and liver oxidative stress (p < 0.01 vs. Normal). Administration of TSGP at 400 and 800 mg/kg·body weight (b.w.) significantly lowered the serum total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), endothelin-1 (ET-1) and thromboxane A

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Chemical and Drug Induced Liver Injury; Cholesterol, LDL; Choline; Endothelium, Vascular; Glutathione Peroxidase; Gynostemma; Liver; Malondialdehyde; Methylamines; Mice; Nitric Oxide Synthase Type III; Oxidative Stress; Plant Extracts; Saponins; Thromboxane A2; Triglycerides

Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21).. IUGR was induced via maternal thromboxane A2-analog infusion in mice.. IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3' distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females.. IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.

Topics: Animals; Blood Glucose; Body Weight; Chromatin; Chromatin Assembly and Disassembly; DNA Methylation; Exons; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Histones; Insulin; Insulin-Like Growth Factor I; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Promoter Regions, Genetic; Risk Factors; Sex Factors; Thromboxane A2

Metformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin.. 16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed.. 18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats.. Metformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.

Topics: Acetylcholine; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Dyslipidemias; Epoprostenol; Hyperinsulinism; Hypoglycemic Agents; Indomethacin; Insulin; Insulin Resistance; Male; Mesenteric Arteries; Metformin; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; Obesity; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium Glutamate; Thromboxane A2

Our present study examines, in mesenteric resistance arteries, possible vasodilation alterations, and the role of NO and COX (cyclo-oxygenase) derivatives, in cirrhosis. The vasodilator response to acetylcholine was analysed in segments from control and cirrhotic rats. The effects of the non-specific COX inhibitor indomethacin, the specific COX-1 inhibitor SC-560 and the specific COX-2 inhibitor NS-398 were analysed in segments from both groups of rats. NO release was measured, and eNOS [endothelial NOS (NO synthase)], phospho-eNOS, iNOS (inducible NOS), COX-1 and COX-2 protein expression was also analysed. The effects of the TP receptor [TXA2 (thromboxane A(2)) receptor] antagonist SQ 29548, the TXA(2) synthesis inhibitor furegrelate, the PGI(2) (prostaglandin I(2)) synthesis inhibitor TCP (tranylcypromine) or TCP+furegrelate were only determined in segments from cirrhotic rats. The vasodilator response to acetylcholine was higher in segments from cirrhotic rats. Indomethacin, SC-560 and NS-398 did not modify the vasodilator response in control rats; however, indomethacin, NS-398 and TCP+furegrelate increased, whereas SC-560 did not modify and SQ 29548, furegrelate or TCP decreased, the vasodilator response to acetylcholine in cirrhotic rats. NO release was higher in cirrhotic rats. Furegrelate decreased, whereas TCP+furegrelate increased, the NO release in segments from cirrhotic rats. eNOS and COX-1 protein expression was not modified, whereas phosho-eNOS, iNOS and COX-2 protein expression was higher in cirrhotic rats. Therefore the increase in iNOS expression and eNOS activity may mediate increases in endothelial NO release. The COX-2 derivatives TXA(2) and PGI(2) may act simultaneously, producing a compensatory effect that reduces NO release and may limit the hyperdynamic circulation.

Topics: Animals; Blood Pressure; Body Weight; C-Reactive Protein; Lipid Metabolism; Liver; Liver Cirrhosis, Experimental; Male; Mesenteric Arteries; Nitric Oxide; Organ Size; Prostaglandins; Prostaglandins A; Rats; Rats, Sprague-Dawley; Spleen; Superoxides; Thromboxane A2; Vasodilation

The aim of this study was to analyze whether endogenous male sex hormones influence the release of thromboxane A2(TXA2) and its role in the electrical field stimulation (EFS)-induced response, as well as the mechanism involved. For this purpose, endothelium-denuded mesenteric arteries from control and orchidectomized male Sprague-Dawley rats were used to measure TXA2 release; EFS-induced response, nitric oxide (NO), norepinephrine (NA), and prostaglandin (PG) I2 release were also measured in the presence of the TXA2 synthesis inhibitor furegrelate. Orchidectomy increased basal and EFS-induced TXA2 release. Furegrelate decreased the EFS-induced contraction in arteries from control rats, but did not modify it in arteries from orchidectomized rats. The EFS-induced neuronal NO release and vasodilator response were increased by furegrelate in arteries from control rats, but were not modified in arteries from orchidectomized rats. Furegrelate did not modify the EFS-induced NA release or vasoconstrictor response in arteries from either control or orchidectomized rats. The EFS-induced PGI2 release was not modified by furegrelate in arteries from control rats, but was increased in arteries from orchidectomized rats. The results of the present study show that endogenous male sex hormone deprivation i) increases non-endothelial TXA2 release and ii) regulates the effect of endogenous TXA2 on the EFS-induced response through different mechanisms that, at the least, involve the NO and PGI2 systems. In arteries from control rats, inhibition of TXA2 formation decreases the EFS-induced response by increasing neuronal NO release. In arteries from orchidectomized rats, the EFS-induced response is unaltered after the inhibition of TXA2 formation, by increasing PGI2 release.

Topics: Animals; Benzofurans; Body Weight; Electric Stimulation; Epoprostenol; Male; Mesenteric Arteries; Nitric Oxide; Norepinephrine; Orchiectomy; Rats; Rats, Sprague-Dawley; Testosterone; Thromboxane A2; Thromboxane-A Synthase

Atherosclerosis is a chronic inflammatory disease of the vasculature influenced by a variety of mediators. Among them, prostanoids, which include prostacyclin and thromboxane (Tx) A(2), have recently received a lot of attention. Previous studies demonstrated that antagonism or deletion of the receptor for TxA(2) retards early atherogenesis in apolipoprotein E-deficient mice, but no data are available in low-density lipoprotein (LDL) receptor deficient mice. In our study, we tested the effect of a novel TxA(2) receptor (TP) antagonist and synthase inhibitor, BM-573, on atherosclerosis development and progression in LDL receptor deficient mice. To this end, the effect of 12 weeks treatment with BM-573 on early or established aortic atherosclerotic lesions of these mice was assessed. In both treatments, while BM-573 did not affect body weight, systolic blood pressure, total plasma cholesterol or triglycerides levels, it partially reduced TxA(2) but did not affect prostacyclin biosynthesis. Moreover, BM-573 significantly decreased early atherogenesis and prevented progression of established atherosclerotic lesions. These results show for the first time that this dual Tx inhibitor is effective in reducing atherogenesis in the LDL receptor deficient mice. They also demonstrate the novel concept that this therapeutic approach halts the progression of the disease and influences the cellular composition of the atherosclerotic plaques.

Topics: Animals; Aorta; Atherosclerosis; Blood Pressure; Body Weight; Cholesterol; Disease Models, Animal; Disease Progression; Epoprostenol; Male; Mice; Mice, Inbred C57BL; Platelet Aggregation Inhibitors; Receptors, LDL; Receptors, Thromboxane; Sulfonylurea Compounds; Thromboxane A2; Triglycerides

Changes in reactivity to phenylephrine in aortas isolated from 2-, 6-, and 10-week ethanol-treated rats and their age-matched control and isocaloric rats were investigated. Chronic ethanol consumption enhances the contractile response of endothelium-intact and -denuded rat aortic rings to phenylephrine, a response that is time-independent. Pretreatment with indomethacin reduced E(max) for phenylephrine in denuded aortas from ethanol-treated rats but not control or isocaloric rats. After indomethacin treatment, no differences in E(max) from phenylephrine were observed among the groups. SQ29548 ([1S-[1alpha-2alpha(Z)3alpha,4alpha]]-7-[3-[[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid), an antagonist of prostaglandin H(2)/thromboxane A(2) (TXA(2)) receptors, did not alter phenylephrine-induced contraction in control or isocaloric aortas. However, in ethanol-treated aortas, E(max) was reduced to control level. Moreover, phenylephrine-stimulated release of thromboxane B(2), a stable metabolite of TXA(2), was higher in tissues from ethanol-treated rats. Simultaneous measurement of the changes in [Ca(2+)](i) and contraction induced by phenylephrine showed that both parameters are higher in the rat aorta from ethanol-treated rats. CaCl(2)-induced contraction in free Ca(2+) solution containing phenylephrine was increased in ethanol-treated aortas. Additionally, the enhancement in CaCl(2)-induced contraction was prevented by SQ29548. The major contribution of the present study is that it demonstrates a detailed description of the mechanisms involved in the enhancement of phenylephrine-induced contraction in rat aorta from ethanol-treated rats. We provided evidence that this response was not different among the three periods of treatment employed in this study and that it is maintained by two mechanisms: an increased release of vascular smooth muscle-derived vasoconstrictor prostanoids (probably TXA(2)) and an enhanced extracellular Ca(2+) influx.

Topics: Animals; Aorta, Thoracic; Arachidonic Acid; Blood Glucose; Body Weight; Calcium; Cardiotonic Agents; Central Nervous System Depressants; Cytosol; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Ethanol; Heart; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Phenylephrine; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Thromboxane A2

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA2 synthase protein levels are higher in cerebral vessel homogenates from testosterone-treated orchiectomized (ORX + T) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORX + T and ORX groups. However, dilator responses to either the selective TxA2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX + T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX + T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA2-mediated tone in rat cerebral arteries by increasing endothelial TxA2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Androgens; Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Male; Middle Cerebral Artery; Orchiectomy; Rats; Rats, Inbred F344; Receptors, Thromboxane; Testosterone; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

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 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

Glucosamine, a naturally occurring amino monosaccharide, has been used to treat or prevent osteoarthritis in humans. Recently, we have revealed that glucosamine inhibits platelet activation in vitro. However, the effect of in vivo administration of glucosamine has not yet been clarified. In this study, we administered glucosamine orally to guinea pigs and examined its effects on platelet functions.. Glucosamine hydrochloride solution (0.5%, 5 mg/ml) was administered orally to guinea pigs ad libitum for 22 days, and platelet rich plasma was collected to evaluate platelet functions in vitro. Guinea pigs received an average of 400 mg glucosamine/animal/day.. Glucosamine-administration suppressed platelet aggregation in response to ADP by 51% (p < 0.01), but not platelet aggregation induced by collagen. Furthermore, glucosamine-administration inhibited the ADP-induced extracellular release of ATP and production of thromboxane A(2) by 91% and 96%, respectively (p < 0.001). In contrast, glucosamine did not affect the body-weights, platelet counts and bleeding time in guinea pigs after the administration.. These observations suggest that glucosamine is likely to exert an inhibitory action on platelets in vivo by suppressing platelet aggregation, ATP release, and thromboxane A(2) production. Thus, glucosamine could be expected as a novel and safe anti-platelet agent.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Administration, Oral; Animals; Bleeding Time; Blood Platelets; Body Weight; Cytoplasmic Granules; Female; Glucosamine; Guinea Pigs; Platelet Activation; Platelet Aggregation; Platelet Count; Receptors, Purinergic P2; Thromboxane A2

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glomerular Mesangium; Male; Methacrylates; Prostaglandins; Proteinuria; Rats; Rats, Inbred OLETF; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

There is a well-known association between diabetes and atherosclerosis. Platelets are involved in the development of atherosclerotic vascular diseases and play a key role in atherosclerotic complications. Diabetes mellitus is related to alteration in the homeostasis of selenium and the protective role of selenium against lipid peroxidation in diabetes is reported. In the present study, thrombin-induced platelet aggregation and thromboxane A2 (TxA2) formation in diabetes and the effect of sodium selenite were evaluated.. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in Wistar rats (n = 21). Thirty of them were used as control rats. A week after streptozotocin injection, 11 of the control rats and 12 of the diabetics were injected with 5 micromol/kg/day of sodium selenite for 4 weeks. Thrombin-induced aggregation of the platelets was evaluated by optical technique. Thromboxane B2 (TxB2), TxA2 metabolite, was measured by enzyme-linked immunoassay (EIA) in thrombin-induced platelets.. The platelet aggregation and TxB2 level increased in diabetic rats. Sodium selenite reversed the increase in platelet aggregation and TxB2 and caused a small but significant (p < 0.05) decrease in the glucose level. The hyperaggregability of platelets in STZ-induced diabetic rats was thought to be related to the enhanced TxA2 formation of platelets. Increase in TxA2 formation implies lipid peroxidation. Sodium selenite decreased the TxA2 formation. Besides its antioxidative effect, further studies are needed to establish the insulin-like effect of selenite because of a small decrease in blood glucose.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Insulin; Lipid Peroxidation; Platelet Activation; Platelet Aggregation; Rats; Rats, Wistar; Sodium Selenite; Streptozocin; Thrombin; Thromboxane A2; Thromboxane B2

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

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

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

Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Aspirin; Body Weight; Cell Adhesion; Cholesterol; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; U937 Cells; Umbilical Veins; Vasoconstrictor Agents

We performed micropuncture studies to determine the role of thromboxane A2 in the exaggerated tubuloglomerular feedback (TGF) activity in young spontaneously hypertensive rats (SHR). Glomerular function was assessed by changes in proximal tubular stop-flow pressure (SFP) produced by different rates of orthograde perfusion through Henle's loop. Seven-week-old SHR exhibited an exaggerated TGF activity compared with Wistar-Kyoto rats (WKY) during euvolemia, confirming earlier studies. During control periods, the feedback-induced maximal SFP response (DeltaSFP) was greater in SHR (18-19 vs. 12-13 mmHg in WKY), whereas basal SFP and proximal tubular free-flow pressure were similar in both strains. In one series, the thromboxane A2 agonist U-46619 was added to the tubular perfusate for a final concentration of 10(-6) M. In WKY, DeltaSFP was increased by 100% to 26 mmHg. In contrast, DeltaSFP in young SHR was unaffected by the thromboxane A2 agonist. In other animals, the thromboxane synthase inhibitor pirmagrel (50 mg/kg) was injected intravenously to inhibit thromboxane production. In SHR, pirmagrel decreased DeltaSFP by 8.5 mmHg and reduced reactivity. Less attenuation was observed in WKY; DeltaSFP was reduced by 3 mmHg, whereas reactivity was unchanged. In other studies, tubular perfusion with the thromboxane receptor inhibitor SQ-29548 (10(-6) M) reduced DeltaSFP more in SHR (7 vs. 3 mmHg in WKY) and also decreased reactivity more in SHR (2.3 vs. 0.5 mmHg. nl-1. min-1). Coperfusion of SQ-29548 and U-46619 resulted in an 85% block of the effect of U-46619 on DeltaSFP. Tubular perfusion with the agonist U-46619 during thromboxane synthase inhibition markedly enhanced DeltaSFP in both strains, with a greater effect in WKY. These results suggest that elevated levels of thromboxane A2 in young SHR contribute to the exaggerated TGF control of glomerular function in SHR during the developmental phase of hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Age Factors; Animals; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Capillaries; Enzyme Inhibitors; Fatty Acids, Unsaturated; Feedback; Hematocrit; Hydrazines; Imidazoles; Juxtaglomerular Apparatus; Kidney Tubules, Proximal; Loop of Henle; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxane A2; Vasoconstrictor Agents

IUGR was induced by maternal administration of synthetic thromboxane A2 (STA2) from the 13th day of gestation. Fetuses and neonates showed a markedly significant weight reduction. In E16 IUGR brain, no pathological abnormalities were found, but morphological changes appeared in the cortical plate of E18 IUGR brain. In E20 IUGR brain, ectopic clusters of differentiating cells cytologically mimicking neuroblasts were found in the neuroepithelial layer, but these abnormal clusters of cells in IUGR brain of late gestation were never observed in PN7. Morphometric analysis of coronal-sectional areas of the brain and cortical plate demonstrated that there were no differences between IUGR rats and controls in E16 and E18. These areas were, however, significantly reduced in E20 and PN7 growth-retarded rats compared with the control. Because the period of STA2 administration coincides with the neuro-developmental stage of cell migration and differentiation, reduction of the uteroplacental blood supply might cause a transient abnormal cytoarchitecture of the cerebral cortex resulting in brain growth retardation.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Brain Diseases; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

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

The main adverse effect of cyclosporine A (CyA) is nephrotoxicity. CyA increases urinary concentrations of thromboxane A2 (TXA2), a potent vasoconstrictor that can be involved in kidney failure induced by CyA. Furthermore, it has been postulated that a relationship exists between oxygen free radicals and the synthesis of arachidonate metabolites in experimental models of CyA nephrotoxicity. We studied the effect of vitamin E (VitE), an oxygen free radical scavenger, on renal function, on glomerular synthesis of thromboxane B2 (TXB2), and on free radicals in rats treated with CyA. Four groups of male Wistar rats were studied: (1) a control group; (2) a group given VitE at 0.05 mg/dl in drinking water for 25 days; (3) a group given CyA at 50 mg/kg body weight/day orally for 10 days; and (3) a group given Vit E + CyA, in which rats were provided with drinking water containing VitE for 15 days and afterwards were treated with VitE and CyA for 10 days. Renal function parameters and glomerular synthesis of TXB2, superoxide anion (02.-), malondialdehyde (MDA), and hydrogen peroxide (H202) were evaluated. CyA decreased body weight, caused deterioration of kidney function and increased glomerular synthesis of TXB2, O2.-, MDA, and H202. Pretreatment with VitE prevented the effects of CyA on kidney function and decreased glomerular synthesis of these mediators. In conclusion, CyA induced glomerular synthesis of reactive oxygen species (ROS) and TxB2. Pretreatment with VitE inhibited acute renal failure induced by CyA, probably by scavenging free radicals and by inhibiting the synthesis of TXB2.

Topics: Animals; Body Weight; Cyclosporine; Free Radical Scavengers; Hydrogen Peroxide; Kidney Diseases; Kidney Glomerulus; Lipid Peroxides; Male; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxides; Thromboxane A2; Thromboxane B2; Vitamin E

Thromboxane A2 (TXA2) is a potent constrictor of both airway and vascular smooth muscle. In addition, plasma exudation is induced in the airways by a thromboxane mimetic (U-46619). Because plasma exudation is associated with a local vasodilatation and increased local blood flow, we hypothesized that the general vasoconstrictor effect of U-46619 would be weaker in the airways than in other vascular beds, perhaps resulting in increased local airway blood flow. We studied the effects of i.v. U-46619 on blood pressure, lung resistance as well as blood flow, plasma exudation in airways and leg skeletal muscle in guinea pigs. We found (1) i.v. U-46619 increases the systemic blood pressure, blood flow in tracheal mucosa but decreases blood flow in leg skeletal muscle; (2) i.v. U-46619 induces plasma exudation in the airways, but not in the leg skeletal muscle; (3) a positive relationship between blood pressure and tracheal blood flow as well as airway plasma exudation, a negative relationship between blood pressure and blood flow in leg skeletal muscle; (4) i.v. U-46619 significantly increases lung resistance. We conclude that i.v. U-46619 induces plasma exudation in airways but not in skeletal muscle, and that this plasma exudation is associated with the increased local blood flow, which in turn is caused by increased inflow pressure and redistribution of the total body blood flow to the airways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Blood Circulation; Blood Pressure; Body Weight; Exudates and Transudates; Guinea Pigs; Muscle, Skeletal; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxanes; Vasoconstrictor Agents

Cyclosporine (CsA)-treated female Wistar rats, in dose of 37.5 microM (45 mg)/kg/day for 7 days, exhibited significantly decreased creatinine clearance (Ccr), and provoked body weight loss (BWL), which is consistent with the development of nephrotoxicity (NT). Urine volume (V) did not change and proteinuria (PU) was not provoked. These changes were associated with significantly diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions. Light-microscopic (LM) sections of rat kidneys showed that all kidneys were affected but the lesions (mainly diffuse vacuolization) were reversible. When CsA-treated animals were pretreated with ketanserine (KTS), which antagonizes (a) the direct vasoconstrictor effect of serotonin (5-HT), and (b) the amplifying effects of 5-HT on other vasoactive substances (such as noradrenaline (NA), alpha 1-receptors, histamine, H2 receptors, and prostaglandin F2 alpha), Ccr and urine volume significantly increased, BWL was partially prevented and the ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions were significantly enhanced. LM sections showed that only 5 of 9 rats were affected but the lesions were of less importance. These observations indicate that the NT induced by CsA in our studies was mediated by 5-HT, a potent vasoconstrictor agent, and by the metabolites of arachidonic acid. However, other vasoactive agents and additional mechanisms could also be implicated.

Topics: Animals; Body Weight; Creatinine; Cyclosporine; Female; Immunosuppressive Agents; Ketanserin; Kidney; Prostaglandins; Proteinuria; Rats; Rats, Wistar; Serotonin Antagonists; Thromboxane A2

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion. 2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats. 3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 +/- 0.05 (SEM) as compared with 1.06 +/- 0.09 ml min-1 g-1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats. 4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 +/- 22.3 versus 56.8 +/- 10.2 pmol 24 h-1 100 g-1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 +/- 2.0 versus 6.4 +/- 0.9 pmol h-1 mg-1 protein (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Blood Pressure; Body Weight; Cholestasis; Female; Kidney; Kidney Glomerulus; Ligation; Organ Size; Phenylacetates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2

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

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

Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Body Weight; Diet, Atherogenic; Disease Models, Animal; Epoprostenol; Female; Hematocrit; Hypercholesterolemia; Lipids; Male; Random Allocation; Risk Factors; Swine; Thromboxane A2; Thromboxane B2

To clarify the possible role of elevated atrial natriuretic peptide (ANP) in the pathophysiology of preeclampsia, we measured ANP, renin activity (PRA), angiotensin II (Ang II), TXB2 (a stable metabolite of TXA2) and 6-keto-PGF1 alpha (a stable end product of PGI2) concentrations in the plasma of 19 normal pregnant women and 35 severe preeclamptic patients at term. Plasma ANP levels in the preeclamptic patients (n = 35, 71.5 +/- 3.8 pg/ml, mean +/- S.E.) and also umbilical plasma ANP (n = 35, 83.0 +/- 4.2 pg/ml) were significantly (p less than 0.01) higher than those of normal pregnant women plasma (n = 19, 58.7 +/- 3.7 pg/ml) and umbilical plasma (n = 19, 47.6 +/- 4.7 pg/ml). There was a significant (p less than 0.01) positive correlation between maternal ANP levels and fetal ANP levels (n = 54, r = 0.44). Plasma PRA and 6-keto-PGF1 alpha levels in preeclampsia were significantly (p less than 0.05) lower than those of normal pregnancy. The ratio of 6-keto-PGF1 alpha/TXB2 in preeclampsia was significantly (p less than 0.01) lower than that of normal pregnancy as we reported previously. There was no significant correlation between plasma ANP level and plasma PRA, Ang II, plasma TXB2 and 6-keto-PGF1 alpha concentrations. Moreover there was no significant correlation between plasma ANP level and the severity of preeclampsia. These data suggest the possibility of a transplacental crossing of ANP secreted by feto-placental unit, which might be, at least in part, responsible for the high ANP levels observed in preeclampsia. The ANP in preeclampsia is not related directly to hypertension, but it may play a substantial role in the regulation or normalization of blood volume and vascular reactivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Renin; Thromboxane A2

Dose-response curves were obtained to bolus injections of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in blood and Krebs-perfused kidneys of male Wistar rats. Vasoconstrictor responses to both NA and 5-HT were significantly attenuated in blood-perfused kidneys of alloxan-treated 14 day diabetic rats compared with non-diabetic animals. Responses to low doses of NA were also significantly attenuated in Krebs-perfused kidneys from diabetic rats but responses to 5-HT were augmented. Dose-dependent potentiation of vasoconstrictor responses to NA and 5-HT in Krebs-perfused kidneys of both non-diabetic and diabetic rats occurred during infusion of the thromboxane A2 (TxA2)-mimetic U46619 [15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid). The potentiation by U46619 (11 ng mL-1) was inhibited in both groups during infusion of the thromboxane receptor antagonist AH23848 [( 1 alpha(Z), 2 beta, 5 alpha]-(+/-)-7-[5[[(1,1'-biphenyl)-4-yl]methoxyl]-2-(4- morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). Infusion of 5-HT in Krebs-perfused kidneys of non-diabetic rats, causing a rise in perfusion pressure of similar magnitude to that produced by infusion of 111ng mL-1 U46619, did not significantly affect responses to bolus injections of NA. Potentiation of vasoconstrictor responses to low concentrations of 5-HT by U46619 was significantly greater in Krebs-perfused kidneys of diabetic rats than kidneys from non-diabetic animals. Activation of vascular TxA2 receptors augments the vasoconstrictor effects of 5-HT in Krebs-perfused diabetic rat kidneys to a greater extent than in non-diabetic kidneys.

Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; In Vitro Techniques; Male; Perfusion; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Serotonin; Renal Circulation; Thromboxane A2

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Insulin; Kidney; Male; Methacrylates; Microscopy, Electron; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effects of low dose indomethacin therapy in primary prevention of diet-induced atherosclerosis of rhesus monkeys was studied. The parameters studied were serum cholesterol concentration, thromboxane A2 (T x B2), prostacyclin (6-keto-PGF1 alpha) in serum/plasma, and the extent and intensity of coronary atherosclerosis. Although indomethacin did not affect serum cholesterol, it reduced serum T x B2 significantly (P less than 0.01). Plasma 6-keto-PGF1 alpha was not restored to the pretreatment level. A significant protective role of the drug was noted as far as coronary atherosclerosis is concerned (P less than 0.01).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Cholesterol; Coronary Artery Disease; Diet, Atherogenic; Disease Models, Animal; Indomethacin; Macaca mulatta; Male; Thromboxane A2

The vasodepressor responses to intravenous injections of arachidonic acid, and the formation of its metabolites, were studied in rats made diabetic 1 or 2 weeks after a 1-dose alloxan treatment. Arachidonic acid dose-dependently decreased the diastolic blood pressure in normal animals, but this hypotensive effect was significantly weaker in 2-week postalloxan-treated rats. Indometacin abolished arachidonic-acid-induced depressor responses in both normal and diabetic animals. Hypotension induced by sodium nitroprusside was of the same magnitude in non-diabetic and insulin deficient rats. Plasma levels of thromboxane B2 were significantly increased in both the 1- and 2-week diabetic rats, being greater in the latter group; those of 6-keto-PGF1 alpha remained unchanged during the 2-week diabetic period. It is concluded that the attenuation by diabetes of depressor responses to arachidonic acid could be due to changes in the thromboxane/prostacyclin balance, with thromboxane formation being elevated whereas prostacyclin generation remains unaffected.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Male; Nitroprusside; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

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

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

Platelet aggregation and thromboxane A2 release in response to adrenaline and the relationship of this response to body weight was investigated in female patients with anorexia nervosa. Platelets obtained from patients with body weights below 75% of the expected average weight (Group I) showed significantly greater aggregation and TXA2 release in response to adrenaline when compared with controls matched for sex and age. Patients with body weights 75-95% of the expected average weight (Group II) did not show enhancement of platelet aggregation or TXA2 release. In Group I patients, platelet hyperaggregability and enhanced TXA2 release induced by adrenaline tended to normalise following inpatient treatment and weight gain: with 0.5 mumol/l adrenaline, the pre-weight gain median aggregation was 65%, whereas the post-weight gain value was 37% - P less than 0.01. Markedly underweight patients also had hyperaggregability following stimulation with ADP and collagen. This hyperaggregability also tended to normalise after weight gain but these changes were not statistically significant. Platelet hyperaggregability (especially in response to adrenaline) in anorexia nervosa is therefore secondary to weight loss and reverts to normal with normalisation of weight. These changes may reflect the previously documented increase in platelet alpha-adrenoceptors in thin patients with anorexia nervosa and their normalisation following weight gain. However, the hyperaggregability in response to agonists other than adrenaline suggests that an additional post-receptor mechanism may be involved.

Topics: Adenosine Diphosphate; Anorexia Nervosa; Body Weight; Collagen; Epinephrine; Humans; Platelet Aggregation; Platelet Count; Thromboxane A2

The effect of spironolactone on the urinary excretion of prostaglandins was studied in patients with liver cirrhosis and ascites. Patients were kept in bed and given a sodium-restricted diet for at least 4 days before spironolactone treatment was considered. Starting from the 5th day of protocol, patients were treated with this diuretic if their spontaneous weight loss had been less than 600 g during the 2 previous days. Patients were distributed in groups according to weight loss during the first 4 days on diuretic therapy: Group I (high responders), II (medium responders) and III (low responders). Group I patients showed higher basal values (4th day of protocol) of urinary sodium (P less than 0.02) and urinary 6-keto-PGF1 alpha (P less than 0.02) than the other patients, but there were no significant differences in the basal excretion rates of PGE2 nor TXB2 among the groups. The therapeutic requirement for spironolactone treatment in patients from Group I was delayed as compared with the other two groups (P less than 0.001) due to the fact that their spontaneous weight loss took place over a long period. For all patients, spironolactone administration produced a significant increase in 6-keto-PGF1 alpha excretion (P less than 0.01) without affecting significantly urinary elimination of PGE2 nor TXB2. A close relationship was found between the spironolactone-induced increments in urinary sodium and urinary 6-keto-PGF1 alpha excretion (r = 0.74, P less than 0.001). It is suggested that the ability of the kidney to synthetize prostacyclin can influence the natriuretic response to spironolactone therapy in patients with liver cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Ascites; Body Weight; Dinoprostone; Female; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Prostaglandins; Prostaglandins E; Sodium; Spironolactone; Thromboxane A2

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

The role of prostanoids in a swine model of coronary artery spasm was examined. Eighteen miniature pigs underwent endothelial denudation of the left coronary artery (left circumflex branch in 14 pigs and left anterior descending branch in 4 pigs) followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the vasoconstrictive effect of thromboxane A2 and the preventive effects of indomethacin and prostacyclin against histamine-induced coronary artery spasm were examined. Intracoronary administration of thiothromboxane A2, 200 micrograms, a stable thromboxane A2 analog, failed to provoke coronary artery spasm (seven of seven cases) but nonselectively constricted the coronary artery by 33%. Intravenous administration of indomethacin, 2 mg/kg, or continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm (four of four and eight of eight cases, respectively), yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine model, prostanoids may not play a primary role in the occurrence of coronary artery spasm.

Topics: Animals; Arteriosclerosis; Body Weight; Cholesterol; Coronary Vasospasm; Disease Models, Animal; Epoprostenol; Histamine; Indomethacin; Male; Prostaglandins; Swine; Swine, Miniature; Thromboxane A2

The prostacyclin-producing capacity of various blood vessels was studied using platelet aggregation bioassay in rats of different ages. Results showed that --the PGI2 producing capacity of arteries was five to tenfold of the respective veins; --in the arteries the PGI2 production calculated for unit vascular mass declined from the centre to the periphery, despite the relative increase of endothelial surface area. This points to the importance of other vascular elements in the control of PGI2 production; --the PGI2 forming activity of some blood vessels increased with the age up to a limit (300-400 g body weight), decreasing thereafter. Based on these results we conclude that major part of PGI2 in systemic blood originates from the large arteries, whereas the low PGI2 production of the veins might play a role, among others, in the more frequent occurrence of venous thrombosis.

Topics: Aging; Animals; Arachidonic Acid; Arachidonic Acids; Biological Assay; Blood Vessels; Body Weight; Epoprostenol; Male; Platelet Aggregation; Rats; Thromboxane A2

Vascular responsiveness to vasoactive eicosanoids as well as vascular prostacyclin and thromboxane production was investigated in 7-10 weeks alloxan-diabetic rats. Aortic rings from diabetic rats exhibited increased responsiveness to carbocyclic thromboxane A2, a thromboxane analogue, when compared to control rat aortae. Isolated perfused hearts of diabetic rats showed increased vascular responsiveness to 9,11-methanoepoxy PGH2 (U-46619), an endoperoxide analogue. Diabetes resulted in a reduction in prostacyclin generation by isolated incubated aortae which was overcome by the addition of arachidonic acid but not by homogenization of incubated aortic tissue. In contrast, prostacyclin, but not thromboxane, generation was elevated in isolated perfused hearts of diabetic animals in response to moderate doses of arachidonic acid, but at high doses of arachidonate, more thromboxane was formed by perfused hearts of diabetic rats. These results suggest that different vessels can either increase or decrease their prostaglandin production in response to diabetes. The alterations in prostanoid production may be due to differential changes in prostacyclin and thromboxane synthesis in vessels which, in turn, may be related to the changes in vascular responsiveness.

Topics: Animals; Aorta, Thoracic; Blood Vessels; Body Weight; Coronary Circulation; Diabetes Mellitus, Experimental; Epoprostenol; Hemodynamics; Male; Organ Size; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxanes