thromboxane-a2 and Hypertension--Renovascular

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

Topics: Animals; Blood Platelets; Cardiomegaly; Cardiovascular Diseases; Dinoprost; Epoprostenol; Hemodynamics; Humans; Hypertension, Renovascular; Inflammation Mediators; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Prostaglandins; Receptors, Prostaglandin; Sepsis; Signal Transduction; Tachycardia; Thromboxane A2

To study the effect of captopril (Cap) on platelet cytosolic free calcium concentration ([Ca2+]i), platelet aggregation (PAg), and plasma TXA2/PGI2 ratio in the renovascular hypertensive rats.. Blood pressure was measured once a week by tail-cuff microphonic manometer. Platelet [Ca2+]i was measured by Fura 2-AM. Plasma angiotensin II (Ang), thromboxane A2 (TXA2), and prostacycline (PGI2) were measured by radioimmunoassay.. Platelet [Ca2+]i and PAg increased (P < 0.01), while plasma Ang and TXA2/PGI2 ratio elevated (P < 0.05) in the renovascular hypertensive rats; platelet [Ca2+]i and plasma TXA2/PGI2 ratio reduced markedly after i.g. Cap 100 mg.kg-1.d-1 compared with saline for 2 wk.. The altered TXA2/PGI2 after Cap treatment contributed to the improvement of the platelet [Ca2+]i and PAg.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Platelets; Blood Pressure; Calcium; Captopril; Epoprostenol; Female; Hypertension, Renovascular; Male; Platelet Aggregation; Rats; Rats, Wistar; Thromboxane A2

To investigate the nature of the arachidonic acid metabolite involved in the altered reactivity of microvessels of two-kidney, one-clip hypertensive rats and the possible contribution of this product to the elevated blood pressure levels found in two-kidney, one-clip hypertension, mesenteric arterioles either perfused in vitro or studied in vivo were used along with blood pressure determinations. The decreased response to acetylcholine observed was normalized by ridogrel, a thromboxane A2 receptor antagonist, and dazoxiben, a thromboxane A2 synthase inhibitor. The smooth muscle response to nitric oxide, tested with sodium nitroprusside, was unaltered in two-kidney, one-clip hypertensive microvessels. Neither ridogrel nor dazoxiben modified the response to this vasodilator. In contrast, the potentiated response to noradrenaline was corrected by ridogrel and dazoxiben in vitro but not in vivo. Noradrenaline and acetylcholine increased the release of thromboxane A2 from the mesenteric microvessels of two-kidney, one-clip hypertensive rats. Ridogrel and dazoxiben decreased but did not normalize the elevated blood pressure of hypertensive rats. Based on these results, we concluded that: 1) the decreased responsiveness of smooth muscle to acetylcholine resulted from an increase in thromboxane A2 formation rather than a decrease in sensitivity to nitric oxide; 2) thromboxane A2 contributes to the increased noradrenaline response in mesenteric microvessels perfused in vitro while in in vivo other blood borne vasoactive agents may also be involved since the potentiated noradrenaline response was not corrected by inhibiting thromboxane A2 synthesis or receptors; 3) in addition to thromboxane A2, another as yet unidentified factor, may contribute to the elevated blood pressure in two-kidney, one-clip hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterioles; Enzyme Inhibitors; Hypertension, Renovascular; Imidazoles; Male; Mesentery; Microcirculation; Nitric Oxide; Nitroprusside; Pentanoic Acids; Perfusion; Pyridines; Rats; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance; Vasoconstrictor Agents

To determine the influence of experimental hypertension on the structure and function of porcine coronary small arteries.. Miniature pigs underwent partial left renal artery constriction and contralateral nephrectomy. Blood pressures were recorded, using indwelling carotid artery catheters. After 4 weeks the pigs were killed, the heart was removed and subepicardial third-order branches of the left anterior descending artery were dissected and mounted in a myograph for morphological and functional assessment.. Final mean +/- SEM systolic and diastolic blood pressures were, respectively, 197 +/- 9 and 142 +/- 7 mmHg (n = 21) for the hypertensive pigs and 125 +/- 4 and 80 +/- 4 mmHg (n = 11) for the sham-operated control pigs. Hypertension was associated with significant left ventricular hypertrophy. The media thickness: lumen diameter ratio was increased significantly in hypertensive intramyocardial small arteries, caused mainly by remodelling (remodelling index 92%) rather than by medial growth. Maximal contractile responses to potassium and acetycholine were significantly depressed in the arteries from hypertensive pigs, whereas endothelium-dependent relaxation responses to bradykinin, substance P and serotonin were not significantly influenced by hypertension.. These results demonstrate that even short-term hypertension induces both structural and functional changes in left ventricular intramyocardial small arteries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cardiomegaly; Coronary Vessels; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Hypertension, Renovascular; Male; Prostaglandin Endoperoxides, Synthetic; Swine; Swine, Miniature; Thromboxane A2; Vasoconstriction

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

Topics: Animals; Blood Pressure; Catecholamines; Constriction; Denervation; Disease Models, Animal; Hypertension, Renovascular; Kidney; Male; Nephrectomy; Potassium; Rats; Rats, Sprague-Dawley; Renal Artery; Sodium; Sympathetic Nervous System; Thromboxane A2; Thromboxane B2

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

Excision of a kidney with three distinct zones of perfusion was required in a patient with renovascular hypertension. One third of the kidney was normal, one third was ischemic from a stenotic artery, and one third was severely ischemic from a completely occluded artery. This provided a unique opportunity to study renal prostaglandin production in hypoperfused and control tissue by radioimmunoassays of incubated tissue slices. The thromboxane-prostacyclin synthesis ratio for the outer cortex increased from 2.2 in control tissue to 5.8 in moderately ischemic tissue and 11.3 in severely ischemic tissue; for the inner cortex, 2.1 to 6.3 and 8.8; and for the medulla, 0.4 to 1.2 and 3.0, respectively . Similar ratios were noted for thromboxane-prostaglandin E2. This correlates, for the first time in man, absolute and relative increases in renal thromboxane synthesis with renovascular hypertension.

Topics: Humans; Hypertension, Renovascular; In Vitro Techniques; Ischemia; Kidney; Male; Middle Aged; Nephrectomy; Prostaglandins; Renal Artery; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Humans; Hypertension, Renovascular; Kidney; Thromboxane A2; Thromboxanes