prostaglandin-h2 and Hypertension

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 nitric oxide-mediated portion of shear stress-induced dilation of rat gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive rats (SHR). Because shear stress-induced dilation is primarily mediated by endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized that in the cremasteric vascular bed the mediation of shear stress-induced dilation by prostaglandins is altered in hypertension. At a constant intraluminal pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0+/-3.1 and 51.7+/-3.6 microm, respectively, whereas their passive diameters were 109.4+/-4.4 and 101.9+/-6.7 microm, respectively. Dilations to increases in shear stress elicited by increases in intraluminal flow (from 0 to 25 microL/min) were significantly less (P<0.05) in cremasteric arterioles isolated from SHR than from WKY. Arachidonic acid (10(-5) mol/L) elicited constrictions in SHR arterioles but dilations in WKY arterioles. The prostaglandin H(2)/thromboxane A(2) (PGH(2)/TxA(2)) receptor antagonist SQ 29,548 (10(-6) mol/L) significantly increased basal diameter by 11% and normalized the attenuated shear stress-induced dilation in SHR, whereas it did not affect basal diameter and arteriolar responses of WKY. Furegrelate, a specific inhibitor of TxA(2) synthase, did not affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid-induced constriction to dilation in SHR arterioles, whereas it did not affect the dilator response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619 (a PGH(2)/TxA(2) receptor agonist) were not different. These results demonstrate that in cremasteric arterioles of hypertensive rats, shear stress elicits an enhanced release of PGH(2), resulting in a reduced shear stress-dependent dilation. Thus, augmented hemodynamic forces can alter the shear stress-induced synthesis of prostaglandins, which may contribute to the elevated vascular resistance in hypertension.

Topics: Animals; Arterioles; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Stress, Mechanical; Thromboxane-A Synthase

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

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

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

Salt loading increases blood pressure in Dahl salt-sensitive (Dahl S) rats. We have previously shown that the mesenteric artery of salt-loaded Dahl S rats exhibits enhanced electrical activity that is corrected by a cycloxygenase inhibitor, indomethacin. Prostaglandin H2 (PGH2) is a product of cycloxygenase that is known as an intrinsic vasoconstricting factor in spontaneously hypertensive rats. Our hypothesis is that tissue production of PGH2 would be involved in the enhanced electrical activity of arteries from salt-loaded Dahl S rats. In the present study, to clarify this possibility, we evaluated the actions of PGH2 on membrane channels in arterial cells from Dahl S rats. Membrane currents were recorded by whole-cell voltage clamp technique in single smooth muscle cells from the mesenteric artery. Application of PGH2 evoked an inward current that was mainly dependent on extracellular Na+ in the physiological extracellular solution. When high Ba2+ solution was used for the extracellular solution, PGH2 also evoked the inward current, suggesting that a divalent cation, such as Ba2+ or Ca2+, could permeate the PGH2-activated channels. In contrast, the L-type Ca2+ channel currents were not enhanced by the application of PGH2. The present results suggest that production of PGH2 contributes to the enhanced electrical activity by activating cation-permeable channels and depolarizing the membrane potential. PGH2 also directly stimulates the Ca2+ influx by activating Ca2+ permeable channels.

Topics: Animals; Calcium Channels; Drug Resistance; Electric Conductivity; Electrophysiology; Hypertension; Ion Channels; Mesenteric Arteries; Patch-Clamp Techniques; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred Strains; Sodium Chloride

We hypothesized that endothelin in addition to prostaglandin (PG)H2 may also contribute to the enhanced myogenic tone of skeletal muscle arterioles of spontaneously hypertensive (SH) rats. Changes in the diameter of isolated, cannulated arterioles (approximately 60 microm) from cremaster muscles of 30-week-old normotensive Wistar Kyoto (WKY) and SH rats were measured as a function of perfusion pressure (20 to 140 mm Hg). Pressure-induced constrictions were significantly enhanced between 60 to 140 mm Hg in arterioles of SH rats compared with those of WKY rats; at 80 and 140 mm Hg the normalized diameter of arterioles (expressed as a percentage of corresponding passive diameter) of SH rats was 11.0% and 15.4% less (P<.05) than that of WKY rats. After inhibition of thromboxane A2-PGH2 receptors by SQ 29,548 (10[-6] mol/L), the still enhanced myogenic response of SH arterioles was eliminated by the removal of endothelium or the administration of BQ-123 (10[-7] mol/L), an endothelin A (ET-A) receptor blocker, which also inhibited constrictions to exogenous ET-1 (10[-11] to 5x10[-10] mol/L). ET-1 elicited comparable responses in arterioles of SH and WKY rats. Thus, in SH rats the enhanced arteriolar constriction to increases in intravascular pressure seems to be due to the production of endothelium-derived constrictor factors PGH2 and endothelin.

Topics: Animals; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Endothelins; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Male; Muscle, Smooth, Vascular; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasomotor System

We tested the hypothesis that a prostanoid-mediated mechanism of vascular contraction is expressed in rats with aortic coarctation-induced hypertension. Rings of descending thoracic aorta taken from normotensive and hypertensive rats were contrasted in terms of constrictor responsiveness to arachidonic acid (AA), AA-induced release of eicosanoids, and ability to convert exogenous prostaglandin (PG) H2 to PGI2. AA (10(-8) to 10(-5) mol/L) increased isometric tension in aortic rings (bathed in Krebs' bicarbonate buffer) of hypertensive but not normotensive rats. AA (10(-5) mol/L) also elicited the release of PGI2, PGE2, thromboxane (TX) A2, and monohydroxyeicosatetraenoic acids (HETEs); this release from the aortic rings of hypertensive rats exceeded the corresponding release from the aortic rings of normotensive rats. However, the rate of conversion of exogenous PGH2 to PGI2 by aortic rings of hypertensive rats was < 50% the rate of conversion by aortic rings of normotensive rats. The constrictor effect of AA in aortic rings of hypertensive rats was abolished by an inhibitor of cyclooxygenase (indomethacin, 10 mumol/L) and a blocker of TXA2-PGH2 receptors (SQ29548, 1 mumol/L) but was not affected by an inhibitor of TXA2 synthesis (CGS13080, 10 mumol/L), suggesting mediation by PGH2. The lipoxygenase inhibitor baicalein (75 mumol/L) also attenuated the constrictor effect of AA in aortic rings of hypertensive rats while decreasing the associated release of HETEs and correcting the impairment in the conversion of PGH2 to PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aortic Coarctation; Arachidonic Acid; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Hypertension; In Vitro Techniques; Intramolecular Oxidoreductases; Isomerases; Isometric Contraction; Lipoxygenase; Lipoxygenase Inhibitors; Male; Prostaglandin H2; Prostaglandins H; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane-A Synthase; Vasoconstriction

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

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 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

Topics: Angiotensin II; Animals; Cardiac Output; Dogs; Female; Hemodynamics; Hypertension; Intestine, Small; Male; Norepinephrine; Perfusion; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Serotonin; Time Factors; Vascular Resistance