ifetroban 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

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

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

This study was designed to investigate involvement of potassium channels in the action of nitric oxide facilitating reduction of basal tone by thromboxane A2/prostaglandin H2 receptor blockade with ifetroban in rings of thoracic aorta taken from rats with aortic coarctation-induced hypertension. Ifetroban-induced reduction of basal tone in aortic rings without drug pretreatment was attenuated (P<0.05) in rings pretreated with the nitric oxide synthesis inhibitor N(omega-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) mol/L; 0.55+/-0.09 g versus 0.23+/-0.07 g). The vasorelaxing effect of ifetroban also was decreased (P<0.05) in preparations pretreated with a potassium channel blocker, either tetraethylammonium (TEA; 10(-2) mol/L) or 4-aminopyridine (4-AP; 3 x 10(-3) mol/L). Ifetroban-induced reduction of basal tone was not attenuated in preparations pretreated first with L-NAME and then with sodium nitroprusside (SNP; 6+/-1 nmol/L) to compensate for the loss of endogenous nitric oxide. However, the facilitatory effect of SNP on ifetroban-induced relaxation of aortic rings pretreated with L-NAME alone was not demonstrable in rings pretreated with L-NAME plus TEA or 4-AP. These observations suggest that a mechanism involving nitric oxide and potassium channels facilitates the reduction in basal tone produced by ifetroban in aortic rings of rats with aortic coarctation-induced hypertension.

Topics: 4-Aminopyridine; Animals; Aorta; Basal Metabolism; Bridged Bicyclo Compounds, Heterocyclic; Hypertension; Male; Muscle Tonus; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxazoles; Potassium Channels; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Tetraethylammonium; Vasodilator Agents

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

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

Rings of thoracic aortae taken from rats made hypertensive by aortic coarctation express a calcium-dependent basal tone. We investigated whether this basal tone is mediated by prostanoids. To this end, we contrasted the effects of indomethacin, an inhibitor of cyclooxygenase, and of ifetroban, an antagonist of thromboxane A2/prostaglandin endoperoxide H2 receptors, on basal tone in aortic rings taken from normotensive and hypertensive rats. Rings with endothelium from normotensive rats were unaffected by indomethacin and ifetroban. However, in endothelium-intact rings from hypertensive rats, the basal tone was reduced 65 to 75% by indomethacin and ifetroban, but not by CGS13080, an inhibitor of thromboxane synthase. The reductions in tone elicited by indomethacin and ifetroban in rings from hypertensive rats were eliminated upon removal of the endothelium and were attenuated when the rings were pretreated with an inhibitor of nitric oxide synthase (N omega-nitro-L-arginine methyl ester or N omega-nitro-L-arginine) or an inhibitor of soluble guanylate cyclase. Neither indomethacin nor ifetroban affected tissue cGMP levels or nitrite release in aortic rings taken from hypertensive rats. However, sodium nitroprusside offset the inhibitory effects of N omega-nitro-L-arginine methyl ester, on the relaxant responses to indomethacin and ifetroban. These data suggest that a constrictor prostanoid other than thromboxane A2, presumably prostaglandin endoperoxide H2 contributes to the implementation of the basal tone in rings from hypertensive rats and that part of the relaxant response to indomethacin and ifetroban is linked to nitric oxide.

Topics: Animals; Aorta, Thoracic; Aortic Coarctation; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Endothelium, Vascular; Hypertension; In Vitro Techniques; Indomethacin; Male; Nitric Oxide; Oxazoles; Prostaglandins; Rats; Rats, Sprague-Dawley; Vasoconstriction

Experiments were performed to determine the effect of chronic therapy with the potent and long-acting thromboxane (TX) A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban, on hypertension development and the incidence of stroke in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP instrumented with radiotelemetry probes, for continuous monitoring of arterial blood pressure, were given 1% NaCl to drink and Stroke-Prone Rodent Diet and were chronically treated with ifetroban (20 mg/kg/day, n = 10) or vehicle (n = 12) starting at 16.5 weeks of age. Ifetroban did not affect blood pressure or the development of proteinuria and cerebrovascular lesions. Chronic administration of a higher dose ifetroban (40 mg/kg/day) starting at 7 weeks of age was also without effect on blood pressure and stroke in noninstrumented saline-drinking SHRSP. These results do not support a major role for TXA2 and its endoperoxide precursors in the elevation of blood pressure and the development of cerebrovascular lesions in saline-drinking SHRSP.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cerebrovascular Disorders; Genetic Predisposition to Disease; Hypertension; Incidence; Male; Oxazoles; Rats; Rats, Inbred SHR; Receptors, Thromboxane; Survival Analysis; Telemetry

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

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