Thromboxane synthetase inhibitors differentially antagonize thromboxane receptors in vascular smooth muscle.
A number of thromboxane (Tx) synthetase inhibitors have been found to prevent thromboxane release in acute cardiopulmonary disorders. However, little is known about Tx receptor antagonism by these substances. Imidazole, UK-37,248 and pinane thromboxane A2 (PTA2) were tested in isolated perfused cat coronary arteries, spirally cut rabbit pulmonary artery strips, and in rabbit and cat platelets for their ability to antagonize vasoconstrictor and aggregatory effects of a stable Tx agonist, carbocyclic thromboxane A2 (CTA2). Imidazole, at concentrations that completely inhibit thromboxane synthesis, failed to antagonize the vasoconstrictor effects of CTA2 in both systems. UK-37,248, at 10 to 1000 micrograms/ml, failed to inhibit CTA2-induced coronary constriction but at 1 microgram/ml reduced rabbit pulmonary artery constriction by 80 +/- 8% (P less than 0.0005). In comparison, 1 micro M PTA2 completely prevented PTA2-induced constriction in both coronary and pulmonary arteries. PTA2 did not antagonize KCl and angiotensin II responses. In platelets, PTA2 but not UK-37,248 prevented arachidonate induced aggregation in rabbit and cat platelets. Some of the beneficial effects of thromboxane synthetase inhibitors may be associated with thromboxane receptor antagonism. Inhibitors structurally similar to TxA2 appear to have greater thromboxane receptor antagonistic activity. This additional activity may be of importance in therapeutics of coronary and pulmonary disorders.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D000081008:Bicyclic Monoterpenes; D001792:Blood Platelets / Q000201:enzymology; D002415:Cats; D003331:Coronary Vessels / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012701:Serotonin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D000081008:Bicyclic Monoterpenes; D007093:Imidazoles; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C029166:dazoxiben; D016718:Arachidonic Acid; D012701:Serotonin; D013928:Thromboxane A2; C020465:pinane-thromboxane A2; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase