sq-29548 and 13-azaprostanoic-acid

A vasoconstrictor-induced prostacyclin (PGI2) production in a perfused rat heart was found, suggesting a mitigating role of PGI2 on coronary vasoconstriction. Treatment of the heart with cyclooxygenase inhibitors (aspirin or indomethacin) decreased PGI2 production by more than 90% and paradoxically reduced the vasoconstriction response. The attenuating effect of cyclooxygenase blockade suggested that endogenous prostanoids contribute to serotonin-, vasopressin- or U46619-induced vasoconstriction. Two prostaglandin (PG) H2/thromboxane A2 (TXA2) receptor antagonists, i.e., 13-azaprostanoic acid (13-APA) and SQ 29,548 were used to investigate putative endogenous vasoconstrictor prostanoids on the exogenously induced vasoconstriction. Retrogradely perfused (5-6 ml/min) rat hearts were rendered guiescent, yet responsive to stimuli, by local injection of lidocaine to the atrioventricular node. Changes in coronary vascular resistance (i.e., perfusion pressure at constant flow) were monitored and the cardiac effluent was collected for analysis of 6-keto PGF1 alpha (the stable metabolite of PGI2) as well as PGF2 alpha by radioimmunoassay. Three vasoconstrictors, i.e., serotonin, vasopressin and the TXA2/PGH2 analog U46619, as well as authentic PGD2, PGE2 and PGF2 alpha were infused. PGD2, PGE2 and PGF2 alpha exerted a dose-related coronary vasoconstriction, as did U46619, serotonin and vasopressin. Treatment with 13-APA (100 microM) or SQ 29,548 (100 nM) almost abolished U46619-induced vasoconstriction. The addition of PGH2/TXA2 receptor antagonists also significantly reduced the pressor effect of exogenously administered PGs, serotonin and vasopressin, with the exception that SQ 29,548 did not significantly antagonize PGE2-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Vessels; Drug Interactions; Fatty Acids, Unsaturated; Hydrazines; Male; Prostaglandins; Prostanoic Acids; Rats; Rats, Inbred Strains; Serotonin Antagonists; Thromboxane A2; Vasoconstriction; Vasopressins

The use of enzyme inhibitors to clarify the role of thromboxane A2 in vasoocclusive disease has been complicated by their non-specific action. To address this problem we have examined the effects of thromboxane A2/prostaglandin endoperoxide receptor antagonism in a canine model of platelet-dependent coronary occlusion. Two structurally distinct thromboxane A2/prostaglandin endoperoxide receptor antagonists, 3-carboxyl-dibenzo (b, f) thiepin-5,5-dioxide (L636,499) and (IS-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3-((2-((phenylamino)-carbonyl)hydrazino)methyl)-7- oxabicy-clo(2.2.1)-hept-2-yl)-5-heptenoic acid (SQ 29,548), were studied to ensure that the effects seen in vivo were mediated by receptor antagonism and did not reflect a nonspecific drug effect. Both compounds specifically inhibited platelet aggregation induced by arachidonic acid and by the prostaglandin endoperoxide analogue, U46619, in vitro and ex vivo, and increased the time to thrombotic vascular occlusion in vivo. When an antagonist (L636,499) was administered at the time of occlusion in vehicle-treated dogs, coronary blood flow was restored. In vitro L636,499 and a third antagonist, 13-azaprostanoic acid, specifically reversed endoperoxide-induced platelet aggregation and vascular smooth muscle contraction. Neither compound altered cyclic AMP in platelet-rich plasma before or during disaggregation. Therefore, reversal of coronary occlusion may reflect disaggregation of platelets and/or relaxation of vascular smooth muscle at the site of thrombus formation through specific antagonism of the thromboxane A2/prostaglandin endoperoxide receptor. Thromboxane A2/prostaglandin endoperoxide receptor antagonists are compounds with therapeutic potential which represent a novel approach to defining the importance of thromboxane A2 and/or endoperoxide formation in vivo.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arterial Occlusive Diseases; Bridged Bicyclo Compounds, Heterocyclic; Coronary Vessels; Dibenzothiepins; Dogs; Fatty Acids, Unsaturated; Hydrazines; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandin Endoperoxides; Prostanoic Acids; Rats; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2