sq-30741 and Myocardial-Ischemia

The platelet products thromboxane A2 and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow.. Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3+/-7.4% decrease in retrograde blood flow (32.1+/-2.1 to 19.6+/-3.2 mL/min; P<0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A2 receptor antagonist SQ30, 741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked.. PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A2.

Topics: Animals; Blood Platelets; Collateral Circulation; Coronary Circulation; Dogs; Myocardial Ischemia; Platelet Activating Factor; Platelet Activation; Thromboxane A2; Vasoconstriction

The myocardial salvage efficacy of a thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the reproducibility of infarct size resulting from a 90 min period of occlusion followed by 5 hr of reperfusion of the left anterior descending coronary artery in saline-treated control ferrets revealed a consistent mean level of tissue damage representing 23.1 +/- 1.4% of the left ventricle. In subsequent studies, ferrets were given the thromboxane receptor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct size from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inhibition of the ex vivo platelet shape change response to U-46,619. Drug administration was not associated with measurable alterations in mean blood pressure, heart rate or the rate-pressure-product. The importance of this finding to clinical utility and the mechanism of the observed cardioprotective action, however, remain unclear. These data indicate that the ferret represents a useful model for the assessment of the myocardial salvage efficacy of TP receptor antagonists and are consistent with attenuation of ischemic myocardial damage by doses of these agents which produce > 96% TP receptor blockade.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Platelets; Blood Pressure; Ferrets; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Orchiectomy; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Reperfusion; Thromboxane A2; Vasoconstrictor Agents