The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.

Abstract

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.