Antithrombotic activity of the phosphodiesterase III inhibitor pelrinone in a canine model of coronary artery thrombosis: enhancement of efficacy with concurrent alpha 2-adrenergic antagonism.
The purpose of this study was to determine if idazoxan, an alpha 2-adrenergic antagonist, could enhance the antithrombotic activity of pelrinone, a PDE III inhibitor, in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Thrombus mass in vehicle-treated animals was 37.9 +/- 8 mg. Pelrinone, 0.625 and 2.5 mg/kg decreased thrombus size by 46 and 21%, respectively, while idazoxan, 0.75 mg/kg decreased thrombus mass by 43%. When this dose of idazoxan was combined with pelrinone, 0.625 and 2.5 mg/kg, thrombus mass was decreased by 71 and 91%, respectively. Antithrombotic efficacy correlated with the ability of these treatments to inhibit epinephrine-sensitized, collagen-induced platelet aggregation. Sixty minutes following drug administration, idazoxan, 0.50 mg/kg inhibited aggregation by 50%, while pelrinone, 0.625 and 2.5 mg/kg inhibited aggregation by 55 and 68%, respectively. Combined administration of idazoxan with pelrinone, 0.625 and 2.5 mg/kg resulted in 80 and 95% inhibition of aggregation, respectively. Similar trends in inhibiting platelet aggregation to epinephrine-sensitized ADP and arachidonic acid were also observed. Experimental treatments did not affect hematocrit or circulating platelet count, although pelrinone was observed to prolong prothrombin time slightly. To examine the effect of drug-induced increases in coronary blood flow on thrombus formation, the potassium channel activator drug cromakalim was studied at a dose (0.1 mg/kg) that increased coronary blood flow by 25-35 ml/min above baseline in sham control animals. Animals treated with cromakalim showed a shorter time to coronary occlusion (103 +/- 11 min) vs. vehicle (173 +/- 24 min) and developed larger thrombi (53.7 +/- 19 mg). These results demonstrate that coronary vasodilation does not contribute to antithrombotic activity in this model. Results from the study also show that alpha-adrenergic inhibition of platelet function can potentiate phosphodiesterase inhibitor antiaggregatory and antithrombotic activity.
Kitzen
J M
JM
Department of Cardiovascular-Metabolic Disorders Pharmacology, Wyeth-Ayerst Research Laboratories, Princeton, New Jersey.
McCallum
J D
JD
Harvey
C
C
Morin
M E
ME
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D019329:Idazoxan; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011743:Pyrimidines; D000244:Adenosine Diphosphate; C055434:pelrinone; D019329:Idazoxan