Potentiation of phosphodiesterase inhibitor antithrombotic activity with alpha-2 adrenergic blockade.

Abstract

The antithrombotic activity of pelrinone, a phosphodiesterase III inhibitor was examined in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Ninety percent of vehicle treated animals developed complete coronary occlusion and thrombus mass was 32.0 +/- 5.8 mg. In a group of animals treated with zomepirac, 10 mg/kg i.v., included as a positive control, thrombus mass was decreased to 10.3 +/- 3.3 mg and incidence of occlusion was reduced to 37.5%. Pelrinone, 5.0 mg/kg i.v. decreased the incidence of occlusion to 50%, thrombus mass to 21.3 +/- 8.3 mg and inhibited platelet aggregation to collagen, ADP and arachidonic acid by 80%, 54% and 87% of baseline, respectively. When yohimbine, an alpha 2-adrenergic antagonist, was co-administered (2.0 mg/kg at the beginning of the experiment +0.5 mg/kg halfway through the experiment) with the same dose of pelrinone, thrombus mass was decreased to 1.0 +/- 0.5 mg and none of the animals developed coronary occlusion. Yohimbine administration by itself at 2.0-3.0 mg/kg showed no evidence of antithrombotic activity (thrombus mass = 32.8 +/- 8.0 mg, incidence of occlusion = 100%). This dose of yohimbine inhibited significantly ADP-induced aggregation in the presence of epinephrine. These results demonstrate that, even though this dose of pelrinone elicited near maximal inhibition of platelet aggregation, the concurrent administration of an alpha 2-adrenergic antagonist was able to potentiate markedly the phosphodiesterase inhibitor antithrombotic activity.

• Authors: J M Kitzen, J D McCallum, C T Pirozzi, T J Colatsky
• Journal: Life sciences (Life Sci) Vol. 48 Issue 7 Pg. PL31-5 ( 1991) ISSN: 0024-3205 [Print] Netherlands
• PMID: 1671293 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-Antagonists
• Fibrinolytic Agents
• Phosphodiesterase Inhibitors
• Platelet Aggregation Inhibitors
• Pyrimidines
• Yohimbine
• zomepirac
• pelrinone
• Tolmetin

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Analysis of Variance
• Animals
• Coronary Thrombosis (drug therapy)
• Dogs
• Drug Synergism
• Female
• Fibrinolytic Agents (pharmacology, therapeutic use)
• Hemodynamics (drug effects)
• Male
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Platelet Aggregation Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Random Allocation
• Tolmetin (analogs & derivatives, pharmacology)
• Yohimbine (pharmacology)