DIPYRIDAMOLE ALONE OR WITH LOW DOSE ASPIRIN DOES NOT PREVENT ACUTE PLATELET THROMBUS FORMATION IN STENOSED DOG CORONARY ARTERIES

Abstract

Dipyridamole (Dip) is reputed to inhibit (I) platelet aggregation (PA) and acute thrombus formation (ATF) by two mechanisms including inhibiting 1.) platelet (Pt) phosphodiesterase, 2.) adenosine (A) reuptake by red cells, which should raise plasma A. Both effects should raise Pt cyclic AMP and thus be a potent platelet inhibitor (PI). Because aspirin (AS) inhibits Pt thromboxane A2 production, a synergistic (S) PI effect for ASA and Dip given together has been postulated and used in clinical trials but this S has never been shown to I ATP in any in vivo model, which reasonably mimics human arterial stenosis. We have shown that ATF followed by embolization, occurs periodically in mechanically stenosed (MS) monkey and rabbit carotid arteries, and dog (D) and pig coronary arteries (CA), causing cyclical reductions in coronary blood flow (CRF) (measured with EMF probes) and periodic acute ischemia, and that these CRF can be abolished with a variety of PI including 3.0 mg/kg of ASA. To determine if there is a S effect between ASA and Dip, in open chest D, Dip was given, 2.0 mg/kg IV to D with a MS circumflex CA and having 14±5 CRF’s per hour, due to periodic ATF; and simultaneously flow measured in an unstenosed normal LAD CA. The frequency and size of CRF’s were not changed by Dip, although ABP decreased 21±9 mm Hg and blood flow in the unstenosed LAD increased 259±47%. A low dose of ASA, 1.0 mg/kg, which by itself diminishes but does not abolish CRF’s in this model was given IV 10 min. after Dip and CRF’s continued unchanged. When a second dose of ASA 1.0 mg/kg was given IV to reach the minimum effective dose of ASA in this model, CRF were abolished in all D. Thus Dip was not effective alone or in combination with low dose ASA to I CRF in this model which simulates the patient with stenosed CA. The majority of clinical trials that show inhibition of ATF, used ASA and Dip together without 3 separate patient groups on Dip alone, ASA alone and ASA plus Dip. The widespread use of Dip with ASA to prevent ATF in man needs to be reevaluated.