REPEATED DIPYRIDAMOLE ADMINISTRATION ENHANCES COLLATERAL-DEPENDENT FLOW AND REGIONAL FUNCTION DURING EXERCISE - A ROLE FOR ADENOSINE

Two main hypotheses concerning the mechanisms responsible for coronary collateral growth suggest the involvement of chemical or mechanical factors. Since we recently demonstrated that the development of the coronary collateral circulation is not closely related to the extent or duration of myocardial ischemia, we hypothesized that chronic repeated vasodilation and increased myocardial blood flow using dipyridamole would enhance collateral development in miniswine with an ameroid-occluded left circumflex coronary artery (LCx). Two days after surgical instrumentation, the animals received dipyridamole (n=9), diltiazem as an adenosine-independent vasodilator (n=8), or control vehicle (n=7) 90 minutes per day, 5 days per week for 8 weeks. At 5 and 8 weeks, transmural blood flow and systolic wall thickening were measured during infusion of dipyridamole, diltiazem, or vehicle. Transmural blood How increased similarly in the LCx and nonoccluded regions at 30 and 60 minutes during infusion of either vasodilator. Thus, we believe that similar mechanical stimulation resulted from dipyridamole and diltiazem infusion. There was no change in blood flow during administration of the vehicle. Systolic wall thickening in the collateral-dependent region was not altered by infusion of dipyridamole, diltiazem, or vehicle. Therefore, both vasodilators increased blood flow without eliciting ischemia. After 8 weeks of repeated treatment with each pharmacological agent, at least 24 hours after the last drug infusion, near maximal physiological capacity of the coronary collateral vessels was assessed during treadmill running (almost-equal-to 240 beats per minute). Transmural myocardial blood flow ratios, expressed as flow in the LCx divided by How in the nonoccluded region of the left ventricle, were similar at rest for animals treated with dipyridamole (0.90+/-0.03), diltiazem (0.97+/-0.05), and control vehicle (0.89+/-0.02). However, collateral-dependent myocardial blood flow during exercise was greater (P<.05) in the dipyridamole-treated animals (0.78+/-0.04) than in either diltiazem-treated (0.63+/-0.09) or vehicle-treated (0.62+/-0.02) animals. LCx systolic wall thickening at rest was similar in animals treated with dipyridamole (44.4 +/- 6.3%), diltiazem (42.2+/-3.0%), and control vehicle (38.1+/-2.8%). During exercise, however, myocardial function in the collateral-dependent region was greater (P<.05) in the dipyridamole-treated (39.2+/-5.2%) compared with diltiazem-treated (23.9+/-4.0%) and vehicle-treated (26.9+/-2.9%) animals. Our results suggest that enhanced collateral-dependent blood flow and function in dipyridamole-treated animals likely result from a direct effect of adenosine and/or from an adenosine-potentiated vascular response to repeated mechanical stress rather than a response simply related to mechanical stimulation.