Two dilatory mechanisms of anti-anginal drugs on epicardial coronary arteries in vivo: indirect, flow-dependent, endothelium-mediated dilation and direct smooth muscle relaxation.
Potential mechanisms of antianginal drugs involve preload and afterload reduction and a dilation of large conduit coronary arteries without a substantial concomitant dilation of the coronary resistance vessels. We analyzed the dilatory mechanism. It consists of two independent components: a direct effect on the arterial smooth muscle and an indirect, endothelium-mediated, shear-stress-dependent effect on the arterial vasculature. Therefore, we tested the relative contribution of these two components in the dilatory response of large coronaries to various antianginal drugs. In chronically instrumented dogs, the outer diameters and the flow in two coronary branches (left circumflex and descending) were registered continuously. A pneumatic occluder implanted distally to the site of the diameter measurements was used in one branch to control flow rates or to maintain constant flow, independent of arteriolar dilation. Increments in flow of more than 100% were elicited by i.v. injections of adenosine, dipyridamole, nifedipine, diltiazem, verapamil, nitroglycerin, ISDN, and molsidomine. All these agents induced a slowly developing dilation of the epicardial coronary arteries (by more than 100 microns), which reached its maximum 90 s after the onset of the increase in flow (while arterial pressure fell). When flow in one branch was experimentally kept constant, the epicardial dilation by adenosine and dipyridamole was completely offset, while it remained unaffected in the control branch with unrestricted flow. Thus, the dilation of the coronary artery by these two drugs is based on the indirect component, caused by the flow-dependent mechanism, in contrast to nitroglycerin-, molsidomine-, and ISDN-induced dilations, which were not affected at all by experimentally limiting the flow.(ABSTRACT TRUNCATED AT 250 WORDS)
D000241:Adenosine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects*; D004176:Dipyridamole / Q000494:pharmacology; D004727:Endothelium / Q000502:physiology; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D002121:Calcium Channel Blockers; D004176:Dipyridamole; D007548:Isosorbide Dinitrate; D000241:Adenosine