Studies on the mode of action of isosorbide dinitrate: A physiologic and biochemical approach

Abstract

The action of isosorbide dinitrate (ISDN) and diltiazem on coronary artery diameter, vascular resistance, and coronary blood flow was determined in instrumented postoperative conscious dogs. Low doses of ISDN were found to increase the diameter of large arteries without affecting coronary blood flow. Higher doses of ISDN produced an increase in both coronary diameter and blood flow. Diltiazem, on the other hand, increased coronary artery diameter and blood flow at all doses tested. Coronary vascular resistance was more sensitive to diltiazem than to ISDN. In isolated canine cardiac Purkinje strands, ISDN produced a concentration-dependent decrease in force development and action-potential duration measured at 50% of repolarization (APD 50). ISDN did not significantly affect action potentials recorded in Purkinje strands depolarized by potassium (22 mmol) and treated with isoproterenol (10 −6M). Diltiazem also decreased Purkinje strand force development and APD 50 in a concentration-dependent manner. Diltiazem, however, was several orders of magnitude more potent than ISDN and completely abolished action-potential genesis in potassium-depolarized, isoproterenol-restored Purkinje strands. Both diltiazem and ISDN were found to relax porcine coronary artery strips contracted by KCl or histamine. Studies on 45Ca flux, in isolated coronary artery rings, indicate that ISDN inhibited both histamine-induced Ca ++ influx and efflux from intracellular sources. The inhibition of Ca ++ efflux and intracellular Ca ++-dependent contraction occurred over a similar ISDN concentration range. ISDN also relaxed bovine coronary artery strips contracted with KCl. No change in cyclic adenosine monophosphate levels occurred during ISDN-induced relaxation of bovine coronary arterial strips. In contrast, cyclic guanosine monophosphate (cGMP) increased markedly in a dose- and time-dependent manner. Moreover, the extent of ISDN-induced relaxation was directly correlated with the increase in cGMP. Calcium transport in mitochondria, sarcoplasmic reticulum, and sarcolemmal membranes of cardiac and vascular smooth muscles was not affected by ISDN. It is postulated that increases in cGMP may be causally linked to relaxation of vascular smooth muscle due to changes in either Ca ++ flux or phosphorylation of proteins or both. In ischemic myocardium of dogs, ISDN appears to prevent damage of mitochondrial phosphorylative respiration.