ROLE OF MICROVASCULAR DISORDERS IN THE PATHOGENESIS OF MYOCARDIAL ISCHEMIA

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We have created animal models of microvascular disorders. Long-term inhibition of nitric oxide synthase with administering chronically an nitric oxide inhibitor (N^<omega>-nitro-L-arginine methyl ester, L-NAME) to rats and pigs caused coronary vascular structural changes (medial thickening and perivascular fibrosis). We examined whether microvascular responses to serotonin is altered in the pig model. After anesthesia, we infused serotonin into the coronary artery and found that the drug significantly decreased coronary blood flow in the L-NAME treated pigs but not in the control pigs.the vasomotor response to serotonin was similar between the two groups. Thus, these data suggest that the enhanced decrease in coronary blood flow to serotonin was due to augmented constriction of microvessels.We aimed to provoke myocardial ischemia in the pig model. We administered papaverine into the coronary artery and found that the drug induced myocardial ischemia (myocardial lactate production). Because the papaverine-induced myocardial ischemia was associated with increased coronary blood flow, we concluded that the papaverine-induced myocardial ischemia was caused by altered distribution of regional myocardial blood flow.We examined effects of L-arginine administration on endothelium-dependent coronary vasodilation in patients with microvascular angina and found that L-arginine supplementation improved acetylcholine-induced endothelium-dependent vasodilation in those patients. We also explored to determined the mechanism of bradykinin-induced coronary vasodilation in humans. We found that the bradykinin-induced coronary vasodilation was nearly completely inhibited by an inhibitor of NO synthesis and markedly augmented by an angiotensin-converting enzyme inhibitor enalaprilat.