The long term goal of the present proposal is to continue an analysis of drug actions on regional myocardial blood flow and cardiac muscle function in different models of ischemia. One major objective will be to determine mechanisms whereby specific pharmacological agents increase coronary collateral blood flow and influence its transmural distribution between subendocardium and subepicardium in dogs with single or multiple coronary occlusions and/or stenoses. Dogs with immature or poorly developed collateral vessels (acute occlusion) and ones with mature or well developed collateral vessels (chronic occlusion) will be used. Myocardial segment function (sonomicrometry) will be monitored in normal, partially ischemic and central ischemic areas and changes in segment shortening (% SS) will be correlated with changes in regional blood flow (radioactive microspheres). By using selective beta and alpha receptor agonists and antagonists, specific bradycardic agents and vagal stimulation, the importance of a number of variables which are thought to influence collateral perfusion, i.e., heart rate, arteriolar resistance in nonischemic myocardium, alpha1 and alpha2 adrenergic receptors, will be investigated. In the multiple occlusion studies, the effectiveness of beta receptor blocking agents, vagal stimulation and specific bradycardic drugs to increase coronary perfusion pressure distal to a partially occluded coronary vessel, thereby increasing collateral blood flow to a totally occluded area will be studied in dogs with immature or well-developed collateral vessels. A second major objective will be to determine the effect of different slow channel calcium entry blockers on collateral function in dogs with well developed collateral vessels. In addition, the relative selectivity of these agents to dilate coronary resistance vessels versus large epicardial conductance and collateral vessels will be assessed. Radioactive microspheres, retrograde pressure and flow will be used as indices of collateral function and dose-response curves to different calcium channel blockers will be obtained by intracoronary or intravenous infusion. Nitroglycerin and adenosine, agents known to selectively dilate collateral vessels or arteriolar resistance vessels, respectively, will be used for purposes of comparison. Since patients with ischemic heart disease often have multiple occlusion and/or stenoses and have widely varying degrees of collateral development, these studies should lend important insight as to mechanisms by which certain pharmacological agents relieve myocardial ischemia.
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