HETEROGENEITY OF CORONARY ARTERY VASOMOTION

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These studies assess coronary vasomotor activity with and without coronary artery disease. Studies will first address the hypothesis that vasomotor responses of different coronary segments are heterogenous due to predominance of different vasodilator mechanisms in each segment by characterizing responses of proximal conductance and distal resistance coronary vessels to endogenous and exogenous vasoactive agents. Proximal coronary vasomotion will be measured by dimension crystals in digital quantitative angiography. Effects on distal resistance vessels will be assessed by flow changes using chronically implanted flow probes or Doppler flow catheters (patients). Effects on intramural conductance arteries will be assessed as changes in peak hyperemic flow (patients and dogs) and transmural flow distribution (dogs) during maximal dilation of resistance vessels. Studies will then address the hypothesis that the endothelium mediates and/or modulates vasomotor responses primarily in proximal and intramural conductance vessels and provides an intrinsic flow sensing mechanism that mediates uniform vasodilation in response to flow increases; endothelial dysfunction will inhibit flow induced dilation of the conductance arteries and limit myocardial perfusion during certain physiologic stresses. Endothelial dysfunction will be induced by (i) in vivo inhibitors (methylene blue, ETYA) and (ii) clinically relevant pathologic conditions (ischemia-/reperfusion, acute hypertension or atherosclerosis) which have been demonstrate to alter endothelial mediated responses. Isolated segments of the proximal coronary artery and bioassay preparations will also be used to compliment intact physiological preparations and to assess abnormalities in endothelium-derived relaxing factor (EDRF) production after endothelial dysfunction. Finally, studies will test the hypothesis that nitrate tolerance occurs primarily in proximal conductance rather than distal resistance vessels; cross tolerance with other activators of guanylate cyclase (EDRF and atrial natriuretic peptide) does not occur. These studies will further clarify fundamental mechanisms of coronary vasomotion during physiologic conditions.