Several lines of clinical evidence suggest primary involvement of coronary vasospasm in the pathophysiologies of angina and myocardial infarction. Although recent experimental evidence has shown that the process of atherosclerosis alters vascular reactivity in favor of hypercontractility and that coronary spasm frequently occurs in atheromatous areas, surprisingly, these observations have not been combined into a study of how vessel reactivity changes during the progression of atherosclerosis. We propose to establish a new, non-thrombogenic model of coronary atherosclerosis in which the lesion is localized, reproducible, morphologically similar to human coronary plaques, and which progresses rapidly in the absence of any overt endothelial damage. The contractile and hemodynamic reactivities of these arteries will be evaluated in vitro at different stages of lesion development in order to identify optimal responsiveness sufficient to term these vessels as potentially spasmodic. Secondly, we propose that there is an imbalance between contractile and vasodilatory influences in these model spasmodic arteries that favors excessive constriction.
Our aim i s to carry out a coordinated series of in vitro experiments to delineate the relative importance of the endothelium and instrinsic and extrinsic factors which adversely affect smooth muscle cell contractility. Lastly, we hypothesize that resistive, endocardial arteries may initiate epicardial spasm observed in some human anginas. The properties of small coronary arteries which may contribute to the pathogenesis of spasm have not been investigated. We plan to examine their physiology in isolation, and the spasmodic influence they may have on the large coronaries when both vessels are in common flow communication. We will induce the plaques by electrical stimulation through a pair of electrodes implanted around the right coronary artery in pigs fed a 2% cholesterol diet for periods of 1-4 weeks. In vitro tests of the excised epicardial and endocardial arteries will be made in perfused, and non-perfused states, and will incorporate mechanical, hemodynamic, pharmacologic, electrophysiological and morphological measurements. The proposed studies are important in that a vitally needed atherosclerotic model useful for further research will be established, and new information pertinent to the spasmodic factors contributing to myocardial ischemia will be identified.
| Nakayama, K; Osol, G; Halpern, W (1989) Differential contractile responses of pressurized porcine coronary resistance-sized and conductance coronary arteries to acetylcholine, histamine and prostaglandin F2 alpha. Blood Vessels 26:235-45 |
| Nakayama, K; Osol, G; Halpern, W (1988) Reactivity of isolated porcine coronary resistance arteries to cholinergic and adrenergic drugs and transmural pressure changes. Circ Res 62:741-8 |
