ORIGINAL ARTICLE Vasomotor Function of Pig Coronary Arteries after Chronic Coronary Occlusion Jinsheng Li, Hector De Leon, Takafumi Ueno, Jianhua Cui, Patrick K. Coussement, Spencer B. King III, Nicolas A. F. Chronos, and Keith A. Robinson Abstract: Placement of an ameroid constrictor in large-conduit pig coronary arteries causes progressive stenosis and distal myo- cardial ischemia. Blood perfusion in the ischemic region is partly dependent on vasomotor responses to neural and humoral factors distal to the occlusion site. To ascertain the degree of impairment of vascular function in pigs, the authors induced myocardial is- chemia by placing an ameroid constrictor in the left circumflex coronary artery and examined vascular reactivity and histopa- thology distal to the constriction site. The sensitivity of the distal left circumflex coronary and nonoccluded control left anterior descending arteries to PGF 2 was similar. After nitric oxide blockade using N w -nitro-l-arginine methylester (L-NAME), the sensitivity and maximal contraction to PGF 2 were significantly increased in both the left circumflex coronary (EC50: 5.86 ± 0.74 vs. 3.28 ± 0.84 μM;C max : 4.63 ± 0.28 vs. 6.25 ± 0.30 g, P < 0.01) and left anterior descending (EC50: 6.57 ± 0.73 vs. 2.78 ± 0.16 μM;C max : 5.09 ± 0.37 vs. 6.95 ± 0.39 g, P < 0.01) arteries. Sub- stance P-induced relaxation (100 pM) was blocked to a larger de- gree in the distal left circumflex coronary artery when compared with the left anterior descending artery (76.9 ± 4.2% vs. 56.4 ± 3.1%, P < 0.05). Endothelium-independent relaxation to sodium nitroprusside was similar in the left circumflex coronary and left anterior descending arteries before and after nitric oxide block- ade. Histopathologic examination showed no major differences between distal left circumflex coronary artery segments and left anterior descending artery controls. However, scanning electron microscopy showed endothelial hypertrophy and activation in specimens from the left circumflex coronary arteries. In sum- mary, as a result of the major hemodynamic changes induced by a chronic constriction and eventual occlusion of a large coronary artery, distal segments underwent adaptive compensatory changes. Such compensation may be related to an increased nitric oxide production by the hypertrophic endothelium in response to alterations in coronary hemodynamics. Key Words: Ameroid constrictor—Myocardial ischemia— Vasoreactivity. ( J Cardiovasc Pharmacol ™ 2003;41: 600–608) H ypercholesterolemia, hypertension, smoking, and dia- betes have all been associated with impaired endothe- lial nitric oxide (NO)-mediated vasodilatation (1,2). The earliest vascular atherosclerotic lesions occur in the endo- thelium lining large blood vessels (3), and coronary arteries located distal to an occlusion have been shown to exhibit altered reactivity to vasoactive agonists (4,5). Headrick et al. found that a brief coronary occlusion and reperfusion resulted in decreased endothelium-dependent relaxation and increased contraction in the segment distal to the oc- clusion (6). Other investigators have reported that chronic coronary occlusion impairs receptor-dependent cAMP- mediated relaxation (7). Griffin et al. demonstrated that ex- ercise improves endothelium-mediated relaxation of chronically occluded coronary arteries by enhancing the production of NO and endothelium-derived hyperpolariz- ing factor (8). Gradual narrowing of atherosclerotic coronary arter- ies leads to myocardial ischemia. Impaired responses of epicardial vessels to vasoactive substances might exacer- bate the compromised perfusion of ischemic myocardium. Therefore, it is important to study the pathologic process and alteration of function in coronary vessels distal to the narrowing site. Placement of ameroid constrictors on pig coronary arteries has become an accepted model to mimic human chronic myocardial ischemia (9,10). Ameroid placement results in a gradual and progressive reduction of the arterial lumen size, which is substantially occluded by 3 or 4 weeks. Basal (resting) blood flow to the chronically occluded artery is maintained at levels comparable to non- occluded vessels via collateral circulation (11,12). How- ever, the conduit artery vasomotor function distal to the site of ameroid constrictors responsible in part for the regu- lation of myocardial perfusion in the affected region has not been thoroughly elucidated. We hypothesized that coronary arteries distal to a site of chronic occlusion would The American Cardiovascular Research Institute, Norcross, Georgia, U.S.A. Received April 2, 2002; accepted August 21, 2002. Address correspondence and reprint requests to Keith A. Robinson, MD, American Cardiovascular Research Institute, 3155 Northwoods Place, Norcross, GA 30071, U.S.A. E-mail: krobinson@acrionline.org This study was funded in part by R01 grant HL 60184-01 from the Na- tional Heart, Lung, and Blood Institute (K. A. Robinson) and the Rich Foundation (H. De Leon, K. A. Robinson). 600 J Cardiovasc Pharmacol  • Volume 41, Number 4, April 2003