This project has the goal of developing a nonhuman primate model of human coronary artery function that can be used to study the effects of the sex steroid hormones, estradiol 17B and progesterone, on coronary reactivity. The purpose of these studies is to find blood vessel mechanisms that will explain the greater chance of coronary vasospasm in post-menopausal women. The project is a multidisciplinary collaborative effort to search for mechanisms using in vivo coronary angiography, in vitro studies of isolated artery contraction and relaxation, and cellula studies of Ca2+ influx and release and steroid receptors in rhesus macaques without atherosclerotic disease. Increased coronary reactivity and vasospasm will be induced by catheter injury followed by pharmacological stimulation. Studies consist of the use of the ergonovine challenge with coronary angiography to compare coronary reactivity in hormonally defined rhesus macaques at the Oregon Regional Primate Research Center. Coronary angiography will be used to study induction of coronary vasospasm in dose-response paradigms with serotonin and thromboxane analog, U46619. Studies of rings of coronary arteries will allow comparison of acute effects of estradiol 17B and progesterone on coronary reactivity, and the influence of endothelial function will be determined. Coronary vascular muscle will be isolated and studied by patched clamp electrophysiological techniques and with optical measurements of intercellular Ca2+ to determine cellular mechanisms that contribute to coronary vasospasm. Endothelial cell interactions with vascular muscle will be studied in co- cultures to determine actions of estradiol 17B and progesterone mediated through endothelial cells. The major focus of the study will be examination of how increased coronary reactivity and vasospasm are prevented by estradiol 17B and progesterone, and the best combination of drugs for estrogen replacement therapy. It is anticipated that these studies will result in improved pharmacological approaches to coronary artery dysfunction in hypoestrogenism.
