ACTIVATOR CALCIUM AND MYOCARDIAL-CONTRACTILITY IN FETAL SHEEP EXPOSEDTO LONG-TERM HIGH-ALTITUDE HYPOXIA

We studied myocardial contractility in fetal sheep from ewes exposed t o similar to 112 days of hypoxia at high altitude (3,820 m). We measur ed the inotropic response to extracellular Ca2+ concentration ([Ca2+]( o), 0.2-10 mM) and ryanodine (10(-10) to 10(-4) M) in isometrically co ntracting papillary muscles and quantified dihydropyridine (DHPR) and ryanodine (RyR) receptors. In hypoxic fetuses, curves describing the f orce[Ca2+], relationship were shifted left, and the top plateaus were decreased by similar to 35% in both left and right ventricles. In norm oxic and hypoxic fetuses, ryanodine (10(-4) M) reduced maximum active tension (T-max) to similar to 25-40% of baseline values, indicating th at the sarcoplasmic reticulum was the chief source of activator Ca2+ a nd that Ca2+ influx alone was not sufficient to activate a contraction of normal amplitude. Hypoxia resulted in a lower T-max in the right v entricle and a lower maximum rate of rise in the left ventricle after treatment with ryanodine. DHPR number did not change, but RyR number a nd the RyR/DHPR in both ventricles were higher in hypoxic fetuses. We conclude that hypoxia decreases contractility, possibly by reducing th e availability of activator Ca2+ Further studies are needed to directl y measure the Ca2+ current and intracellular Ca2+ transient and to exa mine myofilament protein and adenosinetriphosphatase activity.