Myocardial Contractility in Fetal Sheep Exposed to Long-term Hypoxia at High Altitude : Activator Calcium and Beta-adrenergic Receptor Function
We studied myocardial contractility in fetal sheep exposed to ~112 days of hypoxia at high-altitude (3,820 m). We recorded left and right ventricular wet weight, and measured the inotropic responses to extracellular calcium [Ca2+]o (0.2-10 mM), ryanodine (10-10-10-4 M), isoproterenol (10-10-10-6 M), and forskolin (0.01-10 uM) in isometrically contracting papillary muscles. In addition, we quantified dihydropyridine (DHPR), ryanodine (RyR), and β-adrenergic receptor densities, and measured basal and stimulated intracellular cAMP levels. In hypoxic fetuses, left ventricular wet weight was unchanged, but right ventricular weight was ~20% lower than controls. Curves describing the force-[Ca2+]o relationship were left-shifted, and the top plateaus were decreased by -35% in both left and right ventricles. Ryanodine (10"^ M) reduced maximum active tension (Tmax) to -25-40% of baseline values, indicating that the sarcoplasmic leticulum was the chief source of activator calcium. DHPR number did not change, but RyR density and the RyR:DHPR ratios in both ventricles were higher in l9q)CKic fetuses. At the highest concentration of isoproterenol (10 uM), maximum active tension was ~32% and ~20% lower than controls in hypoxic left and right ventricles, respectively. The contractile response to forskolin was severely attenuated in both hypoxic ventricles, β-receptor density was unchanged in the left ventricle, but increased by 55% in the hypoxic right ventricle. KD was not different from controls in either ventricles. Basal cAMP levels were not different from controls, but isoproterenol-stimulated and foreskolin-stimulated cAMP levels were 1.4 to 2-fold higher than controls in both hypoxic ventricles. In summary, there was no ventricular hypertrophy, and hypoxia decreased contractility, possibly by reducing the availability of activator calcium. The blunted contractile responses to isoproterenol and forskolin were not related to down-regulation of the p-adrenergic receptors or adenylate cydase. We speculate that the changes in the inotropic responsiveness to both caldum and P-agonists are linked by a common, as yet unexplored, mechanism, possibly involving decreased A-kinase activity or increased phosphatase activity. The expected changes in the phosphorylation state of several key effector proteins, that would, theoretically, occur in that scenario, are consistent with the observations in study.
Physiology, Myocardial Contraction; Fetal Heart -- physiology; Receptors, Adrenergic, beta; Fetal Anoxia; Sheep
Networked Digital Library of Theses and Dissertations