CARDIAC BETA-ADRENERGIC-RECEPTOR FUNCTION IN FETAL SHEEP EXPOSED TO LONG-TERM HIGH-ALTITUDE HYPOXEMIA

In this study, we hypothesized that a reduction in beta-adrenergic rec eptor number or a decrease in functional coupling of the receptor to t he adenylate cyclase system may be responsible for the blunted inotrop ic response to isoproterenol observed in fetal sheep exposed to high a ltitude (3,820 m) from 30 to 138-142 days gestation. We measured the c ontractile response to increasing doses of isoproterenol and forskolin in papillary muscles from both ventricles, estimated beta-adrenergic receptor density (B-max) and ligand affinity (K-d) using [I-125]iodocy anopindolol, and measured adenosine 3',5'-cyclic monophosphate (cAMP) levels before and after maximally stimulating doses of isoproterenol a nd forskolin. Left ventricular wet weight was unchanged, but right ven tricular weight was 20% lower than controls. At the highest concentrat ion of isoproterenol (10 mu M), maximum active tension was 32 and 20% lower than controls in hypoxemic left and right ventricles, respective ly. The contractile response to forskolin was severely attenuated in b oth hypoxemic ventricles. B-max was unchanged in the left ventricle, b ut increased by 55% in the hypoxemic right ventricle. K-d was not diff erent from controls in either ventricle. Basal cAMP levels were not di fferent from controls, but isoproterenol-stimulated and forskolin-stim ulated cAMP levels were 1.4- to 2-fold higher than controls in both hy poxemic ventricles. The results suggest mechanisms downstream from cAM P in the beta-adrenergic receptor pathway are responsible for the atte nuated contractile responses to isoproterenol.