Beta adrenergic receptor response coupling in hypertrophied hearts.
Reports in the literature have indicated that inotropic responsiveness to isoproterenol (ISO) of hypertrophied rat myocardium is decreased. We have studied possible biochemical mechanisms to explain this. Adenylate cyclase activity in myocardial membranes from 13-week-old spontaneously hypertensive rats (SHR) was unchanged compared to enzyme activity in Wystar-Kyoto (WKY) when measured under basal conditions or following NaF, a guanosine triphosphate analog, MnCl2, or forskolin stimulation. However, ISO-stimulated cyclase activity was decreased as were beta-adrenergic receptor density with no change in receptor affinity. On the other hand, hearts from two-kidney, one clip renal hypertensive rats 6 weeks after initiation of hypertension showed decreased basal, ISO, NaF, and GTP analog-stimulated cyclase activity with no change in Mn++ or forskolin-stimulated activity. In this model, receptor density increased. When the clipped kidney was removed, these changes returned toward normal as did the blood pressure and heart weight. We interpret these data to indicate that in SHR the biochemical defect leading to decreased inotropic responsiveness of hypertrophied hearts is due to decreased beta-adrenergic receptor density, leading to decreased ISO-stimulated cyclase activity. The nucleotide regulatory protein component (N) and the catalytic subunit (C) are not changed. In the renal hypertensive rat, on the other hand, although the C is unchanged, there is a decrease in the activity of N, and this is probably the primary reason why inotropic responsiveness to ISO is decreased. Increases in receptor density seen in this model may possibly be compensatory.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism*; D004082:Dihydroalprenolol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006973:Hypertension / Q000150:complications*; D006977:Hypertension, Renal / Q000150:complications; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol