The cardiac and brain microvessel adenylate cyclase system in deoxycorticosterone acetate-hypertensive rats

Abstract

A decrease in isoproterenol-stimulated adenylate cyclase activity has been shown in various tissues of hypertensive rats, a finding often associated with decreased beta-adrenoceptor number. The present study was undertaken to investigate whether adenylate cyclase stimulation by other hormones is similarly affected. Adenylate cyclase activity in cerebral microvessels under control conditions and following stimulation by isoproterenol, prostaglandin E1, and the adenosine analog 5'-(N-ethylcarboxamide)-adenosine (NECA) was significantly diminished in deoxycorticosterone acetate (DOCA)-hypertensive rats as compared with control rats, as was adenylate cyclase stimulation by GTP, fluoride, and forskolin. Similar results were obtained in cardiac ventricular membranes, apart from the fact that NECA did not influence adenylate cyclase activity in the heart, either in normotensive or in hypertensive rats. In both the heart preparation and the microvessel preparation, beta-adrenoceptor numbers were reduced in DOCA-hypertensive rats. Because the adenylate cyclase data also pointed to functional alteration at the guanine nucleotide regulatory site of the adenylate cyclase complex, the influence of DOCA hypertension on receptor-adenylate cyclase coupling was investigated by competition studies for beta-adrenoceptor binding. In ventricular membranes prepared from DOCA-hypertensive rats, the isoproterenol competition curve for [125I]iodocyanopindolol binding was only slightly altered in the presence of guanylyl imidodiphosphate (50 microM), in contrast to normotensive control rats, in which it was shifted to the right and became significantly steeper. These results are suggestive of decreased guanine nucleotide sensitivity of adenylate cyclase-coupled receptors in DOCA hypertension.