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Atrial natriuretic peptide modulators: Dissociation of receptor binding and particulate guanylate cyclase activity
Author(s) -
Horng Jong S.,
Wyss Virginia L.,
Schirmer Elmer W.,
McCowan Jefferson R.,
Yu Melvin J.
Publication year - 1991
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430230306
Subject(s) - guanabenz , prazosin , atrial natriuretic peptide , chemistry , zona glomerulosa , receptor , endocrinology , medicine , aldosterone , dissociation constant , oxotremorine , npr1 , binding site , natriuretic peptide , pharmacology , agonist , biochemistry , biology , antagonist , angiotensin ii , heart failure
Prazosin stimulated 125 l‐rANP(102–126) binding to bovine adrenal zona glomerulosa membranes (BAZGM) allosterically by converting the lower‐affinity state binding sites into the higher‐affinity state. The modulatory effect could be mimicked by guanabenz and LY193422, and was concentration‐dependent. SC 50 (concentration required to stimulate binding by 50%) values for guanabenz, prazosin, and LY193422 were 13, 25, and 1.8 μM, respectively. Prazosin (30 μM) enhanced 125 l‐ANP(102–126) binding by decreasing the K D from 251 ± 24 to 97.4 ± 8.3 pM without affecting the Bmax. Competitive inhibition of 125 l‐ANP binding by ANP analogs was potentiated by prazosin (30 μM) and LY193422 (50 μM). The modulator‐stimulated 125 l‐rANP(102–126) binding was reversible by the addition of unlabelled ANP analogs during incubation. Previously, we also demonstrated that these modulators potentiated the ANP‐mediated inhibition of ACTH‐induced aldosterone synthesis in rat adrenal zona glomerulosa cells [Horng, J. S., Steinberg, M. I., Wyss, V. L., Wiest, S. A., Schirmer, E. W., McCowan, J. R., and Yu, M. J.: Atrial natriuretic peptide (ANP) receptor modulators: Effects of prazosin and guanabenz analogs on ANP receptor binding and in vitro biological activity. FASEB Journal 3:A733, 1989; Yu, M. J., McCowan, J. R., Steinberg, M. I., Wiest, S. A. Wyss, V. L., and Horng, J. S.: Atrial natriuretic peptide receptor modulators: Effect of disubstituted quinazolines on receptor binding and in vitro biological activity. Journal of Medicinal Chemistry 33:348–353, 1990]. However, neither prazosin nor LY193422 affected basal or ANP‐induced particulate guanylate cyclase activity in rabbit glomeruli. This is the first study to our knowledge in which ANP modulators were demonstrated to potentiate ANP‐mediated response independent of cGMP. Our studies suggest that potentiation of ANP‐mediated inhibition of aldosterone synthesis by these analogs does not involve particulate guanylate cyclase and that these modulators induce a cyclase‐uncoupled, high affinity ANP receptor in the adrenal gland, which might be different from cyclase‐uncoupled ANP clearance receptor.