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TW von Geldern, GP Budzik, TP Dillon, WH Holleman, MA Holst, Y Kiso, EI Novosad, TJ Opgenorth, TW Rockway and AM Thomas
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
A collection of analogues of atrial natriuretic peptide (ANP) were screened for their ability to inhibit ANP-induced cGMP stimulation. The antagonists revealed through this screen are structurally related; almost all are substituted at either aspartate-13 or phenylalanine-26. This tendency is consistent throughout several families of small ANP analogues, suggesting that these two amino acid residues are involved in the process of ANP/cGMP signal transduction. One compound, A74186, was studied in some detail. A74186 is a potent inhibitor of the activation of guanylate cyclase by ANP; it acts with a pA2 of 7.12 in rat vascular smooth muscle cells and shifts the ANP/cGMP dose-response curve by 3 orders of magnitude at a 10 microM concentration. It also inhibits cGMP release in vivo, and at an infusion rate of 10 micrograms/kg-min it completely abolishes ANP-induced natriuresis and diuresis. A74186 does not, however, antagonize the hypotensive or vasorelaxant effects of ANP; in fact it acts as an agonist in these assays. It thus appears that cGMP, although it may mediate the renal responses to ANP, is not responsible for the vascular and hemodynamic effects that result from the action of the hormone.
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