Modulation of exogenous and endogenous atrial natriuretic peptide by a receptor inhibitor. Hypertension

Abstract Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A re-ceptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objec-tive of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n=6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glo-merular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium A trial natriuretic peptide (ANP) is a peptide hor-/ \ mone of cardiac origin1-2 that activates a par-M \- ticulate guanylyl cyclase-linked receptor, the natriuretic peptide-A receptor (NPR-A).34 ANP medi-ates its actions through generation of cyclic GMP (cGMP) and results in natriuresis secondary to in-creases in glomerular filtration rate (GFR) and de-creases in distal tubular sodium reabsorption.5-7 Such actions are consistent with localization of the NPR-A receptor to glomeruli and inner medullary collecting duct cells.56 Although the pharmacological action of ANP is well characterized, the role of endogenous ANP in the control of basal sodium excretion has yet to be established. Further definition of the pharmacological and physi-ological roles of ANP has been prohibited by the lack of a receptor antagonist. HS-142-1 was recently discovered from the fungus culture broth of Aureobasidium sp.8'9 Studies have established that HS-142-1 inhibits binding selectively to the particulate guanylyl cyclase recepto