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Atrial Natriuretic Peptide (ANP) Inhibits Its Own Secretion via ANP_A Receptors: Altered Effect in Experimental Hypertension¹

Departments of Physiology (H.L., O.V.) and Pharmacology and Toxicology (M.T., H.R.) and Biocenter Oulu, University of Oulu, Oulu, Finland

Address all correspondence and requests for reprints to: Heikki Ruskoaho, M.D., Ph.D., Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail: heikki.ruskoaho{at}.oulu.fi

Three atrial natriuretic peptide (ANP) receptors, ANP_A, ANP_B, and ANP_C, have been identified in the heart, suggesting that natriuretic peptides may have direct effects on cardiac function. To characterize the possible role of atrial natriuretic peptide (ANP) in the regulation of its own secretion, we studied here the effects of ANP (greater affinity for ANP_A than for ANP_B receptors) and C-type natriuretic peptide (CNP), a potent activator of ANP_B receptors, on the release of atrial peptides under basal conditions and during acute volume expansion in conscious normotensive Sprague-Dawley rats. The effects of HS-142–1, a nonpeptide ANP_A and ANP_B receptor antagonist, on volume load-induced atrial peptide release in 1-yr-old conscious normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were also studied. As an index of secretion of atrial peptides from the heart, plasma levels of N-terminal fragment of pro-ANP (NT-ANP) were measured. In Sprague-Dawley rats, iv infusion of ANP for 30 min in doses of 0.3 and 1.0 µg/kg·min blocked the plasma immunoreactive NT-ANP (IR-NT-ANP) response to volume load (P < 0.001), whereas CNP had no significant effect. Neither ANP nor CNP infusion had any effect on plasma IR-NT-ANP levels under basal conditions. Bolus administration of HS-142–1 increased baseline plasma IR-ANP concentrations in both WKY and SHR strains (WKY: 3 mg/kg, 46 ± 8 pmol/liter, P < 0.001; SHR: 1 mg/kg, 26 ± 9 pmol/liter, P < 0.01; SHR: 3 mg/kg, 40 ± 12 pmol/liter, P < 0.01). The corresponding increases in plasma IR-NT-ANP concentrations in the SHR in response to administration of HS-142–1 were 0.17 ± 0.06 nmol/liter (P < 0.01) and 0.40 ± 0.14 nmol/liter (P < 0.01). Moreover, HS-142–1 (3 mg/kg) augmented plasma IR-ANP and IR-NT-ANP responses to acute volume load in WKY rats. In contrast, HS-142–1 did not enhance the plasma IR-ANP response to acute volume load in SHR and resulted in a smaller increase in the plasma IR-NT-ANP concentration in SHR than in WKY rats. In conclusion, the findings that ANP, but not CNP, inhibited volume expansion-stimulated NT-ANP release and that HS-142–1, an antagonist of guanylate cyclase-linked natriuretic peptide receptors, increased plasma ANP and NT-ANP concentrations show that endogenous ANP directly modulates its own release via ANP_A receptors in vivo. Furthermore, this modulation of acute volume expansion-induced atrial peptide release appears to be altered in experimental hypertension.

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