ATRIAL-NATRIURETIC-PEPTIDE (ANP) INHIBITS ITS OWN SECRETION VIA ANP(A) RECEPTORS - ALTERED EFFECT IN EXPERIMENTAL-HYPERTENSION

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 regulati on of its own secretion, we studied here the effects of ANP (greater a ffinity for ANP(A) than for ANP(B) receptors) and C-type natriuretic p eptide (CNP), a potent activator of ANP(B) receptors, on the release o f atrial peptides under basal conditions and during acute volume expan sion in conscious normotensive Sprague-Dawley rats. The effects of HS- 142-1, a nonpeptide ANP(A) and ANP(B) receptor antagonist, on volume l oad-induced atrial peptide release in l-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 he art, plasma levels of N-terminal fragment of pro-ANP (NT-ANP) were mea sured. In Sprague-Dawley rats, iv infusion of ANP for 30 min in doses of 0.3 and 1.0 mu g/kg.min blocked the plasma immunoreactive NT-ANP (I R-NT-ANP) response to vol volume load (P < 0.001), whereas CNP had no significant effect. Neither ANP nor CNP infusion had any effect on pla sma IR-NT-ANP levels under basal conditions. Bolus administration of H S-142-1 increased baseline plasma IR-ANP concentrations in both WKY an d 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 concentra tions 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 re sponses to acute volume load in WKY rats. In contrast, HS-142-1 did no t enhance the plasma IR-ANP response to acute volume load in SHR and r esulted 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 C NP, inhibited volume expansion-stimulated NT-ANP release and that HS-1 42-1, an antagonist of guanylate cyclase-linked natriuretic peptide re ceptors, increased plasma ANP and NT-ANP concentrations show that endo genous ANP directly modulates its own release via ANP(A) receptors in vivo. Furthermore, this modulation of acute volume expansion-induced a trial peptide release appears to be altered in experimental hypertensi on.