Comparative bioactivity of atrial, brain, and C-type natriuretic peptides in conscious sheep

Abstract

Although atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) appear to share functional homology, there is doubt concerning a possible endocrine function for C-type natriuretic peptide (CNP) and the relative potency of species-specific forms of these hormones. Accordingly, we have examined the biological effects, interactions, and pharmacokinetics of equimolar doses (0.5 followed by 2.5 pmol.kg-1.min-1, each for 2 h) of species-specific forms of ANP, BNP-26, and CNP-22 in vehicle-controlled studies in normal conscious sheep. Although pharmacokinetics (metabolic clearance rates of 5.7 +/- 1.17, 7.5 +/- 1.36, and 4.7 +/- 0.71 l/min and half-lives of 3.9 +/- 0.42, 2.5 +/- 0.21, and 2.0 +/- 0.18 min for ANP, BNP, and CNP, respectively) are similar, the biological effects and actions on endogenous natriuretic peptide levels differ. Plasma BNP was significantly increased by CNP infusion (P < 0.0001), as was CNP by BNP infusions (P = 0.0009). Compared with ANP and BNP, which were equipotent in stimulating plasma guanosine 3',5'-cyclic monophosphate (cGMP; P < 0.0001 for both) and lowering arterial pressure (P < 0.05 for both) and cardiac output, CNP infusions induced only a small increment in cGMP and had no significant hemodynamic actions. In contrast, all three peptides suppressed plasma aldosterone levels (P < 0.05 for each), yet none induced significant natriuresis. Actions of CNP to increase BNP (and ANP) may account for the observed bioactivity of CNP. The findings show that potentially important interactions occur among all three hormones that need to be considered when interpreting the effects of individual peptides, particularly CNP.