Neutral Endopeptidase Inhibition Potentiates the Effects of Natriuretic Peptides in Renin Transgenic Rats.

Abstract

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)).These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure. (Hypertens Res 1996;19: 229-238) Key Words: neutral endopeptidase 24.11, (S)-thiorphan, ecadotril, TGR(m(Ren2)27), ANP, BNP, CNPThe natriuretic peptides are a family of related polypeptide hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These natriuretic peptides have a common structural motif consisting of a loop of 17 amino acids formed by intramolecular disulfide bonds. Only 6 of the 17 amino acids in this ring differ among the three peptides isolated from the pig, whereas the N-and C-terminals vary both in amino acid composition and length (1,2). Neutral m...

Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats

“…Natriuretic peptides are released by the hypertrophied heart, and their levels are elevated in patients with heart failure (4) and in homozygous Ren2 rats (44). Aliskiren reduced cardiac ANP and BNP expression in the diabetic, heterozygous Ren2 rats of the present study, most likely due to its blood pressurelowering effect.…”

Comparison of the Diagnostic Performance of Three Natriuretic Peptides in Hemodialysis Patients: Which is the Appropriate Biomarker?

“…Our data show that the MR-pro-ANP plasma concentrations were to a much greater extent dependent on residual renal clearance compared to BNP and resulted in concentrations above the upper limit used to diagnose heart failure in all patients. This finding was also evident for NT-pro-BNP plasma concentrations suggesting that the clearance of these fragments is highly dependent on residual function in contrast to BNP which can be eliminated after binding to the natriuretic peptide clearance receptor and the action of neutral endopeptidase [22,23]. The accumulation of the plasma natriuretic peptide concentration limits its clinical use in patients with chronic kidney disease.…”

Uncovering Heart Failure in Patients with a History of Pulmonary Disease: Rationale for the Early Use of B‐type Natriuretic Peptide in the Emergency Department

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