Acute and Chronic Neutral Endopeptidase Inhibition in Rats With Aortocaval Shunt

Abstract

In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/- 28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80 min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure-induced cardiac hypertrophy independent of hemodynamic effects.

Effect of chronic volume overload on baroreflex control of heart rate and sympathetic nerve activity

“…We and others (8,24,28) demonstrated that the inhibition of the angiotensin-converting enzyme or of the angiotensin II type 1 receptor (AT 1receptor) improved the baroreflex control. In the model of chronic volume overload, a moderate activation of the renin-angiotensin-aldosterone system occurs (41), and it is conceivable that this mechanism might contrib-ute to the early depression of baroreflex control of sympathetic nerve activity, which we report in this study. Thus, an influence of humoral activation of the renin-angiotensin-aldosterone system and of ANP might contribute to the impaired baroreflex control of sympathetic nerve activity.…”

“…Several mechanisms could have contributed to the early alterations of baroreflex control in this model. The aortocaval shunt model is characterized by an activated ANP system (40,41). We measured a threefold increase of plasma concentrations of ANP in aorto-…”

Effects of the neutral endopeptidase inhibitor thiorphan on cardiovascular and renal function in cirrhotic rats

“…However, it is becoming increasingly clear that the notion that NEP inhibitors act merely by increasing the blood levels of ANP, ET‐1, and other vasoactive substances is an oversimplification. Rather, recent studies using sinorphan or thiorphan have convincingly demonstrated intrarenal effects, predominantly in the tubules where NEP activity is high, independent of the degree of plasma ANP augmentation which is inconsistent (Trapani et al ., 1989; Willenbrock et al ., 1996; Solter et al ., 2000). Therefore, we remain unconcerned about the insignificant elevations of ET‐1 and ANP in our cirrhotic rats; the significant increase in natriuresis in this group confirms, in our view, the efficacy of the thiorphan dose despite the inability to raise these vasoactive substance levels in plasma.…”

Effects of captopril and omapatrilat on early post-myocardial infarction survival and cardiac hemodynamics in rats: interaction with cardiac cytokine expression

“…Inhibition of NEP potentiates the vasodilator, diuretic, and natriuretic effects of these two peptidergic systems and has beneficial effects in animal models of heart failure (Seymour et al 1993;Rademaker et al 1996;Willenbrock et al 1996). It may thus be postulated that the simultaneous inhibition of ACE and NEP may be superior to ACE inhibition alone post-MI.…”