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

Abstract

1 Cirrhosis is associated with cardiovascular and renal dysfunction including sodium retention. Many vasoactive peptides such as atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are degraded by neutral endopeptidase 24.11 (NEP). We investigated the hemodynamic and renal effects of thiorphan, a NEP inhibitor, in a rat cirrhosis model. 2 Cirrhosis was induced by chronic bile duct ligation, and controls had sham operation. Systemic and renal hemodynamics in conscious, restrained animals were determined using radiolabeled microspheres, and glomerular filtration rate (GFR) was measured by 3 H-inulin clearance. Plasma ANP and ET-1, and renal cGMP and Na + -K + ATPase activity were assayed. These variables were measured at baseline and after intravenous infusion of thiorphan (0.5 mg kg À1 loading dose followed by 0.1 mg kg À1 min À1 Â 30 min). 3 Thiorphan significantly decreased cardiac output, and increased systemic vascular resistance in controls, whereas in cirrhotic rats these variables were unchanged. 4 Compared to the controls, cirrhotic rats showed a decreased baseline GFR and urine sodium excretion, and the latter was significantly increased by thiorphan. 5 Thiorphan increased plasma ET-1 levels in controls, but not cirrhotic rats. ANP levels were not significantly increased in either group by thiorphan. 6 Thiorphan significantly increased cGMP concentrations and decreased Na + -K + ATPase activity of renal medulla but not cortex in cirrhotic rats; no effect was observed in the control rats. 7 We conclude that thiorphan induces natriuresis in cirrhotic rats by a direct renal medullary mechanism via cGMP and Na + -K + ATPase, without affecting systemic hemodynamics. This may potentially be useful in patients with ascites.

Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites

“…Thus these studies stress that a successful natriuretic effect of ANP in the cirrhotic patient depends on suppression of antinatriuretic systems. Other possible mechanisms of ANP resistance could be diminished delivery of sodium to the ANP-sensitive part of the nephron (1, 26); increased renal neutral endopeptidase activity, limiting access of ANP to receptor sites (30); and alteration in renal ANP receptor density or function with a higher ratio of clearance receptors to biologically active receptors (11). We did not determine intrarenal levels of cGMP after sildenafil, and therefore a relative insensitivity of cellular pathways distal to cGMP could potentially also have contributed.…”

Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: A new target to treat portal hypertension?

“…Accordingly, the NEP-inhibitor thiorphan did not alter systemic vascular resistance in cirrhotic rats [47] and sinorphan actually reduced renin secretion in cirrhotic patients [48].…”

Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis

“…Dussaule et al (12) administered single oral doses of sinorphan to 16 patients with ascitic cirrhosis and observed increases in plasma ANP, a natriuretic response, a significant reduction of plasma renin activity, and no effects on arterial pressure. Park et al (36) observed that thiorphan caused natriuresis but did not alter cardiac output and systemic vascular resistance in cirrhotic rats. Neither study evaluated the effects of NEP inhibition on renal perfusion and free water metabolism, AVP plasma levels, and ANP urinary Fig.…”