Effects of the neutral endopeptidase inhibitor thiorphan on cardiovascular and renal function in cirrhotic rats.
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(-1) loading dose followed by 0.1 mg kg(-1) min(-1) x 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.
Liver Unit, Gastroenterology Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
K S
KS
Park
Y
Y
Li
Y
Y
Zhang
A L
AL
Gerbes
H
H
Liu
M G
MG
Swain
S S
SS
Lee
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D015244:Thiorphan / Q000494:pharmacology*
D019332:Endothelin-1; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015244:Thiorphan; D015260:Neprilysin; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP