Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis.
OBJECTIVE
Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats.


METHODS
Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed.


RESULTS
A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P < .05). Liver fibrosis was reduced in group 2 by 30% (P < .05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score.


CONCLUSIONS
Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.
Domenicali
Marco
M
Dipartimento di Medicina Clinica, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
Caraceni
Paolo
P
Giannone
Ferdinando
F
Pertosa
Anna Maria
AM
Principe
Alessandro
A
Zambruni
Andrea
A
Trevisani
Franco
F
Croci
Tiziano
T
Bernardi
Mauro
M
D000818:Animals; D001201:Ascites / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D002251:Carbon Tetrachloride; D002302:Cardiac Output / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D000077285:Rimonabant; D012964:Sodium / Q000652:urine; D012982:Sodium, Dietary / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D012982:Sodium, Dietary; D012964:Sodium; D002251:Carbon Tetrachloride; D000077285:Rimonabant