Vascular, hemodynamic and renal effects of low-dose losartan in rats with secondary biliary cirrhosis.
BACKGROUND
In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to alpha1-adrenoceptor agonists. Recently, the angiotensin II type 1-receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to alpha1-adrenoceptor agonists.


METHODS
We studied, in rats with secondary biliary cirrhosis and sham-operated rats, the effect of 0.5 and 10 mg losartan/kg x day on aortic responsiveness to alpha1-adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function.


RESULTS
In cirrhotic rats, 10 mg losartan/kg x day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg x day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis.


CONCLUSIONS
In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to alpha1-adrenoceptor agonists.
Heller
Jörg
J
Department of Internal Medicine I, University of Bonn, Bonn, Germany. jheller@uni-bonn.de
Trebicka
Jonel
J
Shiozawa
Thomas
T
Schepke
Michael
M
Neef
Markus
M
Hennenberg
Martin
M
Sauerbruch
Tilman
T
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000502:physiology; D008102:Liver Circulation / Q000187:drug effects*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D018340:Receptors, Adrenergic, alpha-1; D008729:Methoxamine; D019808:Losartan; D009638:Norepinephrine