Premium
Vascular hyporesponsiveness to angiotensin II in rats with CCl 4 ‐induced liver cirrhosis
Author(s) -
Hennenberg M.,
Trebicka J.,
Kohistani A. Z.,
Heller J.,
Sauerbruch T.
Publication year - 2009
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2009.02181.x
Subject(s) - endocrinology , medicine , angiotensin ii , receptor , chemistry , angiotensin receptor , stimulation , angiotensin ii receptor type 1 , nitric oxide , arrestin , urotensin ii , g protein coupled receptor
Background Portal hypertension is triggered by vasodilation due to impaired contraction of extrahepatic vessels. Angiotensin II type 1 (AT 1 ) receptor‐induced vasocontraction is mediated by G proteins and may be desensitized by recruitment of β‐arrestin‐2 to the receptor. In this study, we analysed the interaction of AT 1 receptors with β‐arrestin‐2 in the context of vascular hypocontractility in rats with CCl 4 ‐induced cirrhosis. Methods Micronodular liver cirrhosis in rats ( n = 15) was induced by regular CCl 4 exposure. Age‐matched rats ( n = 15) served as controls. Contractility of aortic rings was measured by myography. Protein expressions and phosphorylations were assessed by Western blot analysis, and AT 1 receptor interaction with β‐arrestin‐2 by co‐immunoprecipitation. Results Aortic rings from CCl 4 rats were hypocontractile to angiotensin II independent of nitric oxide synthases ( N ω‐nitro‐ l ‐arginine methyl ester 200 μM). Expression of the AT 1 receptor, Gα q/11 and the contraction‐mediating effector Rho kinase was similar in aortas from both groups. Expression and AT 1 receptor binding of β‐arrestin‐2 were up‐regulated in aortas from CCl 4 rats. Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of β‐arrestin‐2 in aortas from noncirrhotic rats, but no further interaction of AT 1 receptors with β‐arrestin‐2 was found in aortas from CCl 4 rats. While angiotensin II stimulation resulted in Rho kinase activation in aortas from noncirrhotic rats but not in aortas from CCl 4 rats, extracellular signal‐regulated kinase activation in response to angiotensin II was observed in aortas from both groups. Conclusions Vascular hyporesponsiveness to angiotensin II in CCl 4 rats is due to enhanced interaction of the AT 1 receptor with β‐arrestin‐2 and consecutively changed receptor function.