Decreased pressor reactivity to angiotensin II in cirrhotic rats. Evidence for a post-receptor defect in angiotensin action.
We used a model of cirrhosis in the rat, produced by inhalation of carbon tetrachloride for 6 weeks, to investigate the mechanism of resistance to the pressor effects of angiotensin II. The pressor response to angiotensin II was significantly lower in conscious cirrhotic animals than in controls. On the other hand, cirrhotic animals had normal pressor responses to norepinephrine, indicating that a generalized defect in vascular reactivity does not cause the decreased pressor response to angiotensin II. Enhanced baroreceptor activity was not the cause of the decreased pressor response to angiotensin II, since baroreflex control of heart rate after angiotensin II was similar in cirrhotics and controls. Pretreatment with either the converting enzyme inhibitor captopril to reduce circulating angiotensin II or the prostaglandin synthesis inhibitor meclofenamate failed to normalize the response to angiotensin II. Thus, neither prior occupancy of receptors with endogenous angiotensin II nor the production of vasodilatory prostaglandins was responsible for the decreased angiotensin II response. Studies of angiotensin II binding by mesenteric artery smooth muscle particles showed that, in cirrhotic animals, receptor affinity for angiotensin II, was significantly lower than in controls (kd: cirrhosis 1.11 +/- 0.09 nM, control 0.94 +/- 0.13 nM; P less than 0.02), whereas receptor number was significantly increased (cirrhosis 315 +/- 42 fmol/mg protein, control 277 +/- 43 fmol/mg protein, P less than 0.01). However, total binding of AII by vascular receptors from cirrhotics was no different than in controls, since the decrease in affinity negated the increase in receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)
Murray
B M
BM
Paller
M S
MS
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011311:Pressoreceptors / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*
D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D000804:Angiotensin II; D008469:Meclofenamic Acid; D002216:Captopril; D009638:Norepinephrine