Role of calcitonin gene-related peptide in the vascular system on the development of the hyperdynamic circulation in conscious cirrhotic rats.
OBJECTIVE
Calcitonin gene-related peptide (CGRP), a potent vasodilator; plays an important role in modulating vascular tone, acting as a noncholinergic nonadrenergic neurotransmitter. The aim of this study was to assess the role of CGRP, present in the vascular system, in the development of the hyperdynamic circulation observed in liver cirrhosis.


METHODS
Two doses of human alpha-CGRP [8-37], a specific antagonist of CGRP, were administered to cirrhotic and controls rats. Hemodynamics were evaluated using radioactive microspheres in conscious animals. To investigate the arterial depressor effect of exogenous CGRP, we constructed a dose-response curve for mean arterial pressure in cirrhotic and control rats by administering human alpha-CGRP.


RESULTS
The administration of high-dose human alpha-CGRP [8-37] (300 nmol.kg body weight-1.min-1) significantly increased both the mean arterial pressure (21 +/- 2 vs. 13 +/- 1%, p < 0.01) and total vascular resistance (76 +/- 5 vs. 54 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. The splanchnic hemodynamic effects induced by human alpha-CGRP [8-37] were a significant decrease in percent change of portal venous inflow -42 +/- 3 vs. -33 +/- 3%, p < 0.05) and a significant increase in percent change of splanchnic arterial resistance (110 +/- 9 vs. 76 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. Low-dose human alpha-CGRP [8-37] (60 nmol.kg body weight-1. min-1) caused similar hemodynamic changes, but the degree of change was much less than for the high-dose administration. The vascular response to human alpha-CGRP was significantly reduced in cirrhotic rats as compared to controls (ANOVA, p < 0.01). Plasma concentrations of CGRP were significantly elevated in cirrhotic rats.


CONCLUSIONS
CGRP in the vascular system was involved in the modulation of vasodilatation in rats with liver cirrhosis, as demonstrated by the administration of a selective CGRP antagonist and exogenous CGRP.
Hori
N
N
Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan.
Okanoue
T
T
Sawa
Y
Y
Kashima
K
K
D000818:Animals; D001775:Blood Circulation / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D008863:Microspheres; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013152:Splanchnic Circulation / Q000187:drug effects; D013997:Time Factors
D010446:Peptide Fragments; D015740:Calcitonin Gene-Related Peptide