Activation of the renin-angiotensin system in α-calcitonin gene-related peptide/calcitonin gene knockout mice

Objective To test the hypotheses that circulating or tissue renin-angiotensin system (RAS) activity is increased in alpha-calcitonin gene-related peptide (alpha-CGRP) knockout mice, and that this contributes to the increased blood pressure in these mice. Design and methods Three- to six-month-old male alphaCGRP/calcitonin knockout mice and wild-type controls were studied. Mean arterial pressure (MAP) and its response to an angiotensin II type 1 (AT(1)) receptor blocker, losartan (3 mg/kg intravenously), were determined in conscious, unrestrained knockout mice and wild-type mice. Radioimmunoassay and western blot were used, respectively, to determine plasma renin activity (PRA) and AT(1) receptor protein content in tissues. Results Basal MAP and PRA were significantly greater in the knockout mice than in the wild-type mice. In contrast, AT(1) receptor content in the renal medulla was significantly decreased in the knockout mice compared with that in wild-type mice. AT(1) receptor content in the renal cortex and mesenteric resistance arteries was not different in the knockout and wild-type mice. Losartan produced a significant decrease in MAP in the knockout mice compared with that in wild-type mice. Conclusion Activity of the circulating RAS, but not tissue AT, receptor expression, is increased in alphaCGRP/calcitonin knockout mice, which may contribute to the increase in blood pressure in this mouse model. The mechanism(s) responsible for the increased activity of the circulating RAS in the absence of alphaCGRP throughout the developmental stages of these animals remains to be determined.