Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice

Nerves that contain calcitonin gene-related peptide (CGRP) are components o f the sensory nervous system. Although these afferent nerves have tradition ally been thought to sense stimuli in the periphery and transmit the inform ation centrally, they also have an efferent vasodilator function. Acute adm inistration of a CCRP receptor antagonist increases the blood pressure (BP) in several models of hypertension, which indicates that this potent vasodi lator plays a counterregulatory role to attenuate the BP increase in these settings. To determine the role of this peptide in the long-term regulation of cardiovascular function, including hypertension, we obtained mice that have a deletion of the cu-calcitonin gene-related peptide (alpha-CGRP) gene . Although the beta-calcitonin gene-related peptide (beta-CGRP) gene is int act in these mice, alpha-CGRP is by far the predominant species of CCRP pro duced in dorsal root ganglia (DRG) sensory neurons. Initially, we examined the effect of deletion of the alpha-CGRP on baseline BP and beta-CGRP and s ubstance P mRNA expression. Systolic BP was significantly higher in the kno ckout mice (n=7) compared with wild-type in both male (160+/-6.1 vs 125+/-4 .8 mm Hg) and female (163+/-4.8 vs 135+/-33 mm Hg) mice. Next, groups (n=7) of knockout and wild-type mice had catheters surgically placed in the righ t carotid artery for mean arterial pressure recording. With the animals ful ly awake and unrestrained, The knockout mice displayed an elevated mean art erial pressure compared with wild-type in both male (139+/-4.9 vs 118+/-4.9 mm Hg) and female (121+/-3.4 vs 107+/-3.1 mm Hg) mice. Northern blot analy sis of DRG RNA samples confirmed the absence of alpha-CGRP mRNA in the knoc kout mice. Substance P mRNA content in DRG was unchanged between the 2 grou ps: however, beta-CGRP mRNA levels were reduced 2-fold in the knockout mice . These results indicate for the first time that alpha-CGRP may be involved in the long-term regulation of resting BP and suggest that these mice are particularly sensitive to challenges to BP homeostasis because of the loss of a compensatory vasodilator mechanism.