Elevated sympathetic nervous activity in mice deficient in alpha CGRP

alpha -Calcitonin gene-related peptide (alpha CGRP) is a pleiotropic neurop eptide implicated in a variety of physiological processes. To better unders tand the biological functions of alpha CGRP, we developed an alpha CGRP-nul l mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were signif icantly higher in both anesthetized and conscious, unrestrained alpha CGRP- null mice than in corresponding wild-type mice. The elevated MAP in alpha C GRP-null mice was shown to be the result of elevated peripheral vascular re sistance by alpha -adrenergic blockade with prazosin and by transthoracic e chocardiogram, which revealed no significant differences between alpha CGRP -null and wild-type mice in the stroke volume, fractional shortening, and e jection fraction. Moreover, evaluation of autonomic nervous activity by mea suring HR after pretreatment of atropine and/or atenolol and by analyzing a rterial baroreceptor reflexes showed sympathetic nervous activity to be sig nificantly elevated in alpha CGRP-null mice; elevated levels of urinary cat echolamine metabolites and decreased HR variability in mutant mice were als o consistent with that finding. These findings suggest that alpha CGRP cont ributes to the regulation of cardiovascular function through inhibitory mod ulation of sympathetic nervous activity.