Calcitonin Gene-Related Peptide Protects Against Cardiovascular Dysfunction Independently of Nitric Oxide In Vivo

Abstract

The neuropeptide CGRP (calcitonin gene-related peptide) is a potent vasodilator, with a cardioprotective role, although the precise mechanisms are unclear. Here we show the ability of endogenous and exogenous CGRP to restore blood pressure, when nitric oxide synthesis is blocked, in a model of cardiovascular disease associated with endothelial dysfunction and impaired nitric oxide production. Male wild-type and αCGRP knockout mice received L-nitro-arginine methyl ester (150 mg/kg in drinking water) to induce a sustained hypertension with evidence of cardiovascular remodeling. The hypertensive response was exacerbated in L-nitro-arginine methyl ester-treated αCGRP knockouts, indicating that endogenous αCGRP acts in a protective manner, when nitric oxide production is diminished. Exogenous CGRP rescued αCGRP knockout mice from both hypertension and cardiovascular remodeling. Further studies using a nonrecovery protocol with a CGRP receptor antagonist (BIBN4096 BS) revealed that CGRP acts via the canonical CGRP receptor (CLR [calcitonin-like receptor]/RAMP1 [receptor activity-modifying protein]); with no effect of an antagonist (AC187) of a second CGRP-responsive receptor (the amylin-1 receptor, CTR [calcitonin receptor]/RAMP1). Blood flow, in resistance vessels of the exteriorised mesentery, was investigated. Noradrenaline–induced vasoconstriction with recovery, in L-nitro-arginine methyl ester-treated wild-type mice. However, αCGRP knockout, or BIBN4096 BS-treated wild-type mice demonstrated a similar constrictor response to noradrenaline, but significantly impaired blood flow recovery. The combined findings highlight that αCGRP protects against cardiovascular dysfunction, signaling via the canonical CGRP receptor and acting when nitric oxide production is lost, such as in endothelial dysfunction associated with vascular disease. These in vivo results support the proposal that CGRP provides a novel treatment for cardiovascular disease.