Impaired vasodilation in response to perivascular nerve stimulation in mesenteric arteries of TRPV1-null mutant mice

BACKGROUND: The role of the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in perivascular sensory nerves in the regulation of vascular reactivity is largely unknown. This study was designed to test the hypothesis that vasodilation induced by electrical field stimulation (EFS) of perivascular sensory nerves is mediated by the TRPV1 via release of sensory neurotransmitters in wild-type (WT) mice, and this effect is abolished in gene-targeted TRPV1-null mutant (TRPV1(-/-)) mice. METHODS: Isolated mesenteric resistance arteries from WT and TRPV1(-/-)) mice were perfused and pretreated with guanethedine and atropine to block sympathetic and parasympathetic nerve activity, respectively. After precontracting with phenylephrine, changes of vascular diameters induced by EFS were monitored in the absence or presence of the TRPV1 receptor antagonist capsazepine; the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37; or the substance P (SP) receptor antagonist, RP67580. RESULTS: EFS-induced vasodilation was significantly reduced in arteries in TRPV1(-/-)) mice when compared to that of WT mice. Capsazepine and CGRP8-37 attenuated vasodilation induced by EFS in WT but not TRPV1(-/-)) mice. In contrast, RP67580 had no effect on the EFS-induced vasodilation in WT or TRPV1(-/-)) mice. The release of CGRP in the face of EFS challenge was significantly increased in both WT and TRPV1(-/-)) arteries, which was attenuated by capsazepine in WT but not TRPV1(-/-)) arteries. Exogenous CGRP caused dose-dependent vasodilation to a similar degree in WT and TRPV1(-/-)) arteries. CONCLUSIONS: Our data show that in WT mice transmural stimulation of perivascular sensory nerves activates the TRPV1, leading to CGRP release from sensory nerve endings; and blockade of CGRP, but not SP, receptors abolishes TRPV1-mediated vasodilation during EFS. All these effects are impaired in TRPV1(-/-)) mice, indicating that TRPV1 plays a key role in modulating perivascular sensory nerve-mediated vasodilation.