Received for publication November 12, 2007.
Revised February 5, 2008.
Accepted for publication February 5, 2008.

Tissue specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1 (TRPV1)

Abstract

The vanilloid receptor 1 (TRPV1) is a Ca²⁺-permeable nonspecific cation channel, activated by various painful stimuli including ischemia. We hypothesized that TRPV1 is expressed in the arterioles and involved in the regulation of microvascular tone. We found that TRPV1 stimulation by capsaicin (intra-arterial administration) of the isolated, perfused right hindlimb of the rat increased vascular resistance (by 98±21 mmHg at 10 µg), in association with decreased skeletal muscle perfusion and elevation of skin perfusion (detected by dual channel laser Doppler flowmetry). Denervation of the hindlimb did not affect capsaicin-evoked changes in vascular resistance and tissue perfusion in the hindlimb, but reduced elevation of perfusion in the skin. In isolated, pressurized skeletal (m. gracilis) muscle arterioles (diameter: 147±35 µm), capsaicin had biphasic effects: at lower concentrations of capsaicin (up to 10 nmol/L) evoked dilations (max: 32±13%), while higher concentrations (0.1-1 µmol/L) elicited substantial constrictions (max: 66±7%). Endothelium removal or inhibition of nitric oxide synthase abolished capsaicin-induced dilations, but did not affect arteriolar constriction. Expression of TRPV1 was detected by RT-PCR in the aorta and in cultured rat aortic vascular smooth muscle cells (A7r5). Immunohistochemistry revealed expression primarily in the smooth muscle layers of the gracilis arteriole. These data demonstrate the functional expression of TRPV1 in vascular smooth muscle cells mediating vasoconstriction of the resistance arteries. Due to the dual effects of TRPV1 stimulation on the arteriolar diameter (dilation in skin, constriction in skeletal muscle), we propose that TRPV1 ligands represent drug candidates for tissue specific modulation of blood distribution.

Key words: CGRP/amylin, Capsaicin/vanilloid, Ischemia/Reperfusion, Neuropeptides, peptidases