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Tissue-Specific Regulation of Microvascular Diameter: Opposite Functional Roles of Neuronal and Smooth Muscle Located Vanilloid Receptor-1

Tamás Kark, Zsolt Bagi, Erzsébet Lizanecz, Enik T. Pásztor, Nóra Erdei, Ágnes Czikora, Zoltán Papp, István Édes, Róbert Pórszász, and Attila Tóth

Department of Pharmacology and Pharmacotherapy, Institute of Pharmacology (T.K., R.P.), and Division of Clinical Physiology, Institute of Cardiology (Z.B., E.L., E.T.P., N.E.,Á.C., Z.P., I.É., A.T.), Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

The transient receptor potential type V1 channel (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 is involved in the regulation of microvascular tone. We found that TRPV1 stimulation by capsaicin (intra-arterial administration) of the isolated, perfused right hind limb of the rat increased vascular resistance (by 98 ± 21 mm Hg 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 hind limb did not affect capsaicin-evoked changes in vascular resistance and tissue perfusion in the hind limb but reduced the elevation of perfusion in the skin. In isolated, pressurized skeletal (musculus gracilis) muscle arterioles (diameter, 147 ± 35 µm), capsaicin had biphasic effects: at lower concentrations, capsaicin (up to 10 nM) evoked dilations (maximum, 32 ± 13%), whereas higher concentrations (0.1-1 µM) elicited substantial constrictions (maximum, 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 reverse transcriptase-polymerase chain reaction 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. Because of 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.

Address correspondence to: Dr. Attila Tóth, Division of Clinical Physiology, Institute of Cardiology, Medical and Health Science Center, University of Debrecen, 22 Moricz Zs krt, 4032, Debrecen, Hungary. E-mail: atitoth{at}dote.hu