Published online before print October 21, 2004, doi: 10.1161/01.RES.0000148633.93110.24
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Vanilloid Receptor TRPV1, Sensory C-Fibers, and Vascular Autoregulation
A Novel Mechanism Involved in Myogenic Constriction
From the Wolfson Institute for Biomedical Research (R.S.S.), University College London, London, UK; Clinical Pharmacology (S.C., A.A.), The William Harvey Research Institute, Queen Mary’s School of Medicine and Dentistry, London, UK; Novartis Institute (C.D., P.K.), London, UK; Department of Anatomy (C.D.F., S.H.), University College London, London, UK; Centre for Cardiovascular Biology and Medicine (J.K.), The Rayne Institute, University College London, London, UK; and the Sensory Research Group (U.O.), National Creative Research Initiatives, College of Pharmacy, Seoul National University, Kwanak-Gu, Seoul, Korea.
Correspondence to Amrita Ahluwalia, Clinical Pharmacology, The William Harvey Research Institute, Barts and The London Queen Mary’s School of Medicine and Dentistry, Charterhouse Sq, London EC1M 6BQ, UK. E-mail a.ahluwalia{at}qmul.ac.uk
Myogenic constriction describes the innate ability of resistance arteries to constrict in response to elevations in intraluminal pressure and is a fundamental determinant of peripheral resistance and, hence, organ perfusion and systemic blood pressure. However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear. In this study, we show that elevation of intraluminal transmural pressure of mesenteric small arteries in vitro results in a myogenic response that is profoundly suppressed following ablation of sensory C-fiber activity (using in vitro capsaicin desensitization resulted in 72.8±10.3% inhibition, n=8; P<0.05). Activation of C-fiber nerve endings by pressure was attributable to stimulation of neuronal vanilloid receptor, TRPV1, because blockers of this channel, capsazepine (71.9±11.1% inhibition, n=9; P<0.001) and ruthenium red (46.1±11.7% inhibition, n=4; P<0.05), suppressed the myogenic constriction. In addition, this C-fiber dependency is likely related to neuropeptide substance P release and activity because blockade of tachykinin NK1 receptors (66.3±13.7% inhibition, n=6; P<0.001), and not NK2 receptors (n=4, NS), almost abolished the myogenic response. Previous studies support a role for 20-hydroxyeicosatetraenoic acid (20-HETE) in myogenic constriction responses; herein, we show that 20-HETE–induced constriction of mesenteric resistance arteries is blocked by capsazepine. Together, these results suggest that elevation of intraluminal pressure is associated with generation of 20-HETE that, in turn, activates TRPV1 on C-fiber nerve endings resulting in depolarization of nerves and consequent vasoactive neuropeptide release. These findings identify a novel mechanism contributing to Bayliss’ myogenic constriction and highlights an alternative pathway that may be targeted in the therapeutics of vascular disease, such as hypertension, where enhanced myogenic constriction plays a role in the pathogenesis.
Key Words: mechanotransduction • nonselective cation channels • cardiovascular physiology
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