Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction.
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.
Scotland
Ramona S
RS
Wolfson Institute for Biomedical Research, College London, London, UK.
Chauhan
Sharmila
S
Davis
Clare
C
De Felipe
Carmen
C
Hunt
Stephen
S
Kabir
Jahangir
J
Kotsonis
Peter
P
Oh
Uhtaek
U
Ahluwalia
Amrita
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000502:physiology; D005682:Gadolinium / Q000494:pharmacology; D005728:Ganglia, Sympathetic / Q000187:drug effects; D006145:Guanethidine / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D008959:Models, Neurological; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011312:Pressure; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics; D012430:Ruthenium Red / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D013563:Sympathectomy, Chemical; D050916:TRPV Cation Channels; D013779:Tetrodotoxin / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D027682:Cation Transport Proteins; D006893:Hydroxyeicosatetraenoic Acids; D007473:Ion Channels; C107754:MEN 11420; D010456:Peptides, Cyclic; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D026941:Sodium Channel Blockers; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D012430:Ruthenium Red; C085215:SR 140333; D013779:Tetrodotoxin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D005682:Gadolinium; C071423:capsazepine; D002211:Capsaicin; D006145:Guanethidine