Hypotension induced by activation of the transient receptor potential vanilloid 4 channels: role of Ca2+-activated K+ channels and sensory nerves.
OBJECTIVE
To examine the mechanisms involved in hypotension induced by transient receptor potential vanilloid 4 (TRPV4) activation.


METHODS
Wistar rats were given 50 mg/kg capsaicin subcutaneously 1-2 days postnatally to cause degeneration of capsaicin-sensitive sensory nerves. Vehicle was given to the corresponding newborn rats that formed the control group. After being weaned, male rats were picked for further investigation. At the age of 8 weeks, mean arterial pressure and its response to 4alpha-phorbol 12,13-didecanoate [4alpha-PDD, a selective TRPV4 activator, 2.5 mg/kg, intravenous(ly) or i.v.] with or without CGRP8-37 (1 mg/kg per min, i.v.), an antagonist of calcitonin gene-related peptide (CGRP, a potent vasodilator released from sensory nerves), in vehicle or capsaicin-pretreated rats anesthetized with sodium pentobarbital [50 mg/kg, intraperitoneal(ly)] were monitored to observe the contributions of neuropeptides released from sensory nerves to the 4alpha-PDD-induced hypotension. To detect the roles of various vasodilating factors released by vascular endothelium in the hypotensive effect induced by TRPV4 activation, the corresponding inhibitors/blockers, including indomethacin (a cyclooxygenase inhibitor, 10 mg/kg, i.v.), Nomega-nitro-L-arginine (L-NA, a nitric oxide synthase inhibitor, 20 mg/kg, i.v.), apamin [a blocker of small conductance Ca2+-activated K+ (MaxiK) channels, 50 microg/kg, i.v.] combined with charybdotoxin (a blocker of intermediate and large conductance MaxiK channels, 50 microg/kg, i.v.), were used at various time before 4alpha-PDD injection. Plasma CGRP and substance P levels of rats before or after administration were measured using the corresponding radioimmunoassays. At last, immunohistochemistry stainings were performed to observe expression of TRPV4/CGRP/MaxiK in mesenteric resistance arteries and sensory neurons/nerve fibers.


RESULTS
Intravenous administration of 4alpha-PDD produced remarkable hypotension in vehicle-pretreated rats. The depressor effect was attenuated by degeneration of capsaicin-sensitive sensory nerves (P < 0.05) or administration of CGRP8-37 (P < 0.05). In both vehicle and capsaicin-pretreated rats, the combined administration of apamin and charybdotoxin markedly reduced the 4alpha-PDD-induced hypotensive effect (P < 0.05), but i.v. administration of indomethacin and Nomega-nitro-L-arginine did not produce the similar effect. Intravenous administration of 4alpha PDD increased plasma CGRP but not substance P levels in vehicle-pretreated rats only (P < 0.05), which was not affected by indomethacin, Nomega-nitro-L-arginine, or apamin and charybdotoxin. Immunohistochemistry staining showed that TRPV4 colocalized with MaxiK channels in endothelium of mesenteric resistance arteries and with CGRP in sensory neurons/nerve fibers.


CONCLUSIONS
Our data show that the hypotensive effect induced by TRPV4 activation attributes to, at least in part, activation of MaxiK channels and CGRP receptors upon CGRP release from sensory nerves.
Gao
Feng
F
Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, Michigan, USA.
Wang
Donna H
DH
D000818:Animals; D000831:Animals, Newborn; D001030:Apamin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018689:Sensory System Agents / Q000494:pharmacology; D013373:Substance P / Q000097:blood; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D004338:Drug Combinations; D010446:Peptide Fragments; D010703:Phorbol Esters; D024681:Potassium Channels, Calcium-Activated; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D014665:Vasodilator Agents; D018999:Charybdotoxin; C058636:calcitonin gene-related peptide (8-37); D001030:Apamin; C008876:phorbol-12,13-didecanoate; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin