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. CONCLUSION: 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.