Effect of omega-conotoxin GVIA and omega-agatoxin IVA on the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial arteries

This study assesses the effect of neuronal voltage-sensitive Ca2+ channel b lockers, omega-conotoxin GVIA (CTX), and omega-agatoxin IVA (AgTX) on the v asodilation and release of calcitonin gene-related peptide (CGRP), both of which were induced by either application of capsaicin or acute stepwise hyp otension. Changes in pial arterial diameter were determined directly throug h a closed cranial window. The vasodilation of pial artery induced by eithe r CGRP (0.1 mu mol/L) or capsaicin (0.3 mu mol/L) was significantly inhibit ed by CGRP(8-37) (0.1 mu mol/L) (P < 0.05 and P < 0.05, respectively). The autoregulatory vasodilation to acute stepwise hypotension was severely atte nuated by pretreatment with either CTX or AgTX. When the hypotension was ke pt for 2, 4, and 10 minutes, the releasable CGRP-like immunoreactivity (CGR P-LI) level (vehicle, 13.4 +/- 1.5 fmol/mm(2)/30 min) by 10 mu mol/L capsai cin from the isolated pial arteries was significantly reduced in the 4- and 10-minute hypotension groups (11.3 +/- 1.2 fmol/mm(2)/30 min, P < 0.05, an d 11.1 +/- 1.5 fmol/mm(2)/30 min, P < 0.05, respectively), but not in 2-min group. Moreover, the CGRP-LI level released by 10 mu mol/L capsaicin (13.7 +/- 0.9 fmol/mm(2)/30 min) also was significantly depressed by pretreatmen t with 1 mu mol/L CTX to 10.4 +/- 1.0 fmol/mm(2)/30 min (P < 0.01) and with 0.1 mu mol/L AgTX to 8.7 (1.7 fmol/mm(2)/30 min (P < 0.001), as well as by pretreatment with 10 mu mol/L capsaicin (6.0 +/- 1.6 fmol/mm(2)/30 min, P < 0.001). These results suggest that the neuronal N- and P-type voltage-sen sitive Ca2+ channels are implicated in the release of CGRP from capsaicin-s ensitive perivascular sensory nerves in response to acute hypotension, and that the released CGRP may contribute to the autoregulatory vasodilation in the cerebral microcirculation.