NO-mediated MaxiKCa channel activation produces relaxation of guinea pig aorta independently of voltage-dependent L-type Ca2+ channels

(1) The role of L-type Ca²⁺ channels in the relaxation to nitric oxide (NO)-mediated MaxiK_Ca channel activation was examined in guinea pig aorta. (2) Acetylcholine (ACh) produced an endothelium-dependent relaxation of guinea pig aorta precontracted with noradrenaline (NA), which was abolished by an NO synthase inhibitor, N^G-nitro-l-arginine (l-NNA). (3) Both endothelium-dependent relaxation by ACh and endothelium-independent relaxation by an NO donor, (±)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (NOR3), were strongly suppressed by a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), suggesting that increased intracellular cGMP plays the key role in both responses. (4) ACh- and NOR3-induced relaxations were significantly suppressed by iberiotoxin (IbTX), a selective blocker of MaxiK_Ca channels. (5) ACh- and NOR3-induced relaxations were greatly attenuated when arteries were precontracted with high KCl instead of NA, supporting the idea that K⁺ channel activation mediates the relaxant responses. (6) NOR3-induced relaxations were not affected by a L-type Ca²⁺ channel blocker, diltiazem. Furthermore, endothelium-independent relaxation by a K_ATP channel opener, (+)-7,8-dihydro-6,6-dimethyl-7-hyroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole (NIP-121) was not affected by diltiazem and nicardipine. (7) These findings suggest that blockade of L-type Ca²⁺ channels is not a major mechanism responsible for the vascular relaxation due to NO-mediated MaxiK_Ca channel activation in guinea pig aorta.