NO-mediated MaxiK(Ca) channel activation produces relaxation of guinea pig aorta independently of voltage-dependent L-type Ca(2+) channels.

The role of L-type Ca(2+) channels in the relaxation to nitric oxide (NO)-mediated MaxiK(Ca) channel activation was examined in guinea pig aorta. 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). 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. ACh- and NOR3-induced relaxations were significantly suppressed by iberiotoxin (IbTX), a selective blocker of MaxiK(Ca) channels. 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 Ca(2+) channel blocker, diltiazem. Furthermore, endothelium-independent relaxation by a K(ATP) channel opener, (+)-7,8-dihydro-6, 6-dimethyl-7-hydroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano[2,3-f] benz-2,1, 3-oxadiazole (NIP-121) was not affected by diltiazem and nicardipine. These findings suggest that blockade of L-type Ca(2+) channels is not a major mechanism responsible for the vascular relaxation due to NO-mediated MaxiK(Ca) channel activation in guinea pig aorta.