Received for publication April 23, 2008.
Revised May 28, 2008.
Accepted for publication May 29, 2008.

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by K_ATP Channel Openers

Abstract

ATP-sensitive K⁺ (K_ATP) channel openers are vasodilators that activate both plasma membrane and mitochondrial K_ATP channels. Here, we investigated the molecular mechanisms by which diazoxide and pinacidil induce vasodilation by studying diameter regulation of wild-type (SUR2^+/+) and sulfonylurea receptor 2 deficient (SUR2^-/-) mouse myogenic mesenteric arteries. Ryanodine (10 µM), a ryanodine-sensitive Ca²⁺ release (RyR) channel blocker, iberiotoxin (100 nM), a large-conductance Ca²⁺-activated K⁺ (K_Ca) channel blocker, 4-aminopyridine (4-AP, 1 mM), a K_v channel blocker, MnTMPyP (100 µM), an antioxidant, and a combination of ryanodine and 4-AP reduced diazoxide (100 µM)-induced dilation in pressurized (60 mmHg) SUR2^+/+ arteries by 45-77 %. In contrast, these inhibitors did not alter pinacidil (5 µM)-induced dilation in SUR2^+/+ arteries. RT-PCR indicated that SUR2B was the only SUR isoform expressed in SUR2^+/+ mesenteric artery smooth muscle cells, whereas SURs were absent in SUR2^-/- cells. In SUR2^-/- arteries, pinacidil-induced vasodilation was ~10 % of that in SUR2^+/+ arteries, whereas diazoxide-induced vasodilation was similar in SUR2^+/+ and SUR2^-/- arteries. Atpenin (1 µM), a selective electron transport chain complex II (ETC_II) inhibitor, dilated arteries similarly to diazoxide and this effect was attenuated by MnTMPyP and ryanodine + 4-AP. Atpenin also attenuated diazoxide-, but not pinacidil-induced vasodilation. In summary, data indicate that pinacidil-induced vasodilation requires SUR2B, whereas diazoxide-induced vasodilation does not require SURs. Rather diazoxide-induced vasodilation involves ETC_II inhibition, a smooth muscle cell reactive oxygen species elevation, and RyR, K_Ca, and K_v channel activation. These data indicate that K_ATP channel openers regulate arterial diameter via SUR-dependent and -independent pathways.

Key words: Ion channel regulation, Knockout