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Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Department of Physiology, University of Tennessee Health Science Center, Memphis Tennessee (A.A., J.H.J.); and Department of Medicine, University of Chicago, Chicago, Illinois (E.M.M.)

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 (SUR) 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 voltage-gated K⁺ (K_V) channel blocker; manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP; 100 µM), an antioxidant; and a combination of ryanodine and 4-AP reduced diazoxide (100 µM)-induced dilation in pressurized (60 mm Hg) SUR2(+/+) arteries by 45 to 77%. In contrast, these inhibitors did not alter pinacidil (5 µM)-induced dilation in SUR2(+/+) arteries. Reverse transcription-polymerase chain reaction 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 (ETC) complex 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.

Address correspondence to: Dr. Jonathan H. Jaggar, Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue Memphis TN 38163. E-mail: jjaggar{at}physio1.utmem.edu