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

May 31, 2008Molecular pharmacology

Vasodilation caused by ATP-sensitive potassium channel openers involves pathways both dependent and independent of sulfonylurea receptors

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Abstract

Diazoxide-induced vasodilation in mouse arteries was reduced by 45 to 77% with specific channel blockers.

Ryanodine, iberiotoxin, and 4-aminopyridine significantly diminished diazoxide-induced dilation in wild-type arteries.
Pinacidil-induced vasodilation was not affected by the same channel blockers in wild-type arteries.
SUR2B was identified as the only sulfonylurea receptor isoform present in wild-type mesenteric artery smooth muscle cells.
Pinacidil-induced vasodilation in SUR2-deficient arteries was only 10% of that observed in wild-type arteries.
Diazoxide-induced vasodilation was similar in both wild-type and SUR2-deficient arteries.
Diazoxide-induced vasodilation may involve electron transport chain complex II inhibition and activation of several ion channels.

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ATP-sensitive K+ (KATP) channel openers are vasodilators that activate both plasma membrane and mitochondrial KATP 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 microM), a ryanodine-sensitive Ca2+ release (RyR) channel blocker; iberiotoxin (100 nM), a large-conductance Ca2+-activated K+ (KCa) channel blocker; 4-aminopyridine (4-AP; 1 mM), a voltage-gated K+ (KV) channel blocker; manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP; 100 microM), an antioxidant; and a combination of ryanodine and 4-AP reduced diazoxide (100 microM)-induced dilation in pressurized (60 mm Hg) SUR2(+/+) arteries by 45 to 77%. In contrast, these inhibitors did not alter pinacidil (5 microM)-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 microM), 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 ETCII inhibition; a smooth muscle cell-reactive oxygen species elevation; and RyR, KCa, and KV channel activation. These data indicate that KATP channel openers regulate arterial diameter via SUR-dependent and -independent pathways.

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

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