Spontaneous Coronary Vasospasm in K _ATP Mutant Mice Arises From a Smooth Muscle–Extrinsic Process

Abstract

Abstract-In the vasculature, ATP-sensitive potassium channels (K ATP ) channels regulate vascular tone. Mice with targeted gene disruptions of K ATP subunits expressed in vascular smooth muscle develop spontaneous coronary vascular spasm and sudden death. From these models, it was hypothesized that the loss of K ATP channel activity in arterial vascular smooth muscle was responsible for coronary artery spasm. We now tested this hypothesis using a transgenic strategy where the full-length sulfonylurea receptor containing exon 40 was expressed under the control of a smooth muscle-specific SM22␣ promoter. Two transgenic founder lines were generated and independently bred to sulfonylurea receptor 2 (SUR2) null mice to generate mice that restored expression of K ATP channels in vascular smooth muscle. Transgenic expression of the sulfonylurea receptor in vascular smooth muscle cells was confirmed by detecting mRNA and protein from the transgene. Functional restoration was determined by recording pinacidil-based K ATP current by whole cell voltage clamping of isolated aortic vascular smooth muscle cells isolated from the transgenic restored mice. Despite successful restoration of K ATP channels in vascular smooth muscle, transgene-restored SUR2 null mice continued to display frequent episodes of spontaneous ST segment elevation, identical to the phenotype seen in SUR2 null mice. As in SUR2 null mice, ST segment elevation was frequently followed by atrioventricular heart block. ST segment elevation and coronary perfusion pressure in the restored mice did not differ significantly between transgene-negative and transgene-positive SUR2 null mice. We conclude that spontaneous coronary vasospasm and sudden death in SUR2 null mice arises from a coronary artery vascular smooth muscle-extrinsic process.

Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity

“…7B, Lanes 1&2). This data was consistent with previous observations that glibenclamide-sensitive I KATP was absent in both mutant ventricular myocytes [14] and vascular smooth muscle cells [15]. However, BNJ-39 and BN-40 detected the SUR2 short forms in the mutant heart tissues (Fig.…”

“…The glibenclamide effect is expected to be altered in the mutant. Earlier characterizations at the nucleic acid level suggest that the disruption cassette is present in SUR2, which is confirmed by the loss of the conventional glibenclamide-sensitive K ATP currents (I KATP ) in isolated cardiomyocytes [14] and vascular smooth muscle cells [15]. This mouse was thought to be a SUR2 null mouse based on lines of functional data.…”

“…In the SUR2 mutant mouse with a disrupted NBD1, the conventional glibenclamide-sensitive I KATP was previously reported to be absent in both ventricular myocytes [14] and vascular smooth muscle cells [15]. Single channel recordings in the ventricular myocytes isolated from the SUR2 mutant hearts, however, recorded a non-conventional K + current (designated as I KATPn , Fig.…”

Mechanistic Insights of Coronary Vasospasm and New Therapeutic Approaches

“…48) They tested the role of the K -NDP channel in spontaneous coronary vasospasm using the transgenic mice that harbored the K -NDP channel in only vascular smooth muscle cells but not any other cells. They observed not only protein expression but also the restoration of the functional K -NDP channel in the smooth muscle cells.…”

Verdict in the Smooth Muscle K ATP Channel Case

“…Surprisingly, however, when SUR2B is selectively returned to smooth muscle in SUR null mice, to restore smooth muscle K ATP channels, spontaneous coronary vasospasm persists. 6 The phenotype is only rescued when cardiac K ATP channels are restored, 7 suggesting that K ATP channels outside of smooth muscle exert considerable influence over vascular contractility and undermining the central role of smooth muscle K ATP channels in the regulation of vascular tone in the whole animal.…”