This Article Full Text Full Text (PDF) All Versions of this Article: 98/5/682    most recent 01.RES.0000207498.40005.e7v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kakkar, R. Articles by McNally, E. M. Search for Related Content PubMed PubMed Citation Articles by Kakkar, R. Articles by McNally, E. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Arrythmias-basic studies Other Vascular biology Related Article

(Circulation Research. 2006;98:682.)
© 2006 American Heart Association, Inc.

Cellular Biology

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

Rahul Kakkar, Bin Ye, Douglas A. Stoller, Matthew Smelley, Nian-Qing Shi, Kevin Galles, Michele Hadhazy, Jonathan C. Makielski, Elizabeth M. McNally

From the Department of Medicine (R.K., M.S., M.H., E.M.M.) and Committee on Cell Physiology (D.A.S.), The University of Chicago, Ill; and the Department of Medicine (B.Y., N.-Q.S., K.G., J.C.M.), University of Wisconsin, Madison.

Correspondence to Elizabeth M. McNally, MD, PhD, The University of Chicago, 5841 S Maryland, MC6088, Chicago, IL 60637. E-mail emcnally{at}medicine.bsd.uchicago.edu

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.

Key Words: K_ATP channel • sulfonylurea receptor • vasospasm • smooth muscle

Related Article:

A New Insight Into the Pathogenesis of Coronary Vasospasm

Hiroshi Hibino and Yoshihisa Kurachi
Circ. Res. 2006 98: 579-581. [Full Text] [PDF]

This article has been cited by other articles:

				A. Adebiyi, E. M. McNally, and J. H. Jaggar Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K+ Channel Openers Mol. Pharmacol., September 1, 2008; 74(3): 736 - 743. [Abstract] [Full Text] [PDF]

				T. Farzaneh and A. Tinker Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits Cardiovasc Res, September 1, 2008; 79(4): 621 - 631. [Abstract] [Full Text] [PDF]

				C. J. Pepine Provoked Coronary Spasm and Acute Coronary Syndromes J. Am. Coll. Cardiol., August 12, 2008; 52(7): 528 - 530. [Full Text] [PDF]

				M. A. Burke, R. K. Mutharasan, and H. Ardehali The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel Circ. Res., February 1, 2008; 102(2): 164 - 176. [Abstract] [Full Text] [PDF]

				P. P. Dzeja, P. Bast, D. Pucar, B. Wieringa, and A. Terzic Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow J. Biol. Chem., October 26, 2007; 282(43): 31366 - 31372. [Abstract] [Full Text] [PDF]

				B. Malester, X. Tong, I. Ghiu, A. Kontogeorgis, D. E. Gutstein, J. Xu, K. D. Hendricks-Munoz, and W. A. Coetzee Transgenic expression of a dominant negative KATP channel subunit in the mouse endothelium: effects on coronary flow and endothelin-1 secretion FASEB J, July 1, 2007; 21(9): 2162 - 2172. [Abstract] [Full Text] [PDF]

				W. Shi, N. Cui, Y. Shi, X. Zhang, Y. Yang, and C. Jiang Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R191 - R199. [Abstract] [Full Text] [PDF]

				A. Jawaid, T. ur Rehman, and D. K. Rohra Regulation of Human Coronary Vascular Tone: Further Evidence Must Be Sought Before Ruling Out the Direct Role of ATP-Sensitive Potassium Channels in Regulation of Coronary Vasculature Circ. Res., May 26, 2006; 98(10): e73 - e73. [Full Text] [PDF]

				H. Hibino and Y. Kurachi A New Insight Into the Pathogenesis of Coronary Vasospasm Circ. Res., March 17, 2006; 98(5): 579 - 581. [Full Text] [PDF]