HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal KATP channels

Hai Xia Zhang, Alejandro Akrouh, Harley T. Kurata, Maria Sara Remedi, Jennifer S. Lawton, Colin G. Nichols

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Murine ventricular and atrial ATP-sensitive potassium (KATP) channels contain different sulfonylurea receptors (ventricular KATP channels are Kir6.2/SUR2A complexes, while atrial KATP channels are Kir6.2/SUR1 complexes). HMR 1098, the sodium salt of HMR 1883 {1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea}, has been considered as a selective sarcolemmal (i.e. SUR2A-dependent) KATP channel inhibitor. However, it is not clear whether HMR 1098 would preferentially inhibit ventricular KATP channels over atrial KATP channels. To test this, we used whole-cell patch clamp techniques on mouse atrial and ventricular myocytes as well as 86Rb+ efflux assays and excised inside-out patch clamp techniques on Kir6.2/SUR1 and Kir6.2/SUR2A channels heterologously expressed in COSm6 cells. In mouse atrial myocytes, both spontaneously activated and diazoxide-activated KATP currents were effectively inhibited by 10μM HMR 1098. By contrast, in ventricular myocytes, pinacidil-activated KATP currents were inhibited by HMR 1098 at a high concentration (100μM) but not at a low concentration (10μM). Consistent with this finding, HMR 1098 inhibits 86Rb+ effluxes through Kir6.2/SUR1 more effectively than Kir6.2/SUR2A channels in COSm6 cells. In excised inside-out patches, HMR 1098 inhibited Kir6.2/SUR1 channels more effectively, particularly in the presence of MgADP and MgATP (mimicking physiological stimulation). Finally, dose-dependent enhancement of insulin secretion from pancreatic islets and decrease of blood glucose level confirm that HMR 1098 is an inhibitor of Kir6.2/SUR1-composed KATP channels.

Original languageEnglish
Pages (from-to)552-560
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Cardiomyocyte
  • Insulin
  • Nucleotide
  • Patch clamp
  • Sulfonylurea

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