Direct Stimulation of K_ATP Channels by Exogenous and Endogenous Hydrogen Sulfide in Vascular Smooth Muscle Cells

Abstract

ATP-sensitive K+ (K(ATP)) channels in vascular smooth muscle cells (VSMC) are important targets for endogenous metabolic regulation and exogenous drug therapy. H2S, as a novel gasotransmitter, has been shown to relax rat aortic tissues via opening of K(ATP) channels. However, interaction of H2S, exogenous-applied or endogenous-produced, with K(ATP) channels in resistance artery VSMC has not been delineated. In the present study, using the whole-cell and single-channel patch-clamp technique, we demonstrated that exogenous H2S activated K(ATP) channels and hyperpolarized cell membrane in rat mesenteric artery VSMC. H2S enhanced the amplitude of whole-cell K(ATP) currents with an EC50 value of 116 +/- 8.3 microM and increased the open probability of single K(ATP) channels. H2S hyperpolarized membrane potentials by -12 mV in nystatin-perforated VSMC. Furthermore, inhibition of endogenous H2S production with D,L-propargylglycine (PPG) reduced whole-cell K(ATP) currents. PPG alone had no effect on unitary K(ATP) channel currents in cell-free membrane patches. In addition, effects of H2S on K(ATP) channels and membrane potentials were independent of cGMP-mediated phosphorylation. This study demonstrated modulation of K(ATP) channel activity by exogenous and endogenous H2S in resistance artery VSMC, thus helping elucidate cardiovascular functions of this endogenous gas.

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

“…11 PPG is a specific inhibitor of CSE. 3,17 Interestingly, in the presence of PPG that inhibited endogenous H 2 S production or with high glucose to inhibit K ATP channel activities in INS-1E cells, exogenous H 2 S at concentrations equal to or lower than 100 mM significantly increased K ATP channel currents. These results suggest that the functions of K ATP channels in INS-1E cells are related to endogenous H 2 S metabolism.…”

“…17 Recording electrodes were pulled from soft microhematocrit capillary tubes (Fisher Scientific, Nepean, ON) with tip resistance of 2-4 MO when filled with the pipette solution. Currents were recorded with an Axopatch 200-B amplifier (Axon Instruments), controlled by a Digidata 1200 interface and pCLAMP software (version 6.0, Axon Instruments).…”

“…11 Among demonstrated cellular and molecular mechanisms for physiological effects of H 2 S are the activation of K ATP channels by H 2 S. In vascular smooth muscle cells, exogenous and endogenous H 2 S activated K ATP channels at whole-cell and single channel levels. 16,17 It is reasoned that H 2 S would also affect other excitable cells that have functional K ATP channels. Pancreatic b-cells are among these cells and our earlier study in fact demonstrated the activation of K ATP channels in an insulin-secreting cell line, INS-1E, by H 2 S. 11 The K ATP channel-dependent effect of H 2 S on insulin release has also been shown in another insulin-secreting cell line, HIT-T15.…”

Case files of the university of cincinnati fellowship in medical toxicology: Two patients with acute lethal occupational exposure to hydrogen sulfide

“…Endogenous hydrogen sulfide induces vasorelaxation via ATPsensitive K + channels [30,33]. How this system interacts with exogenous hydrogen sulfide, however, is unknown.…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…Endogenous H 2 S could modulate proteins by converting the -SH group of cysteine to an -SSH group (81,133). The K ATP channel reported elsewhere to be mechanosensitive (23,27) is regulated by H 2 S (83,121,144). Besides the K ATP channel, other channels including L-and T-type Ca + + channel, TRPA/ V channels, Cl -channels, and so on, are also subjected to the modulation of H 2 S (90,122).…”