4.6 Article

Intermittent hypoxia in rats reduces activation of Ca2+ sparks in mesenteric arteries

Journal

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00179.2015

Keywords

myogenic tone; ryanodine receptors; sleep apnea; vascular smooth muscle; endothelium

Funding

  1. American Heart Association [HL7736, 10PRE4050028, 12POST8690008, HL088151, HL95640, HL82799, HL123301]

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Ca+ sparks are vascular smooth muscle cell (VSMC) Ca2+-release events that are mediated by ryanodine receptors (RyR) and promote vasodilation by activating large-conductance Ca2+-activated potassium channels and inhibiting myogenic tone. We have previously reported that exposing rats to intermittent hypoxia (IH) to simulate sleep apnea augments myogenic tone in mesenteric arteries through loss of hydrogen sulfide (H2S)-induced dilation. Because we also observed that H2S can increase Ca2+ spark activity, we hypothesized that loss of H2S after IH exposure reduces Ca2+ spark activity and that blocking Ca2+ spark generation reduces H2S-induced dilation. Ca2+ spark activity was lower in VSMC of arteries from IH compared with sham-exposed rats. Furthermore, depolarizing VSMC by increasing luminal pressure (from 20 to 100 mmHg) or by elevating extracellular [K+] increased spark activity in VSMC of arteries from sham rats but had no effect in arteries from IH rats. Inhibiting endogenous H2S production in sham arteries prevented these increases. NaHS or phosphodiesterase inhibition increased spark activity to the same extent in sham and IH arteries. Depolarization-induced increases in Ca2+ spark activity were due to increased sparks per site, whereas H2S increases in spark activity were due to increased spark sites per cell. Finally, inhibiting Ca2+ spark activity with ryanodine (10 mu M) enhanced myogenic tone in arteries from sham but not IH rats and blocked dilation to exogenous H2S in arteries from both sham and IH rats. Our results suggest that H2S regulates RyR activation and that H2S-induced dilation requires Ca2+ spark activation. IH exposure decreases endogenous H2S-dependent Ca2+ spark activation to cause membrane depolarization and enhance myogenic tone in mesenteric arteries.

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