Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides

Mark Nelson, Valerie A. Porter, Adrian D. Bonev, Harm J. Knot, Thomas J. Heppner, Andra S. Stevenson, Thomas Kleppisch, W. J. Lederer, Mark T. Nelson

    Research output: Contribution to journalArticlepeer-review


    Forskolin, which elevates cAMP levels, and sodium nitroprusside (SNP) and nicorandil, which elevate cGMP levels, increased, by two- to threefold, the frequency of subcellular Ca2+ release ('Ca2+ sparks') through ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR) of myocytes isolated from cerebral and coronary arteries of rats. Forskolin, SNP, nicorandil, dibutyryl-cAMP, and adenosine increased the frequency of Ca2+-sensitive K+ (K(Ca)) currents '(spontaneous transient outward currents' (STOCs)] by two- to threefold, consistent with Ca2+ sparks activating STOCs. These agents also increased the mean amplitude of STOCs by 1.3-fold, an effect that could be explained by activation of K(Ca) channels, independent of effects on Ca2+ sparks. To test the hypothesis that cAMP could act to dilate arteries through activation of the Ca2+ spark-K(Ca) channel pathway, the effects of blockers of K(Ca) channels (iberiotoxin) and of Ca2+ sparks (ryanodine) on forskolin-induced dilations of pressurized cerebral arteries were examined. Forskolin-induced dilations were partially inhibited by iberiotoxin and ryanodine (with no additive effects) and were entirely prevented by elevating external K+. Forskolin lowered average Ca2+ in pressurized arteries while increasing ryanodine- sensitive, caffeine-induced Ca2+ transients. These experiments suggest a new mechanism for cyclic nucleotide-mediated dilations through an increase in Ca2+ spark frequency, caused by effects on SR Ca2+ load and possibly on the RyR channel, which leads to increased STOC frequency, membrane potential hyperpolarization, closure of voltage-dependent Ca2+ channels, decrease in arterial wall Ca2+, and, ultimately, vasodilation.
    Original languageEnglish
    Pages (from-to)C1346-C1355
    JournalAmerican Journal of Physiology: Cell Physiology
    Issue number5
    Publication statusPublished - May 1998


    • cAMP
    • cGMP
    • K(Ca) channels
    • Sarcoplasmic reticulum
    • Vasodilation


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