Cyclic nucleotide-elevating agents increased the frequency of Ca2+ sparks and STOCs by two- to threefold in rat arterial myocytes, suggesting a mechanism for vasodilation.
Cyclic nucleotide-mediated vasodilation involves an increase in Ca2+ spark frequency, leading to increased STOC frequency, membrane hyperpolarization, and decreased arterial wall Ca2+.
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 Ca(2+)-sensitive K+ (KCa) 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 KCa channels, independent of effects on Ca2+ sparks. To test the hypothesis that cAMP could act to dilate arteries through activation of the Ca2+ spark-->KCa channel pathway, the effects of blockers of KCa 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.
Porter et al. (Fri,) reported a other. Forskolin, sodium nitroprusside, nicorandil, dibutyryl-cAMP, and adenosine was evaluated on Frequency of subcellular Ca2+ release (Ca2+ sparks) and spontaneous transient outward currents (STOCs). Cyclic nucleotide-elevating agents increased the frequency of Ca2+ sparks and STOCs by two- to threefold in rat arterial myocytes, suggesting a mechanism for vasodilation.