Abstract: | Forskolin, which elevates cAMP levels, and sodium nitroprusside(SNP) and nicorandil, which elevate cGMP levels, increased, by two- tothreefold, the frequency of subcellularCa2+ release("Ca2+ sparks") throughryanodine-sensitive Ca2+ release(RyR) channels in the sarcoplasmic reticulum (SR) of myocytes isolatedfrom cerebral and coronary arteries of rats. Forskolin, SNP,nicorandil, dibutyryl-cAMP, and adenosine increased the frequency ofCa2+-sensitiveK+(KCa) currents"spontaneous transient outward currents" (STOCs)] bytwo- to threefold, consistent withCa2+ sparks activating STOCs.These agents also increased the mean amplitude of STOCs by 1.3-fold, aneffect that could be explained by activation ofKCa channels, independent ofeffects on Ca2+ sparks. To testthe hypothesis that cAMP could act to dilate arteries throughactivation of the Ca2+sparkKCa channel pathway,the effects of blockers of KCachannels (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 externalK+. Forskolin lowered averageCa2+ in pressurized arteries whileincreasing ryanodine-sensitive, caffeine-inducedCa2+ transients. These experimentssuggest a new mechanism for cyclic nucleotide-mediated dilationsthrough an increase in Ca2+ sparkfrequency, caused by effects on SRCa2+ load and possibly on the RyRchannel, which leads to increased STOC frequency, membrane potentialhyperpolarization, closure of voltage-dependentCa2+ channels, decrease inarterial wall Ca2+, and,ultimately, vasodilation. |