Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides.
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
V A
VA
Department of Pharmacology, University of Vermont, Colchester 05446, USA.
Bonev
A D
AD
Knot
H J
HJ
Heppner
T J
TJ
Stevenson
A S
AS
Kleppisch
T
T
Lederer
W J
WJ
Nelson
M T
MT
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004553:Electric Conductivity; D066298:In Vitro Techniques; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D009599:Nitroprusside / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000502:physiology*
D009712:Nucleotides, Cyclic; D015221:Potassium Channels; D014665:Vasodilator Agents; D009599:Nitroprusside; D005576:Colforsin; D009536:Niacinamide; D020108:Nicorandil; D002118:Calcium