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1 Department of Pharmacology, University of Vermont, Colchester, Vermont 05446; and 2 Department of Physiology and The Medical Biotechnology Center, University of Maryland School of Medicine, Baltimore, Maryland 21201
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+
(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.
cAMP; cGMP; vasodilation; sarcoplasmic reticulum; KCa channels
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