Frequency modulation of ca2+ sparks is involved in regulation of
arterial diameter by cyclic nucleotides.
Porter, Valerie A., Adrian D. Bonev, Harm J. Knot, Thomas J. Heppner,
Andra S. Stevenson, Thomas Kleppisch, W. J. Lederer, Mark T. Nelson.
Department of Pharmacology, 55A South Park Drive, University of
Vermont, Colchester, Vermont 05446. Department of Physiology and The
Medical Biotechnology Center 660 W. Redwood St. 519 Howard Hall,
University of Maryland School of Medicine, Baltimore MD 21201
APStracts 5:0014C, 1998.
Forskolin, which elevates cAMP levels, and sodium nitroprusside (SNP)
and nicorandil, which elevate cGMP levels, increased, by 2-3 fold,
the frequency of subcellular calcium release ("Ca2+ sparks")
through ryanodine-sensitive Ca2+ release (RyR) channels in the
sarcoplasmic reticulum (SR) of myocytes isolated from cerebral and
coronary arteries of rat. Forskolin, SNP, nicorandil, dibutryl-cAMP,
and adenosine increased the frequency of calcium-sensitive potassium
(KCa) currents ("Spontaneous Transient Outward Currents" or
"STOCs") by 2-3 fold, consistent with calcium 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 calcium sparks. To test the
hypothesis that cAMP could act to dilate arteries through activation
of 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 entirely prevented by
elevating external potassium. Forskolin lowered average Ca2+ in
pressurized arteries, while increasing ryanodine-sensitive,the
caffeine-induced calcium transients. These experiments suggest a new
mechanism for cyclic nucleotide mediated dilations through an
increase in Ca2+ spark frequency,, caused by effects on SR calcium
load and possibly on the RyR channel, which leads to increased STOC
frequency, membrane potential hyperpolarization, closure of voltage
-dependent calcium channels, decrease in arterial wall calcium and
ultimately vasodilation.
Received 9 September 1997; accepted in final form 13 January
1998.
APS Manuscript Number C466-7.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 28 January 1998