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Volume 272, Number 51, Issue of December 19, 1997
pp. 32240-32246
(Received for publication, August 4, 1997, and in revised form, September 23, 1997)
From the Earlier experiments with animal and human
arteries have shown that farnesol, a natural 15-carbon
(C15) isoprenoid, is an inhibitor of vasoconstriction
(Roullet, J.-B., Xue, H., Chapman, J., McDougal, P., Roullet, C. M., and McCarron, D. A. (1996) J. Clin. Invest. 97, 2384-2390). We report here that farnesol reduced KCl- and norepinephrine-dependent cytosolic Ca2+ transients
in fura-2-loaded intact arteries. An effect on Ca2+
signaling was also observed in cultured aortic smooth muscle cells (A10
cells). In these cells, farnesol reduced KCl-induced [Ca2+]i transients and mimicked the inhibitory
effect of Ca2+-free medium on the
[Ca2+]i response to both 12,13-phorbol myristate
acetate, a protein kinase C activator, and thapsigargin, a specific
endoplasmic reticulum ATPase inhibitor. Perforated patch-clamp
experiments further showed in two vascular smooth muscle cell lines
(A10 and A7r5), a reversible, dose-dependent inhibitory
effect of farnesol on L-type Ca2+ currents
(IC50 = 2.2 µM). Shorter (C10,
geraniol) and longer (C20, geranylgeraniol) isoprenols were
inactive. L-type Ca2+ channel blockade also occurred under
tight (gigaohm) seal configuration using cell-attached, single-channel
analysis, thus suggesting a possible action of farnesol from within the
intracellular space. We finally demonstrated that farnesol did not
affect Ca2+-sensitive pathways implicated in smooth muscle
contraction, as tested with
Farnesol Inhibits L-type Ca2+ Channels in Vascular
Smooth Muscle Cells
,
,
,
,
,
Department of Nephrology, Hypertension and
Clinical Pharmacology, Oregon Sciences Health University,
Portland, Oregon 97201 and the ¶ Franz Volhard Klinic, Max
Delbrück Center,
13122 Berlin, Federal Republic of Germany
-toxin permeabilized arteries.
Altogether, our results indicate that farnesol is an inhibitor of
vascular smooth muscle Ca2+ signaling with plasma membrane
Ca2+ channel blocker properties. The data have implications
for the endogenous and pharmacological regulation of vascular tone by farnesol or farnesol analogues.
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