Membrane depolarization, elevated Ca(2+) entry, and gene expression in cerebral arteries of hypertensive rats.
Elevated intracellular Ca(2+) ([Ca(2+)](i)) has been implicated in contractile and phenotypic changes in arterial smooth muscle during hypertension. This study examined the role of membrane potential and [Ca(2+)](i) in altered gene expression in cerebral arteries of a rat (Dahl) genetic model of salt-sensitive hypertension. Cerebral arteries from hypertensive animals (Dahl salt-sensitive) exhibited a tonic membrane depolarization of approximately 15 mV compared with normotensive (Dahl salt-resistant) animals. Consistent with this membrane depolarization, voltage-dependent K(+) currents were decreased in cerebral artery myocytes isolated from hypertensive animals. Arterial wall Ca(2+) was elevated in cerebral arteries from hypertensive animals, an effect reversed by diltiazem, a blocker of voltage-dependent Ca(2+) channels. This depolarization-induced increase in [Ca(2+)](i) was associated with increased activation of the transcription factor, cAMP response element binding protein, and increased expression of the immediate early gene c-fos, both of which are reversed by acute exposure to the voltage-dependent Ca(2+) channel blocker nisoldipine. This study provides the first information linking altered Ca(2+) handling to changes in gene expression in cerebral arteries during hypertension.
Wellman
G C
GC
Department of Pharmacology, The University of Vermont College of Medicine, Burlington, Vermont 05405, USA. gwellman@zoo.uvm.edu
Cartin
L
L
Eckman
D M
DM
Stevenson
A S
AS
Saundry
C M
CM
Lederer
W J
WJ
Nelson
M T
MT
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002536:Cerebral Arteries / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D015737:Nisoldipine / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D020303:Rats, Inbred Dahl
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D024642:Potassium Channels, Voltage-Gated; D016760:Proto-Oncogene Proteins c-fos; D015737:Nisoldipine; D002118:Calcium