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(Circulation Research. 2001;88:359.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Chronic Nicotine Alters NO Signaling of Ca²⁺ Channels in Cerebral Arterioles

Volodymyr Gerzanich, Fangyi Zhang, G. Alexander West, J. Marc Simard

From the Departments of Neurosurgery (V.G., J.M.S.) and Physiology (J.M.S.), University of Maryland School of Medicine, Baltimore, Md; Division of Neurosurgery (F.Z.), University of Texas at San Antonio Health Science Center, San Antonio, Tex; and Department of Neurological Surgery (G.A.W.), University of Washington School of Medicine, Seattle, Wash.

Correspondence to Dr J. Marc Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201-1595. E-mail msimard{at}surgery1.umaryland.edu

Abstract—Smoking is a major health hazard with proven deleterious effects on the cerebral circulation, including a decrease in cerebral blood flow and a high risk for stroke. To elucidate cellular mechanisms for the vasoconstrictive and pathological effects of nicotine, we used a nystatin-perforated patch-clamp technique to study Ca²⁺ channels and Ca²⁺-activated K⁺ (BK) channels in smooth muscle cells isolated from cerebral lenticulostriate arterioles of rats chronically exposed to nicotine (4.5 mg/kg per day of nicotine free base, 15 to 22 days via osmotic minipump). Two major effects were observed in cells from nicotine-treated animals compared with controls. First, Ca²⁺ channels were upregulated (0.48±0.03 pS/pF [20 cells] versus 0.35±0.01 pS/pF [31 cells], P<0.005) and BK channels were downregulated (12±3 pA/pF [14 cells] versus 34±7 pA/pF [14 cells], P<0.05), mimicking the effect of an apparent decrease in bioavailability of endogenous NO. Second, normal downregulation of Ca²⁺ channels by exogenous NO (sodium nitroprusside [SNP], 100 nmol/L) and cGMP (8-bromo-cGMP, 0.1 mmol/L) was absent, whereas normal upregulation of BK channels by these agents was preserved, suggesting block of NO signaling downstream of cGMP-dependent protein kinase. In pial window preparations, chronic nicotine blunted NO-induced vasodilation of pial vessels and the increase in cortical blood flow measured by laser-Doppler flowmetry, demonstrating the importance of Ca²⁺ channel downregulation in NO-induced vasorelaxation. These findings elucidate a new pathophysiological mechanism involving altered Ca²⁺ homeostasis in cerebral arterioles that may predispose to stroke.

Key Words: Ca²⁺ channel • vascular smooth muscle • nicotine • nitric oxide • cerebral arteriole

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