title: Chronic nicotine alters NO signaling of Ca(2+) channels in cerebral arterioles.
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 Ca(2+) channels and Ca(2+)-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, Ca(2+) 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 Ca(2+) 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 Ca(2+) channel downregulation in NO-induced vasorelaxation. These findings elucidate a new pathophysiological mechanism involving altered Ca(2+) homeostasis in cerebral arterioles that may predispose to stroke.
authors.affiliation: Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA.
authors.forename: V
authors.initials: V
authors.lastname: Gerzanich
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: G A
authors.initials: GA
authors.lastname: West
authors.forename: J M
authors.initials: JM
authors.lastname: Simard
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D015221:Potassium Channels; D020032:Tyrphostins; D009599:Nitroprusside; D001464:Barium; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C038806:1,4-dihydropyridine; D006152:Cyclic GMP; D009543:Nifedipine; C060641:tyrphostin A23; D002118:Calcium