title: Chronic deficit in nitric oxide elicits oxidative stress and augments T-type calcium-channel contribution to vascular tone of rodent arteries and arterioles.
abstract: OBJECTIVE
  As cardiovascular disease is characterized by reduced nitric oxide bioavailability, our aim was to determine the impact of this change on the mechanism underlying vascular tone of pressurized arteries in vitro and in vivo.
  
  
  RESULTS
  We used pressurized cerebral and mesenteric arteries in vitro and skeletal muscle arterioles in vivo to study the contribution of L-type (1 µmol/L nifedipine) and T-type (1 µmol/L mibefradil, 3 µmol/L NNC 55-0396) calcium channels to vascular tone, following acute or chronic inhibition of nitric oxide. Acute inhibition with l-NAME (10 µmol/L) significantly increased the T-type, but not the L-type, channel contribution to vascular tone in vitro and in vivo, and altered the smooth muscle expression of the Cav3.1 and Cav3.2 T-type channels. In pressurized mesenteric arteries of Cav3.1ko and Cav3.2ko mice, acutely treated with l-NAME, the contribution of T-type channels relative to L-type channels was significantly reduced, compared with arteries from wild-type mice.Chronic l-NAME treatment (40 mg/kg/day; 14-18 days) increased blood pressure, vascular superoxide, and the contribution of T-type channels to vascular tone in vivo. The latter was reversed by acute scavenging of superoxide with tempol (1 mmol/L), or inhibition of NADPH oxidase with apocynin (500 µmol/L) or DPI (5 µmol/L).
  
  
  CONCLUSIONS
  We conclude that nitric oxide deficit produces a significant increase in the contribution of Cav3.1 and Cav3.2 T-type calcium channels to vascular tone, by regulating the bioavailability of reactive oxygen species produced by NADPH oxidase. Our data provide evidence for a novel causal link between nitric oxide deficit, oxidative stress, and T-type calcium channel function.
authors: John Curtin School of Medical Research, Australian National University, Canberra ACT 0200, Australia.
authors: Lauren
authors: L
authors: Howitt
authors: Ivana Y
authors: IY
authors: Kuo
authors: Anthie
authors: A
authors: Ellis
authors: Daniel J
authors: DJ
authors: Chaston
authors: Hee-Sup
authors: HS
authors: Shin
authors: Pernille B
authors: PB
authors: Hansen
authors: Caryl E
authors: CE
authors: Hill
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002536:Cerebral Arteries / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase
keywords: Nitric oxide; Reactive oxygen species; T-type calcium channels; Vascular tone