title: Influence of mitochondrial inhibition on global and local [Ca(2+)](I) in rat tail artery.
abstract: Inhibition of oxidative metabolism is often found to decrease contractility of systemic vascular smooth muscle, but not to reduce global [Ca(2+)](i). In the present study, we probe the hypothesis that it is associated with an altered pattern of intracellular Ca(2+) oscillations (waves) influencing force development. In the rat tail artery, mitochondrial inhibitors (rotenone, antimycin A, and cyanide) reduced alpha(1)-adrenoceptor-stimulated force by 50% to 80%, but did not reduce global [Ca(2+)](i). Less relaxation (about 30%) was observed after inhibition of myosin phosphatase activity with calyculin A, suggesting that part of the metabolic sensitivity involves the regulation of myosin 20-kDa light chain phosphorylation, although no decrease in phosphorylation was found in freeze-clamped tissue. Confocal imaging revealed that the mitochondrial inhibitors increased the frequency but reduced the amplitude of asynchronous cellular Ca(2+) waves elicited by alpha(1) stimulation. The altered wave pattern, in association with increased basal [Ca(2+)](i), accounted for the unchanged global [Ca(2+)](i). Inhibition of glycolytic ATP production by arsenate caused similar effects on Ca(2+) waves and global [Ca(2+)](i), developing gradually in parallel with decreased contractility. Inhibition of wave activity by the InsP(3) receptor antagonist 2-APB correlated closely with relaxation. Furthermore, abolition of waves with thapsigargin in the presence of verapamil reduced force by about 50%, despite unaltered global [Ca(2+)](i), suggesting that contraction may at least partly depend on Ca(2+) wave activity. This study therefore indicates that mitochondrial inhibition influences Ca(2+) wave activity, possibly due to a close spatial relationship of mitochondria and the sarcoplasmic reticulum and that this contributes to metabolic vascular relaxation.
authors.affiliation: Department of Physiological Sciences, Lund University, Lund, Sweden. karl.sward@mphy.lu.se
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.forename: Karl
authors.initials: K
authors.lastname: Dreja
authors.forename: Anders
authors.initials: A
authors.lastname: Lindqvist
authors.forename: Erik
authors.initials: E
authors.lastname: Persson
authors.forename: Per
authors.initials: P
authors.lastname: Hellstrand
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D001149:Arsenates / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003486:Cyanides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013623:Tail / Q000098:blood supply; D014475:Uncoupling Agents / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D000900:Anti-Bacterial Agents; D001149:Arsenates; D003486:Cyanides; D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D018340:Receptors, Adrenergic, alpha-1; D014475:Uncoupling Agents; D012402:Rotenone; D000968:Antimycin A; C025657:arsenic acid; D002118:Calcium