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Influence of mitochondrial inhibition on global and local [Ca(2+)](I) in rat tail artery.

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Author

Summary, in English

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.

Department/s

Publishing year

2002

Language

English

Pages

792-799

Publication/Series

Circulation Research

Volume

90

Issue

7

Document type

Journal article

Publisher

American Heart Association

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • Calcium Signaling : drug effects
  • Calcium : metabolism
  • Cyanides : pharmacology
  • Calcium Signaling : physiology
  • Enzyme Inhibitors : pharmacology
  • Female
  • Intracellular Fluid : metabolism
  • In Vitro
  • Glycolysis : drug effects
  • Isometric Contraction : drug effects
  • Mitochondria : drug effects
  • Mitochondria : metabolism
  • Myosin Light Chains : metabolism
  • Phosphorylation : drug effects
  • Rats
  • Sprague-Dawley
  • Receptors
  • alpha-1 : metabolism
  • Adrenergic
  • Rotenone : pharmacology
  • Support
  • Tail : blood supply
  • Non-U.S. Gov't
  • Vasoconstriction : drug effects
  • Arteries : metabolism
  • Arteries : drug effects
  • Arsenates : pharmacology
  • Antimycin A : pharmacology
  • Macrolide : pharmacology
  • Antibiotics
  • Animal
  • Adrenergic alpha-Agonists : pharmacology
  • Uncoupling Agents : pharmacology

Status

Published

Research group

  • Vascular Physiology
  • Cellular Biomechanics
  • Islet cell physiology

ISBN/ISSN/Other

  • ISSN: 0009-7330