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

Swärd, Karl LU ; Dreja, Karl LU ; Lindqvist, Anders LU ; Persson, Erik and Hellstrand, Per LU (2002) In Circulation Research 90(7). p.792-799
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... (More)
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. (Less)
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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
in
Circulation Research
volume
90
issue
7
pages
792 - 799
publisher
American Heart Association
external identifiers
  • pmid:11964372
  • wos:000175179100009
  • scopus:0037134406
ISSN
0009-7330
DOI
10.1161/01.RES.0000015214.40360.84
language
English
LU publication?
yes
id
7a5aea49-ef43-410f-a36e-2c599ea587b9 (old id 107752)
date added to LUP
2007-07-19 15:40:39
date last changed
2017-01-01 07:15:35
@article{7a5aea49-ef43-410f-a36e-2c599ea587b9,
  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.},
  author       = {Swärd, Karl and Dreja, Karl and Lindqvist, Anders and Persson, Erik and Hellstrand, Per},
  issn         = {0009-7330},
  keyword      = {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},
  language     = {eng},
  number       = {7},
  pages        = {792--799},
  publisher    = {American Heart Association},
  series       = {Circulation Research},
  title        = {Influence of mitochondrial inhibition on global and local [Ca(2+)](I) in rat tail artery.},
  url          = {http://dx.doi.org/10.1161/01.RES.0000015214.40360.84},
  volume       = {90},
  year         = {2002},
}