Role of mitochondria in contraction and pacemaking in the mouse uterus

BACKGROUND AND PURPOSE Uterine spontaneous contraction and pacemaking are poorly understood. This study investigates the role of the mitochondrial Ca2+ store in uterine activity. EXPERIMENTAL APPROACH We investigated the effects of mitochondrial and sarco‐endoplasmic reticulum (SER) inhibitors on co...

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Published in:British journal of pharmacology 2010-11, Vol.161 (6), p.1375-1390
Main Authors: Gravina, FS, Parkington, HC, Kerr, KP, De Oliveira, RB, Jobling, P, Coleman, HA, Sandow, SL, Davies, MM, Imtiaz, MS, Van Helden, DF
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biological Clocks - drug effects
Biological Clocks - physiology
Calcium - physiology
Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology
Female
Medical sciences
Mice
mitochondria
Mitochondria - drug effects
Mitochondria - physiology
Organ Culture Techniques
pacemaking
Pharmacology. Drug treatments
Research Papers
Rodents
Rotenone - pharmacology
spontaneous contractions
Studies
Uterine Contraction - drug effects
Uterine Contraction - physiology
uterus
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Summary:BACKGROUND AND PURPOSE Uterine spontaneous contraction and pacemaking are poorly understood. This study investigates the role of the mitochondrial Ca2+ store in uterine activity. EXPERIMENTAL APPROACH We investigated the effects of mitochondrial and sarco‐endoplasmic reticulum (SER) inhibitors on contraction, membrane potential (Vm) and cytosolic Ca2+ concentration ([Ca2+]c) in longitudinal smooth muscle of the mouse uterus. KEY RESULTS The mitochondrial agents rotenone, carbonylcyanide‐3‐chlorophenylhydrazone (CCCP), 7‐chloro‐5‐(2‐chlorophenyl)‐1,5‐dihydro‐4,1‐benzothiazepin‐2(3H)‐one (CGP37157) and kaempferol decreased the force of contractions. The ATP synthase inhibitor oligomycin had no significant effect. The effects of these agents were compared with those of SER inhibitors cyclopiazonic acid (CPA), 2‐amino ethoxyphenylborate (2‐APB) and caffeine. All agents, except CPA and oligomycin, decreased contractile force. CPA and CCCP transiently increased contraction frequency, which returned to control levels, whereas rotenone, CGP37157, kaempferol and 2‐APB decreased frequency and caffeine had no significant effect. Application of the mitochondrial agents when CPA functionally inhibited stores did not change contraction frequency but, with the exception of kaempferol, decreased force. CCCP caused depolarization and maintained increase in [Ca2+]c or depolarization/transient hyperpolarization and transient increase in [Ca2+]c for oestrus and di‐oestrus tissues respectively. Rotenone caused hyperpolarization and maintained increase in [Ca2+]c. CGP37157 and kaempferol caused hyperpolarization but no measurable change in [Ca2+]c. Application of a range of K+ channel blockers indicated a role of Ca2+‐activated K+ (KCa) channels in the CCCP‐ and CGP37157‐induced actions. CONCLUSIONS AND IMPLICATIONS Mitochondria have a modulatory role on uterine contractions, with mitochondrial inhibition reducing contraction amplitude and pacemaker frequency by changes in Vm, [Ca2+]c and/or Ca2+ influx.
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2010.00949.x