Role of mitochondria in spontaneous rhythmic activity and intracellular calcium waves in the guinea pig gallbladder smooth muscle

Abstract

Mitochondrial Ca²⁺handling has been implicated in spontaneous rhythmic activity in smooth muscle and interstitial cells of Cajal. In this investigation we evaluated the effect of mitochondrial inhibitors on spontaneous action potentials (APs), Ca²⁺flashes, and Ca²⁺waves in gallbladder smooth muscle (GBSM). Disruption of the mitochondrial membrane potential with carbonyl cyanide 3-chlorophenylhydrazone, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, rotenone, and antimycin A significantly reduced or eliminated APs, Ca²⁺flashes, and Ca²⁺waves in GBSM. Blockade of ATP production with oligomycin did not alter APs or Ca²⁺flashes but significantly reduced Ca²⁺wave frequency. Inhibition of mitochondrial Ca²⁺uptake and Ca²⁺release with Ru360 and CGP-37157, respectively, reduced the frequency of Ca²⁺flashes and Ca²⁺waves in GBSM. Similar to oligomycin, cyclosporin A did not alter AP and Ca²⁺flash frequency but significantly reduced Ca²⁺wave activity. These data suggest that mitochondrial Ca²⁺handling is necessary for the generation of spontaneous electrical activity and may therefore play an important role in gallbladder tone and motility.