Tetrahexylammonium ions increase Ca2+ sensitivity of contraction of guinea-pig ileal smooth muscle.
Effects of tetraalkylammonium ions, having tetraalkyl chains of increasing length from ethyl to octyl, on inositol-trisphosphate (InsP3)-induced Ca2+ release and contractile mechanics were examined in guinea-pig skinned ileal smooth muscle longitudinal strips. Although tetrahexylammonium ions (THexA) appeared to be the most potent inhibitor of Ca2+ release among the tetraalkylammonium ions examined, an additional and more prominent effect was found, i.e., the contraction induced by Ca2+ release showed a large sustained component in the presence of THexA. Potentiation of the contraction by THexA (above 30 microM) was also observed in skinned fibers in which the sarcoplasmic reticulum function was destroyed by treatment with A23187. The potentiating effect of THexA was the most potent by far among the tetraalkylammonium ions examined and was elicited by Ca(2+)-dependent and GTP-binding-protein-independent mechanisms. The potentiation was not due to activation of myosin light-chain kinase. The selective inhibitors of myosin light-chain kinase, protein kinase C and calmodulin reduced THexA-induced potentiation of contraction only at concentrations above 30 microM, at which non-specific effects are likely. Furthermore, relaxation induced by changing pCa from 4.5 to 8.5 was not affected by 1 mM THexA, suggesting that the potentiating effect is not mainly due to inhibition of myosin light-chain phosphatase. In conclusion, ThexA sensitizes guinea-pig skinned ileal smooth muscle to Ca2+ in a structure-selective manner. This sensitization appears not to be mediated mainly by a GTP-binding protein, by activation of myosin light-chain kinase or protein kinase C, by enhanced Ca2+ binding to calmodulin, or by inhibition of myosin light-chain phosphatase.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Y
Y
Uyama
K
K
Muraki
M P
MP
Walsh
Y
Y
Imaizumi
M
M
Watanabe
D000818:Animals; D001696:Biomechanical Phenomena; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology
D000644:Quaternary Ammonium Compounds; C055292:tetrahexylammonium; D000001:Calcimycin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium