Effects of inhibitors for tyrosine kinase and non-selective cation channel on capacitative Ca(2+) entry in rat ileal smooth muscle.
The effects of tyrosine kinase inhibitors and non-selective cation channel blockers on capacitative Ca(2+) entry were examined in the presence of methoxyverapamil in rat ileal smooth muscles. In Ca(2+)-free solution, carbachol or caffeine produced a rapid contraction mediated by Ca(2+) release from the stores (Ca(2+)-release response), and then led to Ca(2+) depletion of the stores. Subsequently, reintroduction of Ca(2+) caused a transient contraction due to capacitative Ca(2+) entry. Tyrosine kinase inhibitors, genistein and tyrphostin 47 but not herbimycin A, suppressed the responses to Ca(2+)-reintroduction much greater than Ca(2+)-release responses to carbachol or caffeine. Similar inhibitory effects on the responses to Ca(2+)-reintroduction were obtained with daidzein and tyrphostin A1, respective inactive analogue of genistein and tyrphostins. After continuous depletion of the stores with thapsigargin, Ca(2+)-reintroduction produced a sustained contraction, which was inhibited by these agents to different extents, but not by herbimycin A. In beta-escin-treated skinned muscles, genistein slightly reduced Ca(2+)-induced contraction. In fura-2-loaded tissues, SK&F 96365 inhibited contractile and [Ca(2+)](i) responses to Ca(2+)-reintroduction but minimally affected Ca(2+)-release responses. Tetrandrine suppressed both responses to Ca(2+)-reintroduction and to Ca(2+)-release. These results suggest that genistein and tyrphostin 47 inhibit capacitative Ca(2+) entry through an inhibition of Ca(2+) entry channels rather than tyrosine kinase. SK&F 96365, but not tetrandrine, seems to selectively inhibit the contractile responses to capacitative Ca(2+) entry in rat ileal smooth muscles.
Ohta
T
T
Laboratory of Pharmacology/Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, North 18, West 9, Sapporo, Japan. tohta@vetmed.hokudai.ac.jp
Yasuda
W
W
Hasegawa
A
A
Ito
S
S
Nakazato
Y
Y
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D044182:Benzylisoquinolines; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D019284:Thapsigargin / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D000470:Alkaloids; D044182:Benzylisoquinolines; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020032:Tyrphostins; C060152:tyrphostin 47; C009438:tetrandrine; D002110:Caffeine; D019284:Thapsigargin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium