ag-213 and tetrandrine

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.

Topics: Alkaloids; Animals; Benzylisoquinolines; Caffeine; Calcium; Calcium Channels; Enzyme Inhibitors; Genistein; Ileum; Imidazoles; Male; Muscle Contraction; Muscle, Smooth; Protein-Tyrosine Kinases; Rats; Rats, Wistar; Thapsigargin; Tyrphostins