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. 1994 Apr;111(4):1212–1220. doi: 10.1111/j.1476-5381.1994.tb14874.x

Activation of the sheep cardiac sarcoplasmic reticulum Ca(2+)-release channel by analogues of sulmazole.

S J McGarry 1, A J Williams 1
PMCID: PMC1910124  PMID: 8032608

Abstract

1. The effect of sulmazole and several structurally related analogues on cardiac sarcoplasmic reticulum (SR) Ca(2+)-release channel gating and on [3H]-ryanodine binding to isolated SR membrane vesicles has been investigated. 2. The optical isomers, (+)- and (-)-sulmazole, increased the open probability (Po) of single Ca(2+)-release channels incorporated into phospholipid bilayers held under voltage clamp by increasing the frequency and duration of open events. The respective EC50s were 423 microM and 465 microM at 10 microM activating cytosolic Ca2+ and the Hill coefficients for activation were approximately two, suggesting that at least two molecules of either enantiomer are required to bind for channel activation. 3. Similarly the related enantiomers, (+)- and (-)-isomazole, which differ from sulmazole in the position of the pyridine nitrogen (4.5b for sulmazole; 4.5c for isomazole), were approximately as potent as each other and as potent as the isomers of sulmazole with EC50s of approximately 445 microM. 4. In contrast, EMD 46512 and EMD 41000, which are sulmazole and isomazole analogues respectively, each with the methylsulphinyl oxygen removed, increased single-channel Po with EC50s of 42 microM and 40 microM. The open and closed lifetime distributions were similar to those of the less potent analogues and the Hill coefficients were the same, suggesting that these compounds act at the sulmazole site on the Ca(2+)-release channel. 5. All of the compounds tested were able to increase the Po of channels in the absence of activating Ca2+ but were less potent than in the presence of Ca2+. The drugs were effective only when added to the cytosolic face of the channel.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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