The effect of D600 on tonic tension, Na+ inward current, and Na+-Ca2+ exchange in frog heart.
Preparations of frog atrial muscle were stimulated at 0.33 Hz under voltage clamp, and the resulting membrane currents and the twitch contractions (phasic and tonic components) were recorded in presence or absence of D600. It has been suggested earlier that the tonic contractions are regulated by an electrogenic Na+-Ca2+ exchange, while the phasic contractions are closely related to the calcium inward current (Isi). In this study we investigated the effect of D600 on (i) the tonic contractions elicited by long depolarizing pulses of high amplitude and (ii) the tonic contractions increased by veratrine and resulting in a positive inotropic effect (PIE). While 1 microM D600 reduced Isi and the corresponding phasic contractions to less than 30% of their initial values within 5 min, the inhibitory effect of D600 on tonic contractions developed more slowly or higher concentrations of D600 were needed to achieve similar levels of inhibition within the same time. Furthermore, applications of 5-50 microM D600 inhibited the veratrine-induced increase in INa and in tonic contractions, and both of these effects again fully developed within a few minutes of D600 being removed. The results demonstrate that D600 inhibits not only Isi and phasic contractions, but it also decreases the tonic contractions in frog heart. The effect on the tonic component is associated with inhibition of the tetrodotoxin-sensitive Na+ inward current, and the results are interpreted as an effect of D600 on the electrogenic Na+-Ca2+ exchange. These additional effects of D600 should be considered when using this drug as the "specific" calcium channel blocker.
M
M
Horackova
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005711:Gallopamil / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D007474:Ion Exchange; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011894:Rana pipiens; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D007473:Ion Channels; D005711:Gallopamil; D013779:Tetrodotoxin; D012964:Sodium; D014700:Verapamil; D002118:Calcium