The effects of dihydropyridine derivatives on force and Ca2+ current in frog skeletal muscle fibres.

Abstract

SUMMARY1. The effects of dihydropyridine (DHP) derivatives on current through the slow Ca2+ channel and on isometric force were investigated in short toe muscle fibres of the frog (Rana temporaria). The experiments were performed under voltage-clamp conditions with two flexible internal microelectrodes.2. The non-chiral DHP derivative nifedipine was used mainly because it allowed control measurements after the inactivation of the drug with UV light.3. In a TEA sulphate solution containing 4 mM-free Ca2+, nifedipine (1 /l4M) caused no relevant alterations in the time course of successive contractures induced by depolarizing steps to 0 mV of 3-5 min duration followed by a restoration time at -90 mV of 1-5 min.4. When external Ca2+ was replaced by Mg2+, nifedipine caused a dose-dependent shortening of contractures. The effect reached saturation at about 50 % of shortening with 1-5 ,uM-nifedipine. In the absence of divalent cations and with Na+ being the only metallic cation in the solution, shortening became more pronounced and maximum force decreased.5. The application of 2 /sm-nifedipine to a Ca2+-free, Mg2+-containing solution shifted the voltage dependence of force inactivation by 5-10 mV to more negative potentials. 6. Force activation was facilitated by nifedipine. In the presence of 2 /iMnifedipine in a Ca2+-containing solution, threshold potentials (rheobase) as negative as -75 mV were measured under microscopical observation. UV irradiation shifted the threshold potential back to the normal value of about -50 mV.7. The slow Ca2+ inward current was blocked almost completely by 5/#M-nifedipine, even when induced from negative holding potentials (-90 to -

The effects of gadolinium, a stretch-sensitive channel blocker, on diaphragm muscle

“…In the current study, complete blockade of the dihydropyridine Ca 2+ current by 5 mmol nifedipine [17] did not modify the relation between initial length and tetanic tension ( fig. 4d).…”

“…In group 7 (n=8), the effects of 5 mmol nifedipine on the length-active tension curve were studied. At this concentration, nifedipine has been shown to completely block the slow Ca 2+ inward current in skeletal muscle [17]. Forskolin and nifedipine were dissolved in dimethyl sulfoxide, the volume of which did not exceed 1/1,000 (vol/vol) of the bath volume.…”

Control of Calcium Release in Functioning Skeletal Muscle Fibers

“…lea could be eliminated without suppressing calcium release if the drug-occupied intermediate state could still undergo transition to the active, but drug-oc cupied, state during depolarization (41), and if the drug-occupied active state could activate SR calcium release, but could not function as a conducting calcium channel. This interpretation could also account for the potentiating effect of DHPs on contractile activation (36, 48,94,102).…”

Kinetics of inactivation and restoration from inactivation of the L‐type calcium current in human myotubes

“…Considering data from the homologous cardiac isoform of the L_type channel, a candidate region of importance for the process is intramembranous segment S6 of domain I of the á1 subunit and its adjacent extramembranous loops (Zhang et al 1994). Because of the reported effects of Ca¥ antagonists favouring inactivation (Bean, 1984;Pizarro et al 1988;Neuhaus et al 1990) interaction sites of these drugs with the channel might also participate in the process (for review see Striessnig et al 1998). Moreover, characteristics of inactivation have been reported to be influenced by additional subunits coexpressed with á1 in non-muscle cells.…”