Sites of action of nifedipine at the neuromuscular junction

The sites of action of nifedipine at the neuromuscular junction have been determined by studying its effects on indirect, direct muscle twitches and KCl- and caffeine-induced contractures of the rat diaphragm, and its effects on the contractures produced by Ach, carbachol and KCl in the frog rectus abdominis muscle. Cumulative addition of nifedipine [15 - 150 muM] potentiated indirectly and directly evoked muscle twitches. At a stimulation frequency of 1 Hz, nifedipine produced a biphasic response expressed by a potentiation, followed by blockade of the indirect muscle twitches. In preparations kept in solution with low Ca +2 concentration [0.52 mM], the cumulative addition of nifedipine [30 - 120 muM] produced a potentiation, followed by neuromuscular blockade which was reversed by raising Ca +2 concentration. In preparations kept in Ca +2-free solution, nifedipine produced a biphasic effect on the directly evoked muscle twitches. On tetanic tension curve, nifedipine [60 muM] reduced the first phase and produced a tetanic fade of the second phase. Nifedipine [10 muM] potentiated the two phases of KCl- and caffeine- induced contractures in the rat diaphragm. Similarly, nifedipine potentiated the contractures produced by Ach and KCl but reduced that of carbachol in the rectus abdominis muscle. In conclusion, the twitch-potentiating action of nifedipine appears to be mediated at the level of the sarcoplasmic reticulum [SR] and /or cholinesterase enzyme inhibition, while the twitch-inhibitory action of nifedipine appears to be mediated at the level of motor nerve terminals

Potentiation of the stimulation action of Theophylline on the insulin secretion by intracellular ca2+ antagonist, TMB-8

The role of intracellular Ca 2+ stores with cAMP system in insulin secretion has been elucidated by investigating the effects of an intracellular Ca 2+ antagonist, TMB-8, on the glucose-[8.3 mM] stimulated insulin secretion in the absence and presence of theophylline in isolated perfused rat pancreas. TMB-8 [10 muM] alone had no effect on glucose-stimulated insulin secretion. However, theophylline [10 mM] increased the glucose-stimulated insulin secretion by 4-folds. Simultaneous infusion of TMB-8 [10 muM] with theophylline into the isolated perfused pancreas potentiated the stimulatory action of theophylline by 29%. The results were discussed in relation to the set point concept

Evidence for an 2-presynaptic blocking activity of levamisole in the isolated rat vas deferens

The effects of levamisole on the sympathetic transmission and the mechanism underlying these effects were investigated in the field- stimulated rat vas deferens. Levamisole [5-80 muM] potentiated the contraction of the vas deferens induced by field stimulation at low and high frequencies [2, 20 Hz] in a concentration-dependent manner. The extent of potentiation at low frequency was greater than that at high frequency. However, noradrenaline-induced contractions were only potentiated at high concentrations of levamisole [40, 80 muM]. The potentiating effect of levamisole on electrically evoked muscle twitches was completely abolished in the presence of yohimbine and only a slight potentiation was obtained with high concentrations of levamisole. Moreover, in the presence of levamisole [20 muM], the concentration-response curve of clonidine was shifted to the right and the ED50 of clonidine was increased by three-fold. Levamisole was capable of recovering the electrically-evoked muscle contraction after being abolished by cocaine. These data provided a strong evidence for an alpha2-presynaptic blocking activity of levamisole in the isolated rat vas deferens and confirmed its reported uptake blocking activity, only at high concentration