Calcium channel blockers and smooth muscle motility in vitro.
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Biomedical subjects
Publications and source records attributed to J Gintautas.
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Intracerebroventricular injection of (+)-naloxone shortened pentobarbital-induced sleeping times in rats. It does not appear that opiate receptors regulate the duration of narcosis.
Ten term parturients with moderate-severe preeclampsia received intrathecal morphine for labor analgesia. Significant reductions in blood pressure and heart rate, which were unrelated to analgesia, were observed.
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The effects of the calcium (slow) channel blocker verapamil, on non-cardiac excitable membranes were examined in vivo. In barbiturate anaesthetized cats, the effect of intravenously administered verapamil (0.1, 0.2, and 0.4 mg.kg-1) on isometric twitch amplitude of the flexor carpi radialis muscle, elicited by indirect and direct electrical stimulation, was determined. At all doses tested, verapamil significantly reduced muscle twitch amplitude from control values. The effect of dosage on twitch reduction was far more pronounced for indirect than direct stimulation. Full recovery to control was observed by 90 minutes only with the lowest dose (0.1 mg.kg-1 IV). Reduction of twitch amplitude (direct and indirect) lasted the duration of the experiment (180 minutes) for the two higher doses of verapamil. No significant changes in blood pressure, cardiac rate or rhythm were observed. The specific site and mechanism of verapamil's neuromuscular blocking action remains unclear. In clinical situations where potent inhalation agents, adjuncts or neuromuscular blocking agents may be used, therapeutic doses of verapamil may interact to promote muscle weakness.
The effects on indirectly elicited muscle twitch amplitude associated with the calcium (slow) channel blocker, verapamil, with or without pancuronium were investigated using isolated bullfrog sciatic nerve-sartorius muscle preparations. Verapamil (2-8 mM) produced a dose-related depression of indirect muscle twitch height (P less than 0.05). Twitch response was depressed 11% below control by the lowest concentration employed and 86% by the highest concentration. Pancuronium (0.07 mM) depressed neuromuscular function 35% below control (P less than 0.05). The combination of 5 mM or 8 mM verapamil with 0.07 mM pancuronium caused significantly greater degrees of depression than either drug alone. Verapamil produced significant depression of twitch height in vitro in relatively high concentrations. The mechanism of action remains unknown. Verapamil possesses pharmacologic properties that may be unrelated to slow (calcium) channel inhibition. The reduction of muscle twitch height caused by verapamil alone (5 mM) could not be antagonized by neostigmine, calcium, or frequent washings.
Because severe muscular weakness was noted in animals receiving verapamil in doses exceeding those used in humans, we studied the effects of verapamil on neuromuscular function and its correlation with myocardial conduction. The flexor carpi radialis and its nerves were surgically exposed in mechanically ventilated dogs during pentobarbital anesthesia. Indirect and direct electrical stimulation was applied and twitch height recorded following the intravenous administration of verapamil. Twenty animals received one of four dose schedules. The results showed a significant dose-related depression of twitch height to indirect stimulation. Twitch height to direct stimulation was reduced only with the highest dose. The onset of depression of indirect stimulation was temporally associated with onset of A-V conduction delay. However, recovery following indirect stimulation lagged behind recovery of the ECG by 30 min. Recovery times of twitch height following indirect stimulation ranged from 60-208 min and also were dose-related. The qualitative similarity of pancuronium and verapamil on indirect twitch height suggests a similar site of action, i.e., the neuromuscular junction. A presynaptic or postsynaptic effect of verapamil could not be discerned in this study. Verapamil may produce an unrecognized source of weakness in the anesthetized patient either alone or through interaction with anesthetic agents or adjuncts.
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