(+)-Naloxone: antagonism of pentobarbital-induced narcosis.

Intracerebroventricular injection of (+)-naloxone shortened pentobarbital-induced sleeping times in rats. It does not appear that opiate receptors regulate the duration of narcosis.

Intrathecal morphine and blood pressure in preeclampsia.

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.

Effects of verapamil on indirect muscle twitch responses.

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.

Neuromuscular blocking action of verapamil in cats.

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.

Neuromuscular and electrocardiographic responses to verapamil in dogs.

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.

Reversal of procaine conduction blockade by adenine nucleotides in vivo and in vitro.

The effect of the adenine nucleotides on procaine-induced conduction block in rats was investigated in vivo and in vitro. Both adenine and cyclic nucleotides significantly shortened the duration of sciatic nerve blocks in rats without affecting the frequency, degree of block or time of onset. Adenosine 5'-triphosphate (ATP) and N6, O2' dibutyryl 3':5'-monophosphate (db-cyclic AMP) were most effective. In isolated sciatic nerve preparations, the adenine nucleotides (ATP, adenosine 5'diphosphate (ADP), adenosine 5'monophosphate (AMP)) rapidly reversed procaine-induced depression of the action potential. These results suggest that local anesthetic effects may be mediated through interference with the physiological functions of the nucleotides.

Naloxone: analeptic action unrelated to opiate receptor antagonism?

The effects on the duration of sleeping time (ST) of the opiate receptor antagonists, naloxone and naltrexone, were determined in rats anesthetized by intraperitoneal injection of ketamine, halothane, or pentobarbital. Intracerebroventricular administration of naloxone shortened the duration of sleeping time induced by all three anesthetic agents in a dose-related manner. Centrally administered naltrexone (240 microgram) and systemically administered naloxone (50 mg/kg) prolonged the duration of pentobarbital sleeping time without altering duration of ketamine or halothane sleeping time. Naltrexone (120 microgram) had no effect on the duration of ST. This study does not support a role for opiate receptor regulation of the duration of sleeping time. The evidence supports the hypothesis that naloxone may govern the duration of narcosis through the activation of an opposing arousal system in the CNS, unrelated to pharmacologic competition for opiate receptors.