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Tramadol [(1R, 2R) and (1S, 2S)-2-dimethyl-amino-methyl-1-(3-methoxyphenyl) -cyclohexanol hydrochloride] has been used clinically. It binds to micro-opioid receptors with lower affinity than morphine, which suggests that the antinociceptive action of tramadol may not be due to opioid receptor binding. Several lines of evidence have shown that tramadol inhibits the reuptake of monoamines, as do antidepressant drugs such as desipramine. Tramadol inhibits the reuptake of NE and serotonin. The mechanisms of action of tramadol have not been well understood. Recently, some evidences in the mechanisms of action of tramadol have been published. Tramadol inhibits the muscarinic receptor, serotonin receptor, and nicotinic acetylcholine receptor ion-channel, suggesting these receptors might be related to the mechanisms of action of tramadol. In this review, the mechanisms of action of tramadol were reviewed form these findings. Tramadol does not alter renal blood flow (RBF) in normal rats. This suggests that tramadol would be a safe analgesic maintaining RBF during the postoperative period. It would be necessary to study the effects of tramadol on orphan G-ptotein coupled receptor which is related to the pain.

It has been known that various derangements in ionic homeostasis develop following neural trauma. In particular, potassium efflux out of and calcium influx into the cells are thought to play important roles in causing cell damage. Concomitantly we have previously reported that increased extracellular potassium per se provoked by head injury induces convulsive seizure such that the sustained high extracellular potassium leads to animal death. The purpose of the present study was further to examine the beneficial effect of drugs which could inhibit such detrimental ion movements in experimental head injury. Awake male mice of dd-strain were restrained and subjected to head injury using a bakelite weight of 30 gm dropped from a height of 17.6 cm above the skull. This injury resulted in immediate loss of consciousness in 100%, convulsive seizure in about 70% and death in about 30% of animals. The severity of consciousness disturbance was evaluated by a pair of indices in time interval; time required for the recovery of righting reflex (RR) and for the recovery of spontaneous movement (SM). Ethacrynic acid, a loop diuretics, blocks carrier-mediated chloride transport into astroglia associated with sodium and water in the presence of high extracellular potassium. Animals were treated with either 0.5-1.0 mg/kg or 2.0-4.0 mg/kg of ethacrynic acid administered via tail vein 10 min before injury. In the other group of animals, a calcium entry blocker, flunarizine was injected intraperitoneally in doses 5, 10 and 20 mg/kg one hour pre-insult.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the effects of sodium 5-hydroxydecanoate (5-HD) on experimentally induced ischemic arrhythmia and its mechanisms of action by biochemical and electrophysiological techniques. 5-HD, at the single dose of 200 mg/kg (p.o.) or at the one week multiple doses of 3 to 100 mg/kg (p.o.), suppressed the incidence of ventricular fibrillation induced by coronary ligation in rats. 5-HD at the dose of 3 or 10 mg/kg (i.v.) elevated the ischemically decreased ventricular fibrillation threshold in the coronary ligated dogs. In isolated rat heart, 5-HD suppressed the K+ release from ischemic myocardium at the doses of 10(-5) to 10(-3) M. 5-HD at the dose of 10(-4) M decreased the open state probability of ATP regulated K+ channel in isolated myocardial cell of guinea pig. Contents of high-energy-phosphate compounds were markedly decreased in ischemic myocardium of rats, and they were not affected by 5-HD. These results demonstrate the efficacy of 5-HD against experimental ischemic ventricular arrhythmia. Its antiarrhythmic action may be attributed, at least in part, to the suppression of K+ release from ischemic myocardium by possibly inhibiting the ATP regulated K+ channel.

Effects of KW-3049 on electrophysiological properties of the heart were examined using Langendorff-perfused hearts and superfused sinus nodal tissues of rabbits and superfused guinea-pig ventricular muscles. In rabbit hearts, KW-3049 at concentrations above 10(-7) M caused a dose-related prolongation of atrio-His bundle conduction time (AH), whereas His bundle-ventricular conduction time (HV) was unaffected. In spontaneously firing rabbit sinus nodal tissues, KW-3049 at concentrations above 10(-8) M prolonged cycle length significantly. At 10(-6) M, amplitude and the maximum upstroke velocity of sinus nodal action potential were decreased as well. In normally polarized guinea-pig ventricular muscles under 4 mM [K+]0, KW-3049 at concentrations above 10(-6) M shortened the action potential duration without affecting the resting membrane potential and the maximum upstroke velocity of action potential (Vmax). The Vmax of slow action potentials induced by isoproterenol at 10(-7) M was inhibited significantly by additional application of KW-3049 at concentrations above 10(-9) M. At above 10(-8) M, the amplitude and duration of slow action potentials were reduced significantly. The potency of this slow action potential inhibition by KW-3049 was slightly less than that of nifedipine, while it was 10 to 100 times greater than that of verapamil. Spontaneous activity of ventricular muscles induced by BaCl2 at 1 mM was abolished completely at 16 min after application of KW-3049 at 10(-7) M. These results suggest that KW-3049 may have a potent and selective inhibitory action on cardiac slow calcium channels.

The electrophysiologic effects of calcium channel blocking agents, diltiazem, verapamil and nifedipine, on the sinus node function were examined in 43 anesthetized closed-chest dogs in comparison with the effects of propranolol. The parameters of sinus node function, i.e. sinus cycle length (SCL), sinus node recovery time determined by overdrive suppression (SRT), both of which are thought to reflect sinus node automaticity, and sinoatrial conduction time estimated by Strauss method (SACT), were evaluated. Intravenously administered diltiazem (0.2 mg/kg), verapamil (0.1 mg/kg) and propranolol (0.1 approximately 0.2 mg/kg) increased SCL and SRT significantly although the increase of these parameters induced by nifedipine (0.03 mg/kg) was not statistically significant. The calcium channel blocking agents did not significantly affect SACT in contrast with propranolol which showed a prolonging effect. Thus calcium channel blocking agents suppressed sinus node automaticity yet had little effect on sinoatrial conduction.

Using a sarcolemmal vesicle-enriched preparation prepared from canine ventricles, the effects of several sulfhydryl reagents on the Na+-Ca2+ exchange were examined. N-Ethylmaleimide (NEM) significantly inhibited the intravesicular Na+ (Na+i)-dependent Ca2+ uptake but did not remarkably affect the extravesicular Na+ (Na+o)-dependent Ca2+ efflux. Iodoacetamide (IAM) had no significant effect on the Na+i-dependent Ca2+ uptake and somewhat promoted the Na+o-dependent Ca2+ efflux. Dithiothreitol (DTT) did not significantly influence the Ca2+ uptake, was inclined to increase passive Ca2+ efflux and apparently decreased the Ca2+ efflux. DTT added with IAM exhibited a significant depressant effect on the Ca2+ uptake and simultaneously had a remarkable increasing effect on passive Ca2+ efflux. NEM and (DTT + IAM), however, did not significantly alter the Km value for Ca2+. p-Chloromercuribenzoate (PCMB) remarkably inhibited the Na+i-dependent Ca2+ uptake but simultaneously showed a remarkable promoting effect on passive Ca2+ efflux, whereby the Na+o-dependent Ca2+ efflux was factually counteracted. These results suggest the possibility that the direction of the Na+-Ca2+ exchange might be controlled by a modification with NEM and IAM of the thiol group(s) in the protein involved in the Na+-Ca2+ counter-transport and that the reductive cleavage of disulfide bond(s) and a modification with PCMB of thiol group(s) present in the sarcolemmal vesicle-associated protein(s) result in an increased Ca2+ permeability in the vesicular membrane.

Understanding of the electrophysiological properties of the calcium channel in cardiac cell membranes has been hampered because of the difficulties in interpreting voltage-clamp data. Recently, new techniques for isolation of adult heart cells, internal dialyzation of the cell and analysis of the single ion channel current have been established. Some of the previous results and concepts obtained in intact cardiac tissues have been confirmed and new understanding of the nature of the calcium channels has been gained by the techniques. In this article, the author reviews the electrophysiological and electropharmacological properties of the calcium ion channels in cardiac cell membranes. Especially, emphasis is placed on new information gleaned from the new techniques.