Effects of antidepressant drugs on the amygdaloid after-discharge induced by stimulating the amygdala in rats implanted with chronic electrodes, were investigated in correlation with anti-muricidal effects as well as neurotoxicity. Tricyclic antidepressants such as amitriptyline, imipramine and nortriptyline markedly depressed both after-discharge and muricide at doses smaller than neurotoxic doses. The effect of PF-257 was also the same as tricyclic antidepressants. On the other hand, methamphetamine and pipradrol blocked the muricide at doses smaller than neurotoxic doses without depressing the amygdaloid after-discharge. Major tranquilizers, chlorpromazine and clozapine depressed both after-discharge and muricide only at doses larger than those which impaired rotarod performance. Haloperidol, on the contrary, depressed the after-discharge without selectively blocking the muricide. Minor tranquilizers, diazepam and chlordiazepoxide did not block the muricide at doses smaller than neurotoxic doses, although they showed a marked depression of the after-discharge.

View full abstract

In order to observe the effects of morphine on protein metabolism in mouse brain, experimental procedures were carried out over a 7 hr period of infusion. When the analgesia reached a peak, namely around 2 hr after the start of infusion, the in vivo incorporation of radioactive leucine into protein estimated by the dual label technique was uniformally depressed in all the examined subcellular fractions of both brain and liver. After tolerance developed, however, the incorporation of leucine increased to a much higher level than the control in brain subcellular fractions and the increase was masked by naloxone. In contrast, the incorporation into a TCA soluble fraction of the brain S₂, separated by Gray and Whittaker's method, was more than doubled even after 4 hr infusion. While the in vitro incorporation rate of the mitochondrial fraction significantly fluctuated during development of tolerance with naloxone that of the synaptosomal fraction did not fluctuate. The observed coincidence in the time course of development of tolerance and changes in the brain protein synthesis indicates a possible relationship between the phenomena, though the causal nature of the relationship could not be elucidated.

View full abstract

The effect of the boiled supernatant on synaptosomal adenyl cyclase activity of rat cerebral cortex was investigated. The boiled supernatant markedly increased the accumulation of cyclic AMP in synaptosomes when added to adenyl cyclase system by a mechanism presumably unrelated to inhibition of cyclic AMP phosphodiesterase or adenosine triphosphatase. Magnesium ion was required for synaptosomal adenyl cyclase activity and its stimulation by the boiled supernatant. The result discerned by double reciprocal plots showed an increase in Vmax value of adenyl cyclase by addition of the boiled supernatant without significantly altering the affinity for substrate. The enzyme activity was not stimulated by dopamine, histamine and serotonin in either the absence and presence of the boiled supernatant.

View full abstract

Diltiazem, a new 1, 5-benzothiazepine derivative, antagonized calcium ion and thus caused a reduction in the contractile force of isolated papillary muscle. The antagonistic ratio of diltiazem to calcium ion was estimated to be approx. 1 : 100. A lower concentration of diltiazem (2.2×10^-6 M) decreased the contractile force without affecting significantly the intracellularly recorded resting and action potentials. When the concentration of the compound was increased to 2.2×10^-5 M, only the maximum rate of rise of the action potential was reduced, while the other parameters of the action potential were also affected at 1.1 10^-4 M diltiazem. There was no significant change in the resting potential. Under conditions where the contractile force almost disappeared (1.1×10^-4 M), the membrane excitability was retained. It is concluded that dilitiazem is an excitation-contraction uncoupler in the cardiac muscle cell and that the compound may exhibit its negative inotropic action by reducing in some way the intracellular concentration of free calcium ion available for the contractile mechanism.

View full abstract

Effects of S-8527 (1, l-bis[4'-(1″-carboxy-l″-methylpropoxy) phenyl] cyclohexane) on platelet aggregation, adhesiveness and blood coagulation were examined in rats. In animals maintained on a semisynthetic diet containing sucrose (62%) as the only carbohydrate source, platelet adhesiveness increased as compared with that in rats fed a normal chow pellet. Under these experimental conditions, oral dose of S-8527 (30-300 mg/kg) for 14 days decreased platelet adhesiveness and ADP-induced platelet aggregation, but did not decrease collagen-induced platelet aggregation. S-8527 also showed a slight but significant increase of R value of thrombelastograph. In rats which were fed a normal chow pellet oral dose of S-8527 for 14 days did not significantly affect the several tests of platelet function and blood coagulation. These results suggest that S-8527 normalizes the platelet function in a hyper-adhesive state, but does not affect the platelet function in a normal state.

View full abstract

In order to clarify the action of drugs for liver disease, the effect of protoporphyrin (PP) on CCl₄, -induced liver injury was studied. Attention was given to the levels of lysosomal enzymes, some components of the liver, and inhibition of enzymes and lysis of lysosomal membranes by lipid peroxides. Administration of PP to CCl₄-poisoned rats was found to prevent the decrease in lysosomal lipolytic enzyme level in the liver, but not in other enzyme levels tested. The inhibition of lipolytic enzyme by CCl₄, administered may be partially involved in lipid accumulation in the liver. A dose of PP administered to CCl₄-poisoned rats for 8 days depressed the neutral lipid content in the liver nearly to the control value. Methyl linoleate hydroperoxide (hydroperoxide) at a lower concentration of 10^-6% inhibited the lipolytic enzyme activity by 30% and in concentrations ranging from 10^-4 to 10^-3% inhibited β-glucuronidase activity. Addition of PP to the medium containing 10^-6 to 10^-5% hydroperoxide and α-tocopherol reduced the enzyme inhibition further than in the absence of PP. The hydroperoxide in concentrations varying from 10^-6 to 10^-3% caused a partial lysis of liver lysosomal membranes, but addition of PP slightly reduced the damage by the hydroperoxide in concentrations lower than 10^-5%.

View full abstract

The effect of “drugs for liver disease”, protoporphyrin (PP) and phosphorylcholine (PC), on CC1₄-induced liver injury was studied. Attention was given to the levels of microsomal drug-metabolizing enzyme and lipolytic enzyme activities and of some microsomal components such as phospholipid and peroxides. Administration of PP to CC1₄-poisoned rats was found to increase the decreased microsomal drug-metabolizing enzyme activities, aminopyrine N-demethylase, aniline p-hydroxylase, cytochrome P-450 and b₅ and lipolytic enzyme activity in CC1₄-poisoned liver (12-20% increase as compared with those of the poisoned rats), and returned to control levels earlier than in CCl₄-poisoned rats. Furthermore, administration of PP to CC1₄-poisoned rats caused a decrease in the lipid peroxidation. A single dose of PP to normal rats was shown to increase these parameters, to a small extent. One of the mechanisms may be attributed to the fact that PP increases the biosynthesis of the hemoproteins by means of the incorporation of PP into the pigments and protects the membranes from lipid peroxides and the free radicals. On the other hand, administration of PC to the poisoned rats did not enhance the levels of the drug-metabolizing enzyme activities except for aminopyrine N-demethylase. Phospholipid phosphorous content, however, increased by 13-14% when PC was given. Thus, it is considered that PC may enhance the reconstitution of phospholipids in the injured membrane.

View full abstract

The question of whether the coronary blood vessels contain an intrinsic adrenergic mechanism for vasodilatation of physiological significance has been examined in the canine heart-lung preparation with a donor by studying the response of the coronary vessels to epinephrine, norepinephrine, isoproterenol and salbutamol in combination with practolol. To differentiate the vasodilatation mediated through adrenoceptors in the coronary vessels from that resulting from an increase in the myocardial O₂ consumption, a special method of analysis was developed based on the linear relation between the coronary flow and the myocardial O₂ consumption. It was found that all four compounds produced an increase in the coronary flow attributable to an increased myocardial O₂ consumption. Epinephrine and norepinephrine produced a decrease in the coronary flow after practolol which completely abolished the increase in the myocardial O₂ consumption as well as the positive inotropic and chronotropic effects produced by these compounds, while isoproterenol and salbutamol produced an increase. These results indicate that adrenergic β-receptor exists in the coronary subserving a vasodilatation. However, the vasodilatation through this mechanism is of minor importance under physiological conditions and becomes completely masked in the presence of an overwhelmingly strong vasodilatation consequent to an increase in the myocardial O₂ consumption.

View full abstract

Effects of acetylcholine (ACh) and norepinephrine on atrial contractility and pacemaker activity were investigated in isolated and blood-perfused canine atrium preparations with a support dog which were suspended in the blood-filled bath kept at 37°C. The drug was given in two forms of administration, i.e., intraarterial injection into the cannulated sinus node artery or direct administration into the bath. ACh administered into the bath produced a significant decrease in the developed tension from a concentration of 10^-5 g, 'ml and norepinephrine produced a significant increase in the developed tension from 3×10^-6 g/ml. An injection via the sinus node artery resulted in 300 and 100 times greater response to ACh and norepinephrine, respectively, in the tension development. In atrial pacemaker activity, ACh given into the bath did not produce a dose-related decrease while norepinephrine produced a dose-related increase frequently accompanied by an irregularity of rhythmicity.

View full abstract

The aim of the present experiment was to investigate effects of ephedrine and reserpine, administered in vivo, on responses of dog isolated arterial strips to adrenergic drugs, and to study a possible mechanism involved in the reversal of blood pressure responses to dopamine. Dose-dependent contractile responses to adrenaline (A), dopamine (DA) and ephedrine (ED) were depressed in the femoral strips isolated from the ED-treated dogs as compared with those isolated from the untreated dogs. Those to noradrenaline (NA) were potentiated in low concentration and inhibited in high concentration, though those to tyramine (TY) were not altered. Relaxing and contractile responses to isoprenaline (IP) were inhibited. DA did not induce a relaxing effect but a contractile one even in the strips brought to a state of moderate tone with ED or phelypressin. In the strips isolated from the reserpine-treated dogs, contractile responses were to some extent potentiated by NA, A and DA, and significantly by ED, while those to TY were inhibited. Relaxing responses to IP were reduced and contractile responses potentiated. In the strips extirpated from the reserpine and ED-treated dogs, contractile responses to NA and A were potentiated in low concentration and inhibited in high concentration. Those to TY were inhibited in low concentration and tended to be potentiated in high concentration whereas those to DA and ED were not affected. Dose-dependent relaxing effects of DA in the dog renal and mesenteric strips contracted previously by KCl after phenoxy-benzamine were attenuated by treatment with ephedrine in vivo. The results suggested that the dopamine reversal in the blood pressure may be mainly due to actions other than its peripheral effect on the blood vessels.

View full abstract

To produce physical dependence on morphine, phenobarbital and diazepam in rats, these drugs were mixed with the powder form of rat food in concentrations of 0.5 mg/g, 1 mg/g and 2 mg/g of food. One group of rats (the lower dose group) was continuously exposed for I week to two morphine-admixed foods with morphine to food ratios of 0.5 mg/g and 1 mg/g in a cage. The other group (the higher dose group) could choose between two morphine-admixed foods with morphine to food ratios of 1 mg/g and 2 mg/g. After I week, morphine-admixed foods were replaced with morphine free food for 2 days. Both groups of rats showed greatly reduced body weight and food intake after the first 24-48 hr withdrawal. The body weight decrease was greater for rats in the higher dose group. Control groups of morphine dependent rats were kept on the morphine added food diets and showed the same body weight increase as well as normal control rats during the course of these experiments. Physical dependence on phenobarbital and diazepam was produced using the same dosage schedules as with morphine. Both the lower and higher dose groups showed significant decrease in body weight due to withdrawal after 1 week of drug-food exposure. Levallorphan (0.5, 1, 3 and 5 mg/kg, s.c.) administered to morphine dependent rats had dose-dependent effects on the intensity of abstinence symptoms (e.g., diarrhea, piloerection and wet shakes phenomena), maximal decrease in body weight and duration of decreased body weight. Cross-physical dependence between phenobarbital and diazepam was demonstrated by this method.

View full abstract

Effects of practolol, alprenolol and pindolol on blood pressure in the rat were studied. Also effects of these three β-blocking agents on blood pressure and heart rate in spinal rats during adrenaline infusion were studied and compared with those of propranolol. The β-blocking agents produced a sustained pressor action in the rat, and in the spinal rat infused with adrenaline. The magnitude of the pressor action induced by the β-blockers was in the following order: pindolol≥propranolol≥alprenolol>practolol. Minimum doses of these β-blockers required to cause a pressor action in the spinal rat infused with adrenaline were in the following order; practolol>alprenolol≥propranolol≥pindolol. The magnitude of the pressor action produced by the same dose of these β-blockers and minimum doses of these β-blockers required to cause a pressor action in the spinal rat infused with adrenaline seemed to be roughly proportional to their β-receptor blocking activities. It was concluded that the minimum doses of these β-blockers required to cause a pressor action and the magnitude of the pressor action induced by the β-blockers in the spinal rat infused with adrenaline could be used to compare their β-blocking activities and that practolol, a cardioselective β-blocker, seems to block not only cardiac β-receptor but to some extent also peripheral vascular β-receptors.

View full abstract