Journal de pharmacologie最新文献

Aldose reductase (AR) is an enzyme which catalyzes the transformation of D-glucose to sorbitol. Under non physiological conditions, like diabetes for example, the accumulation of polyols in the lens, sorbitol in particular, gives a basis to the osmotic hypothesis of cataract formation. AR inhibitors can protect against such accumulation. Oxidation of the constituents of the lens is a primary phenomenon in cataract formation, and some authors have suggested that the autoxidation of monosaccharides would originate the formation of cataract. For these authors, AR inhibitors would act by trapping the radical intermediates formed, inhibiting the denaturation of proteins in the organ and the lowering of glutathione. There classes of AR inhibitors can be distinguished: flavonoids and their related compounds, spirohydantoins--like sorbinil--and related compounds, and compounds with an acid function such as alrestatine. For each of these three classes, the authors try to establish the structure-activity relationship of the molecules. The possibility of a single site of interaction between AR and the different AR inhibitors is discussed. Differences in the inhibitory effect for a given compound between species, and for one species between tissues have been underlined.

An original experimental model of prostatism is proposed: Prostatic hypertrophy was induced in rabbit by testosterone 5 mg/kg-1. Three days later an increased number of micturitions, a correlate decrease in volume and an increased premictionnal vesical pressure were observed during a perfusion of the bladder in situ by NaCl 1 ml min-1. Phenoxybenzamine was not deeply studied because a lack of satisfaisant dose action-curve. I.V. administration of low doses of nicergoline (50 to 250 mcg/kg-1) reduced the consequences of the induced prostatic hypertrophy on the micturitions. These results are considered as a confirmation of a greater number of alpha 1-adrenoceptors in the bladder than in detrusor and allow us to confirm the use of nicergoline as a medical treatment of urinary retention in prostatic hypertrophy.

Cyclazocine is a benzomorphan derivative, considered as a mixed kappa and and sigma opioid receptor agonist. In experimental study with rats, cyclazocine is known to increase locomotor activity and to produce a bizarre behavioral syndrome including head swaying, backward walking, circling. The present study was undertaken to investigate the effects of various drugs modifying the serotoninergic neuronal systems, upon the locomotor activity and the abnormal behaviors induced by cyclazocine. Pretreatment with p-chlorophenylalanine (PCPA, 400 mg/kg, 72, 48, 24 hr) resulted in an inhibition of the three abnormal behaviors. Pretreatment with p-chloromethylamphetamine (PCMA, 15 mg/kg, 24 hr) antagonized head swaying, backward walking and markedly enhanced locomotor activity. In the contrary, pretreatment with PCMA (2.5 mg/kg, 15 min) resulted in enhanced abnormal behavioral responses to cyclazocine. L-tryptophan (50 mg/kg), 5-hydroxytryptophan (5-HTP, 50 mg/kg), or pargyline (50 mg/kg) inhibited abnormal behaviors and decreased locomotor activity. Serotonin antagonists with affinity fir both 5-HT1 and 5-HT2 receptors, metergoline (0.25-1 mg/kg), methysergide (1-5 mg/kg), amitriptyline (5-20 mg/kg), dl-propranolol (10-40 mg/kg) blocked head swaying and backward walking; only methysergide inhibited circling. All these drugs, except methysergide, markedly enhanced the cyclazocine-induced locomotor activity. In contrast, ketanserine (0.5-2 mg/kg) and pirenperone (0.05-0.2 mg/kg), serotonin antagonists with selective affinity for 5-HT2 receptors had no effects on the abnormal behaviors and locomotor activity. Taken together, these results suggest that a serotoninergic mediation is involved in the cyclazocine-induced abnormal behaviors, and that serotonin exerts an inhibitory control on the locomotor activity produced by the drug. These effects are probably associated with 5-HT1 receptors. Further experiments have shown that the drugs having being able to potentiate cyclazocine-induced locomotor activity, similarly potentiate the locomotor activity induced by levallorphan, morphinan derivative with cyclazocine-like properties but do not enhance the hyperactivity produced by a low dose of morphine. The data reported here, provide a contribution to the informations concerning the neuromediation of the effects of mixed kappa and sigma agonists and allow to compare the mechanism of action of cyclazocine with those of other psychotomimetic drugs.

Influence of aging on cerebral energetic metabolism was evaluated during and after severe hypoglycemia in rats respectively 20 (adults), 60 (matures) or 100 (senescents) week-old. Cerebral content of carbohydrates, amino-acids, ammonia, ATP, ADP, AMP, creatine phosphate and creatine was analysed after 20 min insulin induced hypoglycemia and after 20 min hypoglycemic recovery induced by glucose infusion. In the rats of different ages tested, effect of raubasine (0.85 mg X kg-1 i.p. and i.v.), almitrine (2.68 mg X kg-1 i.p. and i.v.) and association almitrine plus raubasine (at the same doses) on post-hypoglycemic recovery was tested. Aging does not affect the cerebral metabolic disorders occurring in severe hypoglycemia, but rather the metabolic changes during the post-hypoglycemic restitution. In fact there is lower restitution of the concentrations of cerebral cortical metabolites in older rats: the concentrations of many amino-acids and adenylate nucleotides remains largely abnormal. Compared with saline treated post-hypoglycemic rats, raubasine decreases by 15 to 20% cerebral glucose and pyruvate contents in "adults" and "matures" rats and by 10 to 15% glutamate content in rat of different ages tested. Almitrine decreases by 20% cerebral glucose concentration in "matures" and "senescent" rats. In this latter group, almitrine decreases lactate and ammonium contents and increases by 23% glutamine level. In rats of all ages that were submitted to 20 min insulin induced hypoglycemia followed by 20 min glucose induced post-hypoglycemic recovery, the association almitrine plus raubasine decreases by 20 to 30% cerebral glucose, pyruvate and lactate contents and decreases by 15% glutamate. In older brains the association almitrine plus raubasine decreases by 50% cerebral content in ammonium and concomitantly induces an equivalent increase in glutamine content. The effect of the combination almitrine plus raubasine is characterized by an increase in rate of metabolic recovery process in all ages tested.

Cardiac beta-adrenergic receptors (beta AR) were studied in rats after 4 months of diabetes induced by streptozotocin (50 mg/kg, i.v.). Saturation binding studies performed using [125I]-iodocyanopindolol (ICYP) as an antagonist ligand showed that the number and affinity of beta AR were not significantly altered. Analysis of competition curves of ICYP binding by the agonist (-)-isoproterenol showed that diabetes induces an increase in the (-)-isoproterenol IC50 and a steepening of the curve ("pseudo-Hill" coefficient not significantly different from 1) in the absence of Gpp(NH)p, while these parameters were not significantly modified in the presence of Gpp(NH)p (10(-4) M). These results indicates that beta AR were not significantly reduced in number but altered in their capacity to efficiently couple with the GTP-binding protein of adenylate cyclase (AC). These data can be correlated to the alteration of beta-adrenergic stimulation of cardiac AC previously observed after 4 months of diabetes. The characteristics of beta AR alteration at this stage of the disease are similar to those of a first step of a beta AR desensitization process due to overstimulation.

Acute administration of clenbuterol, a lipophilic beta-adrenergic agonist, decreases motor activity and antagonizes the reserpine-induced hypothermia in mice. After chronic administration of clenbuterol, the acute effect on motor activity disappears (tachyphylaxis) and the acute effect on reserpine hypothermia is potentiated (facilitation). These effects of clenbuterol (either acute or chronic + acute treatments) are not abolished after specific lesions of the noradrenergic system by the neurotoxin DSP-4 which reduces the cerebral levels of norepinephrine to 30% of controls. Although it cannot be excluded that a 70% lesion may be insufficient, another explanation is that beta-adrenergic receptors involved in hypomotility and in reserpine-induced hypothermia may not be located on noradrenergic neurons or may be different from the post-synaptic beta-adrenergic receptors which become hypersensitive after DSP-4 denervation.

Using a modified Boyden chamber, random migration and chemotaxis of rat polymorphonuclear leucocytes (PMN) were assessed after incubation in vitro in a solution of colchicine (1.5 X 10(-5) M). The results obtained were compared to random migration or chemotaxis of the same cellular pool treated in vitro or in vivo by N-isopropyl-amino-2-pyrimidine phosphate (isaxonine 4.10(-5) M or 75 and 150 mg/kg respectively). Isaxonine partially inhibited the effect of colchicine on PMN chemotaxis while random migration remained unaffected. Isaxonine might partially inhibit the noxious effect of colchicine on microtubule disruption by a direct effect (polymerization of free tubulin) and/or indirect effect (impairment of disorganizing activity) on PMN microtubules.

A new dopaminergic innervation has been described quite recently: the dopaminergic spinal cord system. In this review are presented the different steps which lead to the individualization of this dopaminergic system and the reported results actually available concerning its probable anatomical organization. Finally, most of the data which illustrate the possible functions of this system are discussed. Interestingly, its participation in the transmission of nociceptive signals and the control of cardiovascular patterns appear now well established. Such functional implications give new information on the possible targets of central dopaminergic agonists and antagonists, particularly at the cardiovascular level.

The pharmacokinetics of sodium thiopental was studied in 9 normal dogs of various ages by the usual bolus method. Data were fittable by a two compartment open model in 8, three compartments were needed in one. Constant-rate infusions, as used in cerebral resuscitation, were performed in 6 of them. As expected, constant blood levels could not be obtained during the distribution phase which lasted about 6 hours. From the individual pharmacokinetic constants, the time equation of infusion rate intended to exactly compensate for distribution was calculated. The resulting "modulated infusions" succeeded in reducing the blood level trough from 50% to 20%. After the end of infusions, the decrease of plasma levels exhibited a non linear pattern which had not been noticeable in the elimination phase after boluses. Such unknown non linearity may lead to systematic errors when calculating pharmacokinetic parameters: this could explain why a complete correction was not obtained with modulated infusions. A better parametrization method in the case of non-linear elimination is under study.