Journal de pharmacologie最新文献

The depolarization produced by acetylcholine (ACh) (5.5 microM-11 mM) and by tetraethylammonium (TEA) (0.95-48 mM) in chick skeletal muscle were recorded using a sucrose-gap external recording device. The gap is constructed from perspex blocks of 3 main chambers which contain the preparation and are superfused with Krebs solution (chamber 1), Krebs solution containing test drug solution (chamber 3) and isotonic sucrose solution (chamber 2). Drugs were added directly into the superfusion stream leading to chamber 3 which contained the distal and active part of the muscle. Recordings of electrical responses were made via a pair of calomel electrodes, in contact with woollen wicks extending from chambers 1 and 3, leading to a preamplifier linked to a cathode ray oscilloscope and a potentiometric pen recorder. The results showed that TEA, a potassium channel blocker, produced a small depolarization (about 1 mV), whereas ACh produced a large depolarization (about 8 mV), and that the TEA-induced depolarization was in part due to the release of endogenous ACh at the neuromuscular junction. Other findings include the characteristic feature of TEA-induced depolarization, i.e. its long latency (about 1 min) and the biphasic response, a small depolarization followed by an after-hyperpolarization (about 2 mV). The results are in favour of the possibility that TEA may act at both pre- and postsynaptic membranes at the avian neuromuscular junction.

The binding of different drugs were investigated on benzodiazepines and GABA receptors using P2 fraction or 0.05% Triton X-100 treated membrane preparation (TX-100 P) obtained from rat's CNS. Bicuculline and picrotoxin have the ability to modulate the specific 3H-flunitrazepam binding to its receptor present in P2 fraction; this modulation decreases for bicuculline and disappears for picrotoxin when a TX-100 P was used. Bicuculline at the opposite of picrotoxin displaces 3H-GABA binding on TX-100 P. The beta-CCE binds to the brain benzodiazepines receptor with a high affinity (IC50 = 8.5 nM on TX-100 P) and does not inhibit the binding of 3H-GABA on TX-100 P. On the contrary, other related carbolines such as harmine, harmaline, harmane and harmalol have a much lower ability to inhibit flunitrazepam binding (IC50 between 28 and 130 microM with TX-100 P) and can also inhibit 3H-GABA binding (IC50 between 75 and 186 microM with TX-100 P). But the inhibition of 3H-GABA binding by those related carbolines can't be reversed by a benzodiazepine like flunitrazepam or a benzodiazepine antagonist like Ro 15-1788.

Global forebrain ischemia was induced in unanesthetized rats by electrocauterization of the vertebral arteries and transient occlusion of the common carotid arteries for 30 minutes. Local cerebral blood flow (l-CBF), cortical tissular pO2 (tpO2), electrocorticogram (ECoG), mean arterial pressure, pH and blood gas determinations and neurologic deficit were evaluated during and after ischemia. Cerebral ischemia induced a substantial decrease in l-CBF and tpO2 and the ECoG was flattened. One hour after ischemia, the neurologic deficit was at its maximum, l-CBF was still decreased and ECoG depressed. Twenty-four hours later, the neurologic deficit was still present but ECoG, l-CBF and tpO2 had returned to their preischemic values. Treatments with naloxone were performed during, after or during and after ischemia. When naloxone was administered during or after ischemia, postischemic neurologic deficit was not influenced by the treatment. A slight but significant improvement of the neurologic score was observed when naloxone was injected during ischemia and infused thereafter. Our results show that this experimental model of cerebral ischemia is suitable for quantification of neurologic alterations during the postischemic period. The slight improvement observed with naloxone suggests that endogenous opioids may have a minor role in the neurologic consequences of ischemia.

Responses to the beta-adrenoceptor agonists isoprenaline (Iso) (non selective), salbutamol (Sal) (beta 2-selective) and noradrenaline (NA) (beta 1-selective) were studied on incubated and superfused rat lung strip. In both conditions, Iso and Sal elicited dose-related relaxations of lung strip and these responses were unaffected by the presence of phentolamine (Phen) 10(-5) M. Contractile responses to NA were obtained when it was used alone whereas in the presence of Phen 10(-5) M, NA elicited relaxant responses. The relative potencies of Iso : Sal : NA (plus Phen) were 100 : 20 : 0.69. This demonstrates that beta 2-adrenoceptor is the predominant beta-subtype involved in responses. Propranolol (10(-4) M) completely abolished the relaxant responses to Iso. However, after the addition of Iso tissue responded normally to drugs acting by other mechanisms. Thus, relaxations were obtained with caffeine and contractions with acetylcholine (AcH) or NA. This shows that responses to Iso are mediated only by beta-adrenoceptors. Propranolol and the selective beta-blocking agents butoxamine (beta 2) and atenolol (beta 1) competitively antagonized the effects of Iso. The Schild plots obtained had slopes which did not differ significantly from -1 and mean pA2 values were: 7.82 for propranolol; 6.32 for butoxamine and 5.22 for atenolol. These experiments were carried out in the absence of catecholamine uptake inhibitors, since in a preliminary set of experiments no significant changes of lung strip responses to Iso were observed in the presence of cocaine (10(-5) M) or corticosterone (10(-5) M). In conclusion, it appears that incubated rat lung strip possesses intrinsic tone and, although it cannot be considered a representative preparation of peripheral airways, it provides a valid model for investigating the direct-effects of drugs which act at beta-adrenoceptors.

Structure-activity relationships were studied in vitro on a number of natural and artificial steroids in order to assess their progestagen specificity. These substances included a new compound derived from 19 nor progesterone, TX066 or nomegestrol acetate, and two synthetic intermediates, TX045 and TX071, all prepared by Laboratoires Theramex. The experiments involved binding competition on the cytosolic receptors prepared from target organs against specific radiolabelled ligands. Relative affinities were determined in rats against progesterone (P), aldosterone (A) and dexamethasone (DM), by displacement of: (3H)-ORG 2058 from the progestagen receptor of uterus, (3H)-A from Type I (mineralocorticoid) receptor of the kidneys and (3H)-DM from glucocorticoid receptors of the kidney (Type II) and of the liver. The various modifications introduced in the progesterone molecule led to sequences in competition potency which were either parallel or opposite in the progesterone compared to the 19 nor progesterone series. The main practical conclusion is that TX066 which is intended for use as a progestagen presents very little mineralo- and glucocorticoid activities at the receptor level, while its affinity for the progestin receptor is nearly as good as that of progesterone. The two derivatives TX045 and TX071 displayed very little or no progestagen affinity while their mineralo- and glucocorticoid potencies were between those of 19NP and TX066.

The polyethylene glycols (PEG) frequently used as solvents of non hydrosoluble molecules present toxic and pharmacodynamic properties. The effect of PEG 300 (10 ml/kg) on the modifications of the central nervous system (CNS) previously induced by a subchronic intoxication with triethyltin salt (TEE) (2 mg/kg p.o. for 5 days) has been studied in rat. The following parameters are recorded: measure of brain edema, concentration of the aminergic neurotransmitters in four different brain areas, neurological status, behaviour, mortality. The PEG 300 antagonizes or reduces some of the effects of the TEE: edema, behavioral disturbances, mortality. On the opposite, no change in the amines and their metabolites induced modifications is observed. This selective antagonism towards some of the components of TEE brain toxicity brings more information on pharmacological properties of this solvent and opens a discussion on the role of neurotransmitters on brain edema.

A comparison was made of contractions produced by submaximal doses of oxytocin, noradrenaline, PGE2 and PGF2 alpha in estrogen-dominated rat uterus after the preparation had been loaded in Ca-free medium supplemented with EDTA 3 mM. The experiments were carried out in the presence of EDTA 1 mM to complex the contaminating Ca. The contraction was sustained as long as the preparation was exposed to the drug and was relaxed by washing. Cumulative concentration-response curves to oxytocin (6.25-100 microM), noradrenaline (0.05-1.6 mM), PGE2 (0.1-1.6 microM) and PGF2 alpha (0.02-0.32 microM) were made. The threshold concentration for PGF2 alpha was much lower than for PGE2, oxytocin and noradrenaline. Isoprenaline (10- -10(-4)M), KCl (56.3 mM) and caffeine (5 mM) were added. The results showed that isoprenaline and KCl did not produce contractile response. Caffeine produces only a small decrease in the resting tension and this effect is not reversible. After addition of noradrenaline, a concentration of oxytocin (6 microM) produced a uterine contraction smaller than the control response of uterus to oxytocin. The response to the oxytocin applied after washing out the caffeine was the same as the control response. All agonists tested that were capable of inducing uterine contraction in Ca-free medium act through specific receptors. This suggests a relation between receptor-operated Ca-channels and intracellular Ca-stores.

The effects of clomipramine treatment (5 mg/kg s.c. a day during 21 days) on dog platelet alpha 2-adrenoreceptivity were investigated. The radioligand binding studies on platelet membrane preparations showed that the antidepressant treatment promotes a decrease in the number of [3H]-yohimbine binding sites. The measurement of the inhibition of PGE1-induced cyclic AMP accumulation in the whole platelet indicated that the biological event immediately associated with alpha 2-adrenergic stimulation was not modified. The aggregatory response to ADP or ADP plus adrenaline was totally abolished in clomipramine-treated platelets. The diastolic pressor responses to noradrenaline or adrenaline injections (after propranolol and prazosin administration) in chloralose anaesthetized dogs were not affected by clomipramine treatment. This work shows that variations in the binding capacities of alpha 2-adrenergic sites are not always linked to modifications of related physiological events.

The effect of indomethacin (10 mg.kg-1 i.p.) on frontal cerebral blood flow has been investigated in male Sprague Dawley rats using the hydrogen clearance technique. Indomethacin elicited a marked reduction in cerebral blood flow in awake free-moving animals. The response to indomethacin was prevented by pretreatment with pentobarbital (50 mg X kg-1, i.p.). On the other hand, indomethacin was able to antagonize the cerebral vasodilation due to apomorphine chlorhydrate (2 mg X kg-1, i.p.), dexamphetamine tartrate (3 mg X kg-1, i.p.) or immobilization stress. Taken together, the above results lead to the suggestion that indomethacin can suppress the coupling of cerebral blood flow to brain metabolism. Further investigations are needed to ascertain whether this uncoupling influence is related to brain cyclooxygenase inhibition.