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Showing papers in "Archives internationales de pharmacodynamie et de thérapie in 1985"


Journal Article
TL;DR: 5-CT not only has a binding, but also a functional specificity for 5- HT1 receptors, which seems to be a useful tool for investigating 5-HT1 receptor mediated functional responses.
Abstract: The pharmacological effects of 5-hydroxytryptamine (5-HT) on heart rate, arterial blood pressure and urinary bladder pressure in the rat, and on the bronchi and ileum of the guinea-pig were compared with those of 5-carboxamidotryptamine (5-CT), a compound which binds specifically and with high affinity to 5-HT1 binding sites in rat brain membranes. 5-HT caused a transient bradycardia and a triphasic blood pressure response consisting of an initial short-lasting hypotensive, a pressor and, finally, a longer-lasting depressor phase. Analysis with mecamylamine, cyproheptadine and ketanserin indicated that the initial bradycardia and hypotension, and the pressor and tachycardic responses to 5-HT were due to, respectively, the M and 5-HT2 receptors. 5-CT showed no or little activity on these receptors, but elicited a marked hypotensive response. The prolonged hypotensive effects of both 5-HT and 5-CT were apparently mediated by 5-HT1 receptors, since they were unaffected by cyproheptadine or ketanserin, but were antagonized by high doses (greater than 2.5 mg.kg-1) of methysergide, which has an appreciable affinity for 5-HT1 binding sites. On the guinea-pig bronchi and the rat urinary bladder, which were contracted by 5-HT via 5-HT2- and, in the case of bladder, also via M-type 5-HT receptors; 5-CT was without any effect. The guinea-pig isolated ileum was relaxed by low concentration (5 X 10(-6) M), probably via 5-HT1 receptors demonstrated in this tissue, and contracted by higher concentrations of 5-CT. However, the contractile effect of 5-HT on the ileum, exerted via the M- and 5-HT2-type 5-HT receptors, was much more than that of 5-CT. Our results demonstrate that 5-CT not only has a binding, but also a functional specificity for 5-HT1 receptors. This compound seems to be a useful tool for investigating 5-HT1 receptor mediated functional responses.

70 citations


Journal Article
TL;DR: Yohimbine was able to reverse the inhibitory effects of alpha2 agonists, the antisecretory effect of these agents predominantly involved the action on alpha2 adrenoceptors.
Abstract: The antisecretory and gastric ulcer protective effects of clonidine were studied in four different experimental models in rats. The effects were compared with two other alpha2 agonists guanfacine and B-HT 920 at equimolar dose basis. Clonidine (0.05-1 mg/kg) produced antisecretory effect at all doses but the maximum effect was noticed at 0.1 mg/kg. Its ulcer protective effect against immobilization stress-induced ulcers was comparable to diazepam but was not completely reversed by Ro 15-1788, a benzodiazepine antagonist. Clonidine showed an inhibitory response on basal gastric secretion in the continuous perfusion technique. It also reversed the effects of systemically administered indomethacin on gastric acid secretion and ulcers. Guanfacine produced a biphasic response on basal gastric secretion. The excitatory response was prolonged by bilateral vagotomy and inhibited by cimetidine treatment. Tachyphylaxis was observed in its excitatory response. It also showed inhibitory effects on pyloric ligation and indomethacin-induced gastric acid secretion. While B-HT 920 shared the antisecretory effects of clonidine and guanfacine in pyloric ligation, stress and drug-induced gastric secretion and ulcer protection, it had little or no effect on basal secretion in the continuous perfusion of the stomach. Since yohimbine was able to reverse the inhibitory effects of alpha2 agonists, the antisecretory effect of these agents predominantly involved the action on alpha2 adrenoceptors.

52 citations


Journal Article
TL;DR: The results suggest that the antinociceptive activity of these six antidepressant drugs in acute experimental pain could involve opiate mechanisms.
Abstract: The antinociceptive effects of tricyclic and atypical antidepressants were studied using the rat tail mechanical method. Clomipramine produced analgesia at the doses of 30 and 40 mg/kg, desimipramine at 10, 20 and 40 mg/kg, maprotiline at 20 and 30 mg/kg, mianserin at 30 mg/kg, nomifensine at 1, 2.5 and 5 mg/kg, indalpine at 10, 20 and 40 mg/kg, viloxazine at 60 and 80 mg/kg. Naloxone (0.8 mg/kg) abolished the antinociceptive action of these antidepressant drugs. These results suggest that the antinociceptive activity of these six antidepressant drugs in acute experimental pain could involve opiate mechanisms.

48 citations


Journal Article
TL;DR: Hypolaetin-8-glucoside, a novel flavonoid isolated from Sideritis mugronensis and possessing anti-inflammatory and gastroprotective properties in the rat, was compared with the structurally related flavonoids hypoletin, isoscutellarein, rutin, quercetin and kaempferol for inhibitory effects on the enzymes soybean 15-lipoxygenase and snake venom phospholipase A2.
Abstract: Hypolaetin-8-glucoside, a novel flavonoid isolated from Sideritis mugronensis and possessing anti-inflammatory and gastroprotective properties in the rat, was compared with the structurally related flavonoids hypolaetin, isoscutellarein, rutin, quercetin and kaempferol for inhibitory effects on the enzymes soybean 15-lipoxygenase and snake venom phospholipase A2. The aglycone flavonoids dose-dependently inhibited snake venom phospholipase A2 but the glycosides hypolaetin-8-glucoside and rutin were inactive. All 6 flavonoids inhibited soybean 15-lipoxygenase with no differences between glycosides and aglycones, although flavonols appeared more active than flavones. The inhibition of these enzyme activities cannot explain the anti-inflammatory action of hypolaetin-8-glucoside, unless a significant proportion of the drug reaches the target tissue as the aglycone, hypolaetin.

44 citations


Journal Article
TL;DR: Urapidil proved to possess modest but significantbeta 1-adrenoceptor blocking activity, accompanied by a certain degree of intrinsic sympathomimetic activity (TSA) at the level of the cardiac beta 1- adrenoceptors.
Abstract: Urapidil is a novel antihypertensive agent, chemically related to uracil. Its cardiovascular profile was evaluated in a variety of pharmacological models. Urapidil caused a significant decrease of blood pressure in intact rats, both hypertensive (SHR) and normotensive (WKY), as well as in α-glucochloralose-anaesthetized cats. Reflex tachycardia was not observed. An analysis in pithed rats showed that urapidil is an α-adrenoceptor blocking drug with an obvious selectivity for postsynaptic α1- over α2-adrenoceptors. The α1-adrenoceptor blocking potency proved quantitatively less than that of prazosin. Experiments on isolated aorta preparations and radioligand binding studies confirmed the selectivity of urapidil for α1- over α2-adrenoceptors. The involvement of urapidil with presynaptic α2-adrenoceptors proved negligible. Urapidil proved to possess modest but significant β1-adrenoceptor blocking activity, accompanied by a certain degree of intrinsic sympathomimetic activity (TSA) at the level of the cardiac β1-adrenoceptors. No significant interaction with vascular β2-adrenoceptors was observed. High doses of urapidil caused pressor effects of a probably unspecific nature; neither α-adrenoceptors nor 5HT-receptors were involved. When injected into the vertebral artery of the cat, urapidil caused a significant central hypotensive effect which was different from that of clonidine and related drugs, since it could not be blocked by yohimbine (α2-receptor antagonist). Similarly, the modest sedation produced by urapidil in mice remained uninfluenced by yohimbine. The urapidil molecule does not contain any stereoisomers. Accordingly, one and the same molecule possesses the following pharmacodynamic properties: postsynaptic α1-adrenoceptor blockade; weak postsynaptic α2-adrenoceptor blockade; modest but selective β1-adrenoceptor blockade with ISA; central hypotensive activity not mediated by central α2-adrenoceptors.

41 citations


Journal Article
TL;DR: In anesthetized dogs, relaxed by suxamethonium and ventilated, the effect of repeated injections of clonazepam on the EEG spiking activity maintained by an infusion of pentetrazole was studied; there was no indication for the development of acute tolerance.
Abstract: Dogs were treated with clonazepam, 0.5 mg/kg orally, b.i.d., for 3-6 weeks. The development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold by infusion of pentetrazole, 10 min after i.v. injection of 0.1 mg/kg clonazepam. In all 6 dogs tolerance was apparent after 1-2 weeks of treatment; in 1 dog the anticonvulsant effect had been totally lost after 3 weeks of treatment. Tolerance is regarded to be "functional" since the elimination half-life of clonazepam increased considerably with the duration of the treatment. One day after withdrawal of clonazepam the convulsive threshold had fallen below the control value in all dogs, but 1 week later it had recovered to the control level. Other signs of physical dependence after withdrawal were hyperthermia in 2 dogs as well as anorexia with weight loss in 5 out of the 6 dogs. In anesthetized dogs, relaxed by suxamethonium and ventilated, the effect of repeated injections of clonazepam on the EEG spiking activity maintained by an infusion of pentetrazole was studied; there was no indication for the development of acute tolerance.

36 citations


Journal Article
TL;DR: The results suggest that nipradilol possesses an alpha 1-adrenoceptor blocking action; it possesses very weak or practically no presynaptic alpha 2-blocking activity but shows a non-competitive antagonistic action on postsynapticalpha 2-adRenoceptor mediated contractile responses.
Abstract: Nipradilol competitively antagonized norepinephrine- or phenylephrine-induced contractile responses of guinea-pig thoracic aorta. These actions of nipradilol were about 6 times less potent than those of phentolamine. Nitroglycerin showed a non-competitive antagonistic action on norepinephrine-induced contractions of aorta. Furthermore, nipradilol competitively inhibited norepinephrine-induced contractions of rat vas deferens and dose-dependently reduced the phenylephrine-induced inhibitory responses in rabbit ileum. These antagonistic actions of nipradilol were 30 to 100 times less potent than those of phentolamine. Nitroglycerin did not appreciably affect these alpha-adrenoceptor mediated responses in rat vas deferens and rabbit ileum. The inhibitory action of clonidine on the twitch contraction of rat vas deferens produced by intramural stimulation was only slightly antagonized by nipradilol (pA2 = 5.4). Nipradilol and nitroglycerin showed a non-competitive antagonistic action on clonidine-induced contractions of canine saphenous vein after the exposure to phenoxybenzamine, while phentolamine competitively inhibited the clonidine responses. These results suggest that nipradilol possesses an alpha 1-adrenoceptor blocking action; it possesses very weak or practically no presynaptic alpha 2-blocking activity but shows a non-competitive antagonistic action on postsynaptic alpha 2-adrenoceptor mediated contractile responses.

33 citations


Journal Article
TL;DR: The oral analgesic activities of 15 NSAIDs were determined in the phenylquinone-induced writhing test in mice to predict human dosages of NSAIDs according to the equation Y = 8.26X + 535, where Y is the projected human daily dosage (mg).
Abstract: The oral analgesic activities (ED50's) of 15 NSAIDs were determined in the phenylquinone-induced writhing test in mice. ED50 values (mg/kg) were: acetylsalicylic acid (182), fenclofenac (168), phenylbutazone (129), ibuprofen (82.2), diflunisal (55.6), benoxaprofen (25.4), naproxen (24.1), mefenamic acid (20.7), indomethacin (19.0), meclofenamate sodium (9.60), sulindac (7.20), fenoprofen calcium (3.70), tolmetin (1.30), zomepirac sodium (0.70), and piroxicam (0.44). Significant linear correlations were found between mouse ED50 values and the various recommended human analgesic or anti-inflammatory dosages. Thus, analgesic ED50 values (mg/kg p.o.) in mice (X) may be used to predict human dosages (Y) of NSAIDs according to the equation Y = 8.26X + 535, where Y is the projected human daily dosage (mg).

29 citations


Journal Article
TL;DR: 8-OH-DPAT exerts potent hypotensive and bradycardic effects in the unanesthetized spontaneously hypertensive rat, and whether this effect is the result of serotonin receptor activation is not yet clear.
Abstract: 8-Hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), a reported serotonin receptor agonist, was found to produce drops both in mean arterial blood pressure (MAP) and heart rate in unanesthetized spontaneously hypertensive rats. The hypotensive episodes were elicited whether the compound was given intraperitoneally (minimum hypotensive dose = 0.02 mg/kg), orally (7.5 mg/kg or intracerebroventricularly (0.014 mg/kg). No bradycardia, however, was elicited following intracerebral infusions of 8-OH-DPAT. The bradycardia and hypotension were moderate in duration (1-4 hr). The serotonin receptor blocking agents cyproheptadine (5 mg/kg i.p.) and methergoline (1.0 mg/kg i.p.) failed to reduce either of the cardiovascular actions of 8-OH-DPAT. Methiothepin (0.5 mg/kg), another serotonin receptor blocker which produces falls in MAP itself, failed to attenuate 8-OH-DPAT-induced hypotension, but did block 8-OH-DPAT-induced bradycardia. 8-OH-DPAT exerts potent hypotensive and bradycardic effects in the unanesthetized spontaneously hypertensive rat. Whether this effect is the result of serotonin receptor activation is not yet clear.

25 citations


Journal Article
TL;DR: The nootropic drug, oxiracetam (25 or 50 mg/kg i.p.), was tested in two inbred strains of mice, subjected to shuttle-box avoidance training, and improved avoidance acquisition in good performers BALB/c mice more than in poor performers C57BL/6 mice.
Abstract: The nootropic drug, oxiracetam (25 or 50 mg/kg i.p.), was tested in two inbred strains of mice, subjected to shuttle-box avoidance training. The drug improved avoidance acquisition in good performers BALB/c mice more than in poor performers C57BL/6 mice. In both cases the avoidance facilitating action was evident only if training was preceded by a five-day pretreatment. The nootropic prototype, piracetam (100 mg/kg), facilitated avoidance acquisition in pretreated BALB/c, but not in C57BL/6 mice.

25 citations


Journal Article
TL;DR: Experiments in Ca++-free medium indicate the existence in the proximal colon of a significant intracellular Ca++ store which could be mobilized during carbachol but not high K+-induced tonic contractions.
Abstract: Exposure of isolated segments of rat duodenum and proximal colon to either high K+ (55.9 mM) or carbachol (0.1 mM) produced a typical biphasic contraction whose tonic component appears to be almost entirely dependent upon the presence of extracellular Ca++. Verapamil and nifedipine suppressed high K+-and carbachol-induced tonic contractions of both duodenum and proximal colon but a large component of carbachol-induced contraction of proximal colon was insensitive to these substances. Verapamil and nifedipine were: a. 5 and 3 times more effective in antagonizing high K+-induced tonic contractions in the rat duodenum than in the proximal colon, respectively, and b. 10 and 4 times more effective in antagonizing high K+ than carbachol induced tonic contractions of rat duodenum, respectively. The verapamil- or nifedipine- resistant component of carbachol induced tonic contraction of proximal colon was suppressed by drugs which, like octylonium bromide and urethane, have been shown to interfere with mobilization of Ca++ from intracellular storage sites. Experiments in Ca++-free medium indicate the existence in the proximal colon of a significant intracellular Ca++ store which could be mobilized during carbachol but not high K+-induced tonic contractions. These findings indicate that, in the rat intestine, significant regional differences exists in Ca++ pools mobilized by different activating stimuli and in sensitivity to the blocking action of drugs which interfere with Ca++ mobilization from either intra- or extracellular Ca++ pools.

Journal Article
TL;DR: The data suggest that GABA can inhibit sympathetic neurotransmission in rabbit ear artery through the stimulation of a prejunctional receptor of the GABAB subtype.
Abstract: GABA 100 microM inhibited neurogenic vasoconstrictor responses elicited in rabbit ear artery by field stimulation at various frequencies. GABA was ineffective both on resting tone and on noradrenaline (0.05-5 microM)- and high-K+ (24-54 mM)-induced tonic contraction. GABA effectiveness against field stimulation-induced vasoconstriction was inversely related to the frequency of stimulation. This action of GABA was mimicked by a selective GABAB agonist, such as baclofen (100 microM), but not by selective GABAA agonists as muscimol (100 microM) and homotaurine (100 microM). The selective GABAB antagonists 5-aminovaleric acid (1 mM) and homotaurine (100 microM) completely suppressed the inhibitory effect of GABA on field stimulation-induced vasoconstrictions. GABA action was partially reversed also by the selective GABAA antagonist picrotoxin (100 microM); however, this drug "per se" determined an increase in amplitude of field stimulation-induced contractions which in turn could have determined the minor effect of GABA. As a whole these data suggest that GABA can inhibit sympathetic neurotransmission in rabbit ear artery through the stimulation of a prejunctional receptor of the GABAB subtype.

Journal Article
TL;DR: It is concluded that the neurotoxic and nephrotoxic effects of lithium carbonate and haloperidol might be a consequence of increased lipid peroxidation in the cerebral cortex and the kidney, respectively.
Abstract: Lithium carbonate as well as haloperidol increased lipid peroxidation in rat cerebral cortex synaptosomes and rat kidney homogenates while sulpiride had no significant effects. A combination of lithium carbonate and haloperidol caused a greater increase in lipid peroxidation than did either lithium carbonate or haloperidol alone. It is concluded that the neurotoxic and nephrotoxic effects of lithium carbonate and haloperidol might be a consequence of increased lipid peroxidation in the cerebral cortex and the kidney, respectively.

Journal Article
TL;DR: It is suggested that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon, and the protective effect of flunarizine againstTXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.
Abstract: The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.

Journal Article
TL;DR: The results suggest that the behavioral features of yawning induced by apomorphine, physostigmine and pilocarpine differ from one another, and that physiological yawning as well as physostIGmine-induced yawning may be mediated by endogenous acetylcholine which stimulates both muscarinic and nicotinic receptors.
Abstract: Apomorphine, a dopamine receptor agonist, physostigmine, an anticholinesterase agent and pilocarpine, a cholinergic receptor agonist, produced yawning in rats, with the most effective doses being 0.25 mg/kg, 0.2 mg/kg and 4 mg/kg, respectively. The yawning induced by these drugs is characterized by differences in direction of head moving, tongue protruding and duration of the yawn. The apomorphine-induced yawn was characterized by a slow and wide opening of the mouth with the head moving mainly downward and with a marked protrusion of the tongue. The apomorphine-induced yawn was 3.6 sec in duration. Physostigmine elicited a similar yawn to that seen with apomorphine, except for moving of the head in the upward direction. The pilocarpine-induced yawn was characterized by the head moving forward with a high frequency but without tongue protrusion and lasted 1.8 sec. The frequency of physiological yawning was low, but the behavioral posture was almost similar to that of physostigmine-induced yawning. The characteristics of yawns induced by these agents were unchanged at all doses of the drugs. Different doses altered the frequency of yawning. After pretreatment with mecamylamine, the apomorphine- and physostigmine-induced tongue protruding was inhibited and the duration of the yawning induced by the both drugs was shortened. The results suggest that the behavioral features of yawning induced by apomorphine, physostigmine and pilocarpine differ from one another, and that physiological yawning as well as physostigmine-induced yawning may be mediated by endogenous acetylcholine which stimulates both muscarinic and nicotinic receptors.

Journal Article
TL;DR: Results suggest that oxatomide exerts inhibitory effects on SRS-A activities, and that such effects could partly explain the anti-allergic effects of the compound.
Abstract: Effects of oxatomide, an orally active anti-allergic drug, on several activities of slow reacting substance of anaphylaxis (SRS-A) and synthetic leukotrienes (LT) C4, D4 and E4 were investigated. In addition, such activities of oxatomide were compared with those of FPL-55712. Oxatomide, at a concentration of 3 X 10(-8) M or higher, inhibited the phasic contractions of isolated guinea-pig ileum induced by partially purified SRS-Agp and SRS-Arat which were anaphylactically generated from guinea-pig lung fragments and rat peritoneal cavities, respectively. The 50% inhibitory concentrations (IC 50) of oxatomide to the contractions by SRS-Agp and SRS-Arat are 2.7 +/- 0.9 X 10(-7) M and 1.6 +/- 0.3 X 10(-7) M, respectively. Oxatomide also inhibited the LTC4, LTD4, histamine or serotonin-induced contractions of ileum. FPL-55712, a specific SRS-A antagonist, inhibited SRS-Agp, SRS-Arat, LTC4 or LTD4-induced contractions at concentrations ranging from 10(-9) M to 10(-6) M without affecting histamine and serotonin responses. Oxatomide produced dose-dependent relaxations of isolated guinea-pig tracheal and lung parenchymal strips precontracted with LTD4 and histamine. Oxatomide, at doses 10 and 30 mg/kg (p.o.), inhibited significantly the increase in vascular permeability produced by LTC4, LTE4, histamine and serotonin in rats. These results suggest that, although less effective and less selective as compared with FPL-55712, oxatomide exerts inhibitory effects on SRS-A activities, and that such effects could partly explain the anti-allergic effects of the compound.

Journal Article
TL;DR: The results indicate that purinergic mechanisms are involved in the maintenance and modulation of the seizure threshold within the limbic system.
Abstract: The effects of 2-chloroadenosine (2-CLA), a metabolically stable analogue of adenosine, on amygdaloid and hippocampal kindled seizures were examined in rats. Intraperitoneal injections of 2-CLA, 1.0 mg/kg, did not modify the evolution of either amygdaloid or hippocampal kindled seizures. 2-CLA in the dose of 3.0 mg/kg shortened the duration of both behavioral and electrographic convulsive manifestations while the dose of 5.0 mg/kg completely blocked the evolution of the kindled seizures. The results indicate that purinergic mechanisms are involved in the maintenance and modulation of the seizure threshold within the limbic system.

Journal Article
TL;DR: Phenoxybenzamine prevents and amyl nitrite reverses the otherwise lethal effects of cyanide, indicating that early death caused by cyanide may be due in part to cardiovascular-respiratory failure in addition to the classic poisoning of the cytochrome oxidase system.
Abstract: The use of amyl nitrite and phenoxybenzamine in the treatment of acute cyanide poisoning was evaluated. Sixty anesthetized beagle dogs were injected i.v. with sodium cyanide (2.5 mg/kg) and were followed for changes in the heart rate, electrocardiogram, respiration, blood pressure and methemoglobin concentration. Twenty control dogs died within 5 to 7 min, showing severe bradycardia, a sharp drop in arterial blood pressure, and respiratory paralysis. Pretreatment with phenoxybenzamine (0.5 mg/kg) prevented these changes in 8 of 10 dogs; however, this drug was ineffective if given after the cyanide. In contrast, amyl nitrite given after cyanide administration reversed both the cardiovascular changes and the respiratory paralysis in 24 of the 30 dogs studied. These changes occurred before the formation of significant amounts of methemoglobin and indicate that early death caused by cyanide may be due in part to cardiovascular-respiratory failure in addition to the classic poisoning of the cytochrome oxidase system. These studies indicate that phenoxybenzamine prevents and amyl nitrite reverses the otherwise lethal effects of cyanide.

Journal Article
TL;DR: The results suggest that the differential effects were produced by actions not related to the cyclo-oxygenase inhibition although the more consistent decrease of convulsive behavior may have resulted from inhibition of PG synthesis.
Abstract: Release of prostaglandins (PGs) from brain tissue increases during experimentally-induced and spontaneous seizures. However, whether PGs or other arachidonic acid metabolites have a role in induction of seizures is still unclear. The effectiveness of pretreatment with PG synthetase inhibitors on pentylenetetrazol (PTZ)-induced models of epilepsy was investigated in free-moving rats with chronically-implanted supracortical electrodes. The effects on the electrocortical and motor manifestations of both a subconvulsive (30 mg.kg-1) and a convulsive (60 mg.kg-1) dose of PTZ were examined. Mefenamic acid (15 or 50 mg.kg-1), meclofenamic acid (15 or 50 mg.kg-1), ibuprofen (30 or 90 mg.kg-1) and paracetamol (300 or 450 mg.kg-1) delayed the onset of PTZ-induced convulsions. But mefenamic acid and meclofenamic acid also potentiated the excitatory effects of both subconvulsive and convulsive doses of PTZ. Indomethacin (3, 10 or 30 mg.kg-1) had no significant effect. The results suggest that the differential effects were produced by actions not related to the cyclo-oxygenase inhibition although the more consistent decrease of convulsive behavior may have resulted from inhibition of PG synthesis.

Journal Article
Gross R, M. Kayser, Schramm M, R. Taniel, G Thomas 
TL;DR: The Calcium-agonistic dihydropyridine BAY K 8644 due to its novel mechanism of action could be the precursor of a new class of positive inotropic or antihypotensive drugs.
Abstract: The hemodynamic effects of the dihydropyridine-derivative BAY K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl)-pyridine-5-carboxylate), a chemical analogue of Nifedipine, were evaluated in 9 conscious, chronically instrumented dogs. Compared to Nifedipine, BAY K 8644 displays an opposite pharmacological profile. Dose-dependent hemodynamic effects are observed at doses of 4 micrograms/kg i.v. and above. With 32 micrograms/kg i.v. BAY K 8644 increases total peripheral vascular resistance by 100%. It causes a rise of both, systolic and diastolic, blood pressure up to 196/138 mm Hg at spontaneous sinus rhythm and up to 216/162 mm Hg when keeping heart rate constant at 150 beats/minute. Spontaneous heart rate reflexly drops to 52 beats/minute. Cardiac contractility as indicated by LV(dP/dt)max markedly increases from 2800 to 5600 mm Hg/s at spontaneous sinus rhythm and from 2900 to 6100 mm Hg/s while pacing at 150 beats/minute. These effects are apparently neither affected by alpha-adrenergic blockade with Phenoxybenzamine (5 mg/kg i.v.) nor by beta-blockade with Propranolol (0.5 mg/kg i.v.) but can be reserved by equivalent doses of Nifedipine. In conclusion, the Calcium-agonistic dihydropyridine BAY K 8644 due to its novel mechanism of action could be the precursor of a new class of positive inotropic or antihypotensive drugs.

Journal Article
TL;DR: It is suggested that gentamicin reduces glucose-induced insulin release by blocking the entry of Ca2+ into the B-cells, and alters the recognition and subsequent metabolism of glucose, and the system responsible for insulin secretion.
Abstract: These experiments were performed in order to determine the mechanism of action of the aminoglycoside antibiotic gentamicin on insulin release by isolated islets. Gentamicin significantly reduced the insulin release in the absence as well as in the presence of increasing concentrations of glucose. This effect was immediate and promptly reversible. In the presence of glucose plus high concentrations of K+ the antibiotic did not affect insulin secretion. Gentamicin did not change 86Rb efflux from perifused islets or the glucose metabolism in incubated islets. These data show that gentamicin does not alter the recognition and subsequent metabolism of glucose, and the system responsible for insulin secretion. We suggest that gentamicin reduces glucose-induced insulin release by blocking the entry of Ca2+ into the B-cells.

Journal Article
TL;DR: It is suggested that SCG does not affect the activity of the RAR or decrease the tracheal pressure in response to histamine challenge in an anesthetized dog, whereas SCG is effective in decreasing the response of both these parameters to antigen challenge when given prophylactically presumably by stabilizing the mast cell membrane.
Abstract: Sodium cromoglycate (SCG) blocks histamine release from sensitized mast cells challenged by antigen in vitro. Yet, not all the observed effects of SCG in vivo can be explained by this mechanism alone. Rapidly-adapting or "irritant" receptors (RAR) are thought to mediate reflex bronchoconstriction. Others have proposed that SCG may desensitize these receptors to histamine. We administered aerosols of histamine (100 micrograms/ml given for 3 min) before and after SCG (20 mg/ml aerosol for 5 min) to adult, mongrel dogs. SCG did not reduce the increase in tracheal pressure or RAR activity in response to histamine challenge. We also administered aerosols of Ascaris suum antigen (7 min) to dogs which had shown a positive skin reaction to subepidermal injection of this antigen. SCG attenuated both the increase in tracheal pressure and RAR nerve activity in response to the antigen challenge. These findings suggest that SCG does not affect the activity of the RAR or decrease the tracheal pressure in response to histamine challenge in an anesthetized dog, whereas SCG is effective in decreasing the response of both these parameters to antigen challenge when given prophylactically presumably by stabilizing the mast cell membrane.

Journal Article
TL;DR: The results suggest that alpha-adrenoceptors play a minor role in 5-HT-induced contractions in both tissues and indicate that 5-hydroxytryptamine receptors in human umbilical vessels are less sensitive to certain 5- HT2 antagonists than those of other tissues.
Abstract: In order to characterize the 5-hydroxytryptamine (5-HT) receptors, the contractile effects of both 5-HT and alpha-adrenoceptor agonists were studied in helically-cut human umbilical artery and vein in the presence of different antagonists. Noradrenaline, phenylephrine and clonidine caused maximum contractions in vein amounting to only 9%, 14% and 11% of the maximum effect of 5-HT, respectively. The maximum effects of noradrenaline and phenylephrine in artery were only 18% and 29% of that of 5-HT. Clonidine failed to induce contractions in the artery. The alpha 1-adrenoceptor blocker, prazosin (1 X 10(-6) and 1 X 10(-5)M) did not antagonize 5-HT-induced contractions in the tissues studied. However, yohimbine, an alpha 2-adrenoceptor blocker, shifted the concentration-effect curves of the 5-HT to the right without any reduction in the maximum responses in both tissues. The pA2 values for yohimbine against 5-HT (6.46 and 6.72 in artery and vein, respectively) were different from the values for yohimbine against alpha 2-adrenoceptor agonists (8.2 and 8.6 against clonidine and M-7, respectively) in dog saphenous vein which contains postsynaptic alpha 2-adrenoceptors. 5-HT2 receptor antagonists, ketanserin (1 X 10(-7)-1 X 10(-6)M) and mianserin (1 X 10(-7)-1 X 10(-6)M) competitively antagonized 5-HT-induced contractions in both tissues. The pA2 values for ketanserin (7.89 and 7.86 in artery and vein, respectively) and mianserin (8.06 and 7.73 in artery and vein, respectively) were significantly lower than those obtained in other tissues which were shown to contain 5-HT2 receptors by the other authors. The results suggest that alpha-adrenoceptors play a minor role in 5-HT-induced contractions in both tissues. Yohimbine antagonized 5-HT action competitively, by blocking probably 5-HT receptors. The results also indicate that 5-HT receptors in human umbilical vessels are less sensitive to certain 5-HT2 antagonists than those of other tissues. A third subtype of 5-HT receptors different from the 5-HT1 and 5-HT2 receptors may be present in the human umbilical artery and vein.

Journal Article
TL;DR: The results obtained suggest that the action of flavoxate is due to direct smooth muscle relaxation and does not involve anticholinergic activity.
Abstract: In order to clarify the pharmacological activity of flavoxate, its effect on the tone and spontaneous activity of the guinea-pig isolated ureter and of the muscle strip from rat urinary bladder were studied. Flavoxate, as well as papaverine, reduced all three parameters considered on the guinea-pig isolated ureter, namely: peristaltic motility, endoluminal pressure and longitudinal muscle contractility. In the same test, verapamil (a calcium antagonist), emepronium and atropine (both anticholinergic drugs) were used for comparison. Using strips of rat urinary bladder depolarized by KCl, flavoxate, papaverine and verapamil displayed a relaxant activity, while anticholinergic compounds such as atropine, hyoscine and emepronium failed to relax this tissue. In another series of experiments the effects of flavoxate and anticholinergic drugs on the contraction elicited by vagal electrical stimulation of the guinea-pig isolated stomach in toto were assayed. The results obtained suggest that the action of flavoxate is due to direct smooth muscle relaxation and does not involve anticholinergic activity.

Journal Article
TL;DR: It is concluded that prolonged cold storage on the isolated canine intermediate auricular artery may not cause complete denervation of adrenergic nerve fibers and responsiveness to vasoactive substances except histamine remains almost the same in non-stored vessels.
Abstract: Using the cannula inserting method, we investigated the effects of prolonged cold storage (5-7 days, at 4 degrees C) on vasoconstrictor responses of the isolated and perfused canine intermediate auricular artery to norepinephrine, tyramine, serotonin, histamine, prostaglandin F 2 alpha and potassium chloride. The vasoconstrictor responses to norepinephrine and potassium chloride were slightly enhanced by prolonged cold storage but not significantly, and those to serotonin and prostaglandin F 2 alpha were not influenced at all. On the other hand, the dose-response curve for tyramine shifted to the right in a parallel manner, and histamine-induced vasoconstriction was markedly potentiated by prolonged cold storage in a maximal increase in perfusion pressure. From these results, it is concluded that prolonged cold storage on the isolated canine intermediate auricular artery may not cause complete denervation of adrenergic nerve fibers and responsiveness to vasoactive substances except histamine remains almost the same in non-stored vessels.

Journal Article
TL;DR: The highly specificalpha 1-adrenoceptor antagonist 3H-prazosin was used to characterize alpha 1- adrenoceptors in smooth muscles of the cistern wall of teats of lactating cows and binding was rapid, readily reversible, stereospecific and saturable.
Abstract: The highly specific alpha 1-adrenoceptor antagonist 3H-prazosin was used to characterize alpha 1-adrenoceptors in smooth muscles of the cistern wall of teats of lactating cows Binding was rapid, readily reversible, stereospecific and saturable Scatchard analysis of saturation binding data on bovine teat membranes revealed that 3H-prazosin bound to a single class (Bmax = 128 +/- 13 fmol/mg of membrane protein) of noncooperative sites (Hill coefficient = 095 +/- 002) with high affinity (KD = 047 +/- 005 nM) Competition binding studies with 9 antagonists and 8 agonists, indicated that 3H-prazosin labeled the alpha 1-receptor

Journal Article
TL;DR: The results suggest that the hypotensive response to apomorphine in normotensive dogs is mainly mediated by activation of peripheral dopaminergic mechanisms.
Abstract: The effects of apomorphine on blood pressure and heart rate were studied in normotensive chloralose anaesthetized dogs. Intravenous apomorphine (200 micrograms/kg) induced both a marked decrease of blood pressure and an increase in heart rate. These two cardiovascular responses to intravenous apomorphine were suppressed by haloperidol (1 mg/kg i.v.) or phentolamine (1 mg/kg i.v.). In contrast, pretreatment with atropine (1 mg/kg i.v.) only abolished the chronotropic (but not the hypotensive) response to apomorphine. Intravenous (500 micrograms/kg) but not intracisternal (50 micrograms/kg) domperidone suppressed the hypotensive responses elicited by intravenous or intracisternal apomorphine. In contrast, domperidone, injected either by intravenous or intracisternal route, abolished apomorphine-induced tachycardia. In adrenal demedullated dogs, the hypotensive response to apomorphine was abolished. These results suggest that the hypotensive response to apomorphine in normotensive dogs is mainly mediated by activation of peripheral dopaminergic mechanisms. The drug decreases blood pressure through stimulation of dopaminergic receptors located on sympathetic nerve terminals and on the adrenal medulla leading to a decrease of the release of catecholamines.

Journal Article
TL;DR: The biochemical adaptation to intermittent normobaric hypoxic-normoxic exposures was characterized by the decrease of the muscular contents of creatine phosphate, citrate, alpha-ketoglutarate and glutamate, in absence of significant changes in the Vmax of the muscle enzymes tested.
Abstract: Muscular glycolytic fuels, intermediates and end-products (glycogen, glucose, glucose-6-phosphate, pyruvate, lactate), Krebs cycle intermediates (citrate, alpha-ketoglutarate, succinate, malate), related free amino acids (glutamate, alanine), ammonia, energy store (creatine phosphate), energy mediators (ATP, ADP, AMP) and energy charge potential were evaluated. Furthermore the maximum rate (Vmax) of the following muscular enzyme activities was evaluated in the crude extract and/or mitochondrial fraction: for the anaerobic glycolytic pathway: hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase; for the tricarboxylic acid cycle: citrate synthase, malate dehydrogenase; for the electron transfer chain: total NADH cytochrome c reductase, cytochrome oxidase. The rat gastrocnemius muscles were analyzed in normoxia and after repeated, alternate hypoxic and normoxic exposures (12 hours of hypoxia daily; for 5 days). Naftidrofuryl was administered daily at three different doses: 10, 15 and 22.5 mg/kg i.m., 30 min before the beginning of the experimental hypoxia. The biochemical adaptation to intermittent normobaric hypoxic-normoxic exposures was characterized by the decrease of the muscular contents of creatine phosphate, citrate, alpha-ketoglutarate and glutamate. This adaptation occurred in absence of significant changes in the Vmax of the muscle enzymes tested. By naftidrofuryl treatment, in gastrocnemius muscle from hypoxic rats both alpha-ketoglutarate and creatine phosphate contents maintained normal values, while glutamate concentration remained reduced to subnormal values. With the exception of hexokinase, naftidrofuryl treatment did not modify the Vmax of marker enzymes related to energy transduction.

Journal Article
TL;DR: There are clear functional interactions between these two compounds at the GABA-benzodiazepine receptor complex in the CNS, and that the nature of these interactions differs for picrotoxin and pentylenetetrazole.
Abstract: The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined in combination with those of picrotoxin and pentylenetetrazole on social and exploratory behaviour in the rat. Both Ro 15-1788 (10 mg/kg) and picrotoxin (2 mg/kg) reduced social interaction, but there was no additive effect of these drugs together. Ro 15-1788 (10 and 20 mg/kg, which had no intrinsic effects in the holeboard alone) antagonized the reductions in exploratory head-dipping and motor activity produced by low (2 mg/kg), but not by high (4 mg/kg), doses of picrotoxin. In contrast, pentylenetetrazole (20 mg/kg) enhanced the reduction in social interaction produced by Ro 15-1788 (10 mg/kg), in accordance with previous findings that the reductions in spontaneous behaviour in the holeboard produced by pentylenetetrazole are enhanced by Ro 15-1788. These results show that there are clear functional interactions between these two compounds at the GABA-benzodiazepine receptor complex in the CNS, and that the nature of these interactions differs for picrotoxin and pentylenetetrazole.

Journal Article
TL;DR: The results indicate that isoproterenol-induced heart failure in the SHR might be a useful model for selecting compounds designed to treat this disease.
Abstract: The haemodynamic and metabolic effects on the heart due to high doses of isoproterenol were compared in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. In baseline conditions, the hypertrophied SHR heart displayed perfectly constant haemodynamics but had fewer energy reserves than the WKY heart. Isoproterenol (2 X 25 mg/kg, s.c.) caused high mortality, myocardial ischaemia, and heart failure in the SHR. These effects were accompanied by anaerobic metabolism. In the WKY rats, on the other hand, isoproterenol caused no changes in ST-segment elevation and no cardiac insufficiency; in addition, aerobic metabolism was maintained. A marked drop in coronary perfusion pressure and excessive accumulation of calcium in the myocardium account, in part, for the effects seen in the SHR. The results indicate that isoproterenol-induced heart failure in the SHR might be a useful model for selecting compounds designed to treat this disease.