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PubMed1978

Atropine blockade of cholinergic drugs on rabbit stomach muscle.

The competition between atropine and a full agonist, carbachol, was tested on dibenamine-pretreated smooth muscle of rabbit stomach. Even after extensive irreversible blockade by dibenamine, atropine blockade of the response to carbachol was still competitive and the atropine affinity constant was unchanged. This differed from the noncompetitive action of atropine in blocking the contractile effects of partial agonists such as pilocarpine or heptyl trimethylammonium. The results thus indicate that it is not possible to convert a full agonist into a partial agonist merely by reducing the number of available cholinergic receptors. The present study compares the competitive effect of atropine on the actions of the full agonist carbachol, under conditions of irreversible blockade, with the competitive effect of atropine on partial agonists such as pilocarpine or heptyl trimethylammonium.

Animals↗
PubMed1976

Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (II). Analysis by the uptake saturation model.

Curves of experimentally plotted log (dose ratio-1) vs.-log [B] for the antagonism between adrenergic beta-mimetics, isoproterenol (ISO) and trimetoquinol (TMQ), and various beta-antagonists in relaxation of guinea-pig trachea could not be reasonably fitted to Schild's equation which has been commonly used in the analysis of drug-antagonism. Taking into consideration the saturable uptake process of the drug used herein, the equation presented in this paper fitted fairly well to the experimental curves and explains the following results: 1, TMQ was more strongly antagonized than ISO by all the blocking agents tested, that is, the apparent modes of antagonism were different between ISO and TMQ although they are considered to interact with the same receptor site. 2, The slope of the curve for a given antagonist markedly differed between ISO and TMQ. It is hypothesized that ISO is more easily taken up than TMQ. This was experimentally confirmed: i.e., ISO was potentiated about 8 fold by inhibiting the uptake process with dibenamine while TMQ was not. By pretreatment with dibenamine, the log (dose ratio-1) vs.-log [B] curve for the ISO-propranolol antagonism was shifted upward and superimposed with the theoretical curve of antagonism in which uptake of the agonist was neglected.

Adrenergic beta-Agonists↗
PubMed1978

Antisecretory effect of imidazole and its derivatives in an isolated gastric mucosa preparation and an anesthetized young chicken preparation; comparison with a histamine H2-receptor antagonist.

We invesigated the influences of imidazole on the basal and the secretagogue-stimulated gastric acid secretion in isolated bullfrog gastric mucosa preparations and in anesthetized young chickens. Imidazoles (1 x 10(-4) g/ml) readily depressed the basal acid secretion in gastric mucosa in vitro. The inhibitory effect of imidazole was diminished considerably after washing out of the drug. The maximum acid secretion elicited by tetragastrin or bethanechol was completely antagonized by imidazole (1 x 10(-4) g/ml). The stimulatory action of histamine or dibutyryl cyclic AMP was also remarkably depressed in the presence of imidazole (3 x 10(-4) g/ml). after dibenamine pretreatment (5 x 10(-5) g/ml) for 60 min, the isolated gastric mucosa preparation became refractory to tetragastrin, bethanechol and histamine, but responded to dibutyryl cyclic AMP. Imidazole protected the histamine sensitivity against dibenamine blockade in the concentration of 5 x 10(-4) g/ml. In anesthetized young chickens, imidazole (200 mg/kg, s.c.) depressed tetragastrin- and histamine-stimulated gastric acid secretion. The effects of the imidazole derivatives and several antagonists (metiamide, atropine, diphenhydramine, acetazolamide and 2,4-dinitrophenol) on acid production were compared with that of imidazole. From these results, it is concluded that imidazole has a potent antisecretory effect on the basal and the secretagogue-stimulated acid secretion.

Animals↗
PubMed1982

Studies on chemotherapy of parasitic helminths (VIII). Effects of some possible neurotransmitters on the motility of Angiostrongylus cantonensis.

Effects of some possible neurotransmitters such as GABA, adrenergic drugs, and 5-HT and their antagonists on the motility of Angiostrongylus cantonensis were studied. Paralysis was caused by GABA, avermectin BIa (Av-BIa), piperazine and alpha-adrenergic agonists such as adrenaline, noradrenaline, phenylephrine, clonidine and methoxamine, but not by beta-adrenergic agonists such as isoproterenol. The paralysis by GABA or Av-BIa was antagonized by GABA antagonists such as picrotoxin and/or bicuculline with cholinergic agents such as N-methylcytisine (N-MC) or eserine. The paralysis elicited by alpha-adrenergic agonists was antagonized by alpha-adrenergic antagonists such as phentolamine and dibenamine, but not by beta-adrenergic antagonists such as propranolol. 5-HT affected the motility of A. cantonensis paralytically or spastically. The paralysis induced by 5-HT was antagonized by alpha-adrenergic antagonists such as phentolamine and dibenamine, while the contraction induced by this compound was further stimulated by N-MC, but antagonized by strychnine. Other agents such as glutamine, glycine, aspartic acid, taurine, and substance P showed little effect on the motility of A. Cantonensis. From these findings on the neuropharmacological properties of A. cantonensis, it is suggested that this worm is useful as an excellent nematodal model for the investigation of anthelminthics. In addition, this worm may also useful as one of screening models of drugs affecting the central nervous system in mammals.

Angiostrongylus↗
PubMed1984

Comparison of kinins derived from rat stomach tissue and produced by catheptic enzyme in rat stomach.

Four uterine-contractile substances (a, b, c and d) and three uterine-contractile substances (a', c' and d') were obtained from the reaction mixture of rat plasma kininogen with the kinin-forming enzyme in rat stomach and the homogenate of the rat stomach with 0.2% acetic acid, respectively. By high performance liquid chromatography with a Zorbax ODS reversed-phase column, the retention times of materials a, c and d were found to be equal to those of materials a', c' and d', and they were not equal to those of kallidin, methionyl-lysyl-bradykinin (MLBK) and bradykinin (BK). The retention time of material b was equal to that of BK. The uterine-contractile activities of the materials a, b, c, d, a', c' and d' were all abolished by chymotrypsin, but not by trypsin treatment. These materials all relaxed the isolated rat duodenum in the presence of atropine, dibenamine, diphenhydramine and propranolol, and they produced a fall in rabbit blood pressure after administration of atropine, dibenamine and propranolol. The content ratios of a: b: c: d and a': c': d' were 4: 4: 67: 25 and 65: 19: 16, respectively, as calculated from the uterine-contractile activities of these materials.

Animals↗
PubMed1985

Displacement by alpha-adrenergic agonists and antagonists of 3H-prazosin bound to the alpha-adrenoceptors of the dog aorta and the rat brain.

To characterize the alpha 1-adrenoceptors in the dog aorta and the rat brain and to assess the antagonistic potencies of various chemicals inclusive of newly synthesized ones, radioligand binding assays were performed, and the potencies thus obtained were compared with those obtained from pharmacological observations. Reproducible binding to and displacement from the dog aorta of 3H-prazosin were observed. The rank orders of the inhibition of 3H-prazosin binding to the membrane preparations of the aorta expressed as IC50 (the concentration of drugs inhibiting 50% of maximal specific binding of 3H-prazosin) were: prazosin greater than YM09538 greater than phentolamine greater than yohimbine greater than phenoxybenzamine greater than labetalol greater than S-596 greater than dibenamine greater than K-351 greater than propranolol greater than hydralazine greater than N-696 for alpha-blockers and I-epinephrine greater than clonidine greater than I-norepinephrine greater than phenylephrine greater than I-isoproterenol for agonists. IC50 values of phenoxybenzamine, labetalol, dibenamine and K-351 obtained in the brain preparations were higher than those obtained in the preparation of the aorta. There was a good correlation (r = 0.90) between the IC50 values obtained in the dog aorta and in the rat brain, suggesting that the alpha 1-adrenergic receptors in the dog aorta and the rat brain resemble each other. Good correlations (aorta, r=0.97 and brain, r=0.94) were also observed between IC50 values derived from the binding assay in the aorta or the brain and the pA2 values obtained as regards to the contractile response of the rat aorta to phenylephrine. Thus, this method could be useful for the assessment of newly synthesized chemicals as alpha-adrenergic antagonists.

Adrenergic alpha-Agonists↗
PubMed1986

Beta-carbolines selectively antagonize the cholecystokinin action in isolated guinea-pig gallbladder muscle.

Two beta-carbolines, methyl beta-carboline-3-carboxylate (beta-CCM) and ethyl beta-carboline-3-carboxylate (beta-CCE), caused the parallel shift of the dose-response curve for cholecystokinin (CCK) in isolated guinea-pig gallbladder muscle. The Schild plot regarding the parallel shift in the dose-response curves had a regression line with a slope of 1.03 and a pA2 value of 5.17 for beta-CCE, while the method of van Rossum gave a pA2 value of 5.24 for beta-CCE and 5.53 for beta-CCM. Both the beta-carbolines protected CCK receptors in the gallbladder muscle from alkylation by dibenamine, but beta-CCM did not protect acetylcholine receptors from dibenamine alkylation. These results suggest that beta-CCM and beta-CCE, so-called inverse agonists of benzodiazepines (BZP), antagonize the CCK action in the gallbladder muscle in a competitive manner, and the antagonism takes place at CCK receptor sites. No spare receptors for CCK were found in the guinea-pig gallbladder muscle.

Alkylation↗
PubMed1981

Evidence for adrenergic transmission in the circular smooth muscle of the guinea-pig seminal vesicle.

Spontaneous contractile activity of the circular smooth muscle of the guinea-pig seminal vesicle consists of twitch-like contractions with a mean frequency of 2.7/min. The amplitude of responses to repetitive stimulation depended on the frequency of stimulation at constant pulse duration and on the pulse durations at constant frequency of stimulation. Mechanical summation in the tension development was observed at low frequency of repetitive stimulation. Adrenaline, noradrenaline and phenylephrine increased the frequency and amplitude of spontaneous contractions. The excitatory actions of adrenaline and noradrenaline were antagonized by phentolamine and phenoxybenzamine. DOPA, metanephrine and normetanephrine were not effective. Tyramine enhanced the spontaneous activity and its action was antagonized by phentolamine. Isoprenaline, at high concentrations, enhanced spontaneous activity, but in the presence of phentolamine, the spontaneous activity was inhibited by isoprenaline and orciprenaline. Isoprenaline inhibited the enhanced spontaneous activity induced by adrenaline, noradrenaline and tyramine. Spontaneous contractions were potentiated by tetrodotoxin, procaine, guanethidine and dibenamine but were not affected by nicotine and phenoxybenzamine. Evoked responses to repetitive stimulation were blocked or suppressed by tetrodotoxin, yohimbine, nicotine, guanethidine and phentolamine. The evoked responses were partially inhibited by phenoxybenzamine. In contrast, evoked responses were enhanced by hexamethonium and dibenamine. These results provide further support for the conclusion that the innervation of the circular smooth muscle of the guinea pig seminal vesicle is mainly alpha-excitatory adrenergic.

Animals↗
PubMed1975

Prevention of myocardial generation in hamsters with hereditary cardiomyopathy.

A number of drugs have been tested for their ability to prevent or change the course of skeletal and heart lesions occurring with a 100% incidence in cardiomyopathic hamsters (UM-X7.1). These drugs were selected because they act either on the metabolism or turnover of Ca or on adrenergic receptors. Verapamil (Isoptin), a potent inhibitor of myocardial transmembrane Ca conductivity, was found to completely prevent the myocardial lesions in myopathic hamsters. The hamsters were 28 to 30 days of age at the beginning of the experiment and were injected subcutaneously twice daily during 30 consecutive days in doses of 0.5 mg during the first week and 0.75 mg during the subsequent weeks. The protection afforded by Verapamil was no longer evident 30 days after interruption of the treatment. The severity of both cardiac and skeletal muscle lesions was found significantly lowered in hamsters receiving Dibenamine. It is assumed that Verapamil acts mainly by preventing excessive calcium influx in cardiomyocytes, whereas Dibenamine improves the microcirculation, which is deficient during the necrotizing phase of the polymyopathy. The latter assumption rests on the fact that, in myopathic hamsters, the reactivity pattern of alkaline phosphatase is altered at the level of the capillaries of cardiac and skeletal muscles.

Alkaline Phosphatase↗
PubMed1979

[Effect of biologically active agents on the feeding response of Dileptus anser].

A study was made of the effects of pharmacological agents--adrenaline, noradrenaline, serotonine, dibenamine, theophylline, and emidazole--on the phagocytar activity of Dileptus anser. These effects were estimated in terms of food response changes towards chemical food models (CFM) made in cysteine, lecithine or tween-40 solutions. The above pharmacological agents were also tested as phagocytosis inductors. Of these, only adrenalin appeared to be an effective inductor of the food response. The CFM, made in adrenaline, was stimulated by 10(-6) M theophylline, and inhibited with 10(-4)--10(-8) M imidazole. The addition of 10(-3)--10(-12) M adrenaline or 10(-8)--10(-10) M serotonine to the Dileptus-containing medium stimulated phagocytosis of CFM. 5.10(-6) M dibenamin decreased phagocytotic intensity of CFM. 10(-6) M theophylline stimulated, while 10(-4) M inhibited the food response. It is proposed that protozoans have receptors capable of accepting hormones. A possible role of the system of cyclic AMP in transporting hormonal and food stimules in protozoans is discussed.

Animals↗
PubMed1979

Early mortality and temperature regulation in burned mice following administration of catecholamines and adrenergic receptor blocking drugs.

The effect of catecholamines and adrenergic receptor blocking drugs on mortality and body temperature was studied in mice subjected to burn, tourniquet, and endotoxin shock at an environmental temperature of 25 degrees C. Epinephrine and norepinephrine (0.5 mg/kg) injected intraperitoneally postburn increased shock mortality significantly (p less than 0.05); pretreatment with these catecholamines had no effect. Pretreatment of burn- and tourniquet-traumatized mice with propranolol (25 mg/kg) significantly decreased shock mortality, while pretreatment with dibenamine (25 mg/kg) significantly lowered early mortality after endotoxin. None of the catecholamines or their blocking drugs significantly prevented the characteristic immediate fall in core temperature after the three types of shock. At 6 days postburn, however, a combination of propranolol and dibenamine caused a marked fall in core temperature (p less than 0.05). These results indicate that beta-catecholamine agonists could play an important role in acute burn mortality and that both alpha- and beta-catecholamine agonists could significantly influence body temperature regulation and metabolic rate during the late postburn period.

Animals↗
PubMed1980

Differential inhibiton of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses in pithed rats.

The relative potencies of alpha adrenoceptor antagonists at pre- and postsynaptic receptors were assessed by comparing their effects on increments in plasma norepinephrine levels and blood pressure during stimulation of the sympathetic outflow from the spinal cord of pithed rats. Since increments in blood pressure are related to the logarithms of increases in plasma norepinephrine, the latter appear to reflect levels of the catecholamine at vascular alpha receptors. Phenoxybenzamine, dibenamine and chlorpromazine were found to block preferentially postsynaptic alpha receptors, phentolamine and tolazoline were nearly equipotent at pre- and postsynaptic receptors and mianserin and piperoxan were more potent inhibitors of presynaptic alpha receptors. Phenoxybenzamine and dibenamine were much more effective in blocking the pressor responses to sympathetic stimulation than administered norepinephrine. The opposite was true of mianserin and piperoxan, whereas phentolamine appeared to be about equipotent in blocking the pressor response to stimulation and norepinephrine. These results suggest that the pressor effects of administered norepinephrine is mediated by different receptors (alpha-2-type) than is the pressor response to stimulation of the sympathetic outflow which appears to be mediated by alpha-1-type adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1982

Calmodulin, activated cyclic nucleotide phosphodiesterase, microtubules, and vinca alkaloids.

Calmodulin 1.8 and 10.6 microM, inhibited the polymerization of bovine brain microtubules by 30 and 50%, respectively. Two 55,000- to 68,000-dalton calmodulin-binding protein as well as calmodulin-dependent and -independent phosphodiesterases (PDE) were found associated with microtubule proteins. Among the antimicrotubule drugs, such as colchicine, podophyllotoxin, griseofulvin, and vinca alkaloids (vinblastine, desacetylvinblastine amide, and vincristine), the vinca alkaloids were selective inhibitors of calmodulin-activated PDE activity. This action of vinca alkaloids resides in the catharanthine moiety of vinblastine molecule. An alpha 2 inhibitor, yohimbine, affects the microtubules, and a series of alpha-adrenoceptor blocking agents were examined for their effects on calmodulin-dependent PDE. The relative order of the potency is phenoxybenzamine = dibenamine greater than phentolamine greater than yohimbine greater than prazosin greater than tolazoline, and the first four drugs in this series were selective inhibitors of calmodulin action. Inasmuch as phenoxybenzamine and dibenamine are alkylating agents, the effects of antineoplastic alkylating agents on the calmodulin action were also examined. Busulphan, melphalan, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and streptozotocin (up to 4 mM) were not selective inhibitors of calmodulin action. Maytansine, a vinca alkaloid-type antimicrotubule agents as well as an alkylating agent, selectively inhibited the calmodulin with a potency similar to vincristine. In addition, phenoxybenzamine affected Ca2+-dependent fluorescence induced by the interaction between calmodulin and hydrophobic fluorescent probes, whereas vinblastine was ineffective. However, the binding of vinblastine to calmodulin is calcium dependent. Studies such as these suggest the importance of physical and structural considerations in drugs binding to calmodulin as well as at least two different binding sites for drugs on calmodulin.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Use of selective antagonists for determining the types of receptors mediating the actions of 5-hydroxytryptamine and tryptamine in the isolated rabbit aorta.

Competitive and noncompetitive antagonists were used to study the receptors which mediate the contraction elicited by 5-hydroxytryptamine (5-HT) and tryptamine (TRP) in the isolated rabbit aorta. The response to 5-HT was more susceptible to inhibition by competitive antagonists selective for 5-HT receptors, such as cyproheptadine, 5-methylgramine, 5-methoxygramine or 2-bromolysergic acid diethylamide, than was the response to TRP; the estimated apparent dissociation constants (KB value) for each antagonist was significantly lower when 5-HT rather than TRP was the agonist. If either of the two agonists and an antagonist were competing for the same single receptor, the KB value should be independent of the agonist. The 5-HT response was also more sensitive to the noncompetitive antagonist, dibenamine. A noncompetitive antagonist of alpha adrenergic receptors, benextramine tetrahydrochloride monohydrate (BHC), depressed the maximal TRP response 25 to 35% without affecting the 5-HT response. After blockade of alpha adrenergic receptors with BHC, KB values determined for each of the competitive antagonists using either 5-HT or TRP were no longer significantly different. Also after blockade by BHC, TRP and 5-HT responses were now equally sensitive to dibenamine. After adrenergic nerve terminals had been removed by stripping off the adventitia of the aorta, the response to TRP was still partially antagonized by BHC. It is concluded that in this preparation TRP directly activates both alpha adrenergic and 5-HT receptors and the 5-HT response is mediated by the 5-HT receptor with no involvement of alpha receptors.

Adrenergic alpha-Antagonists↗
PubMed1964

STUDIES ON THE HYPERGLYCAEMIA INDUCED BY CHLORPROMAZINE IN RATS.

Chlorpromazine induces in rats a marked and long-lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.

Adrenal Medulla↗
PubMed1964

ACTIONS OF SYMPATHOMIMETIC DRUGS ON THE SMOOTH MUSCLE AT THE JUNCTION OF THE BILE DUCT AND DUODENUM STUDIED IN SITU.

The actions of adrenaline, noradrenaline, phenylephrine and isoprenaline have been examined on flow through the terminal bile duct and on the tone of the duodenum in the vicinity of the terminal bile duct. These drugs were injected intravenously, or intra-arterially into the blood supply of the junction of the bile duct and duodenum. The effects of the antagonistic drugs, dibenamine and dichloroisoprenaline, were also tested. Isoprenaline always relaxed the duodenum and increased the flow through the bile duct. Adrenaline, noradrenaline and phenylephrine relaxed the duodenum, but had variable effects on the flow through the bile duct. It is concluded that adrenaline acts directly on the smooth muscle of the bile duct to contract it, but the influence of the neighbouring duodenal muscle may nevertheless result in an increase in flow through the duct.

Animals↗
PubMed1964

DISTRIBUTION OF (2-BROMOETHYL)ETHYL(NAPHTH-1-YMETHYL-(14C))AMINE HYDROBROMIDE IN THE RAT.

(2-Bromoethyl)ethyl(naphth-1-ylmethyl)amine hydrobromide (SY28) is a halogenoalkylamine related to dibenamine. A dose of 10 mg/kg injected intravenously into rats antagonizes the pressor response to adrenaline for 36 hr. If this amount of SY28 labelled with (14)C in the 1-methyl position is administered, specific radioactivity is present in blood and tissues many days after the antagonism of adrenaline is relieved. The (14)C is excreted in bile and in urine, but not in expired air. It is present in fat but not to a greater extent than it is in other tissues. It does not cross the placental barrier. There is no evidence that slow release from a lipid depot accounts for the long duration of action.

Adipose Tissue↗
PubMed1999

Physiological color change in the bullfrog, Rana catesbeiana.

Adults of Rana catesbeiana maintained for 4 days in 12:12 light/dark regimen exhibited a rhythmic color change of 24 hr. Under constant light, however, the rhythm disappeared, and the reflectance values gradually became greater, that is the animals became lighter. Under constant darkness, the rhythm was also abolished, but the animals tended to a darker color. On black background the skin darkening proceeded at a faster rate as compared to the skin lightening of animals adapting to a white background. The difference in color change rate suggests that the darkening responses are probably mediated by an increase in a circulating hormone, whereas skin lightening probably results from the serum level decrease of the same hormone. Most certainly, this hormone is alpha-MSH, as the in vitro assays demonstrated its high potency as a full darkening agonist (EC50 = 9 x 10(-10) M). Prolactin (EC50 = 7.7 x 10(-8) M) and endothelins 2 (EC50 = 1.3 x 10(-6) M) and 3 (EC50 = 4.8 x 10(-7) M) were also full agonists, but 100- to 1000-fold less potent than alpha-MSH. Isoproterenol, in the absence or presence of dibenamine, and endothelin-1 also elicited darkening responses in a dose-related manner, but reaching only 23% and 35% of the maximal darkening, respectively. Isoproterenol darkening effect was completely blocked by propranolol, confirming its action through beta-adrenoceptors. These results, taken together with the lack of lightening activity of norepinephrine on alpha-MSH-darkened skins, suggest that R. catesbeiana melanophores do not possess very active beta-adrenoceptors and lack alpha-adrenoceptors. On the other hand, the lightening agonist melatonin elicited only half-maximal dose-dependent reversal of MSH-induced darkening. Our results suggest that the chromatic rhythm is not endogenous, and most likely is determined by the light/dark cycle effect on alpha-MSH secretion.

Animals↗