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At least 199 records · Page 11Linked to original sources
PubMed1990

A study of the inhibition of adrenaline-induced vasoconstriction in the isolated perfused liver of rabbit.

We have studied the action of a series of vasoactive and antispasmodic agents on the intrahepatic vasoconstriction induced by adrenaline in the isolated perfused liver of rabbits. The arterial and portal venous resistance, oxygen consumption, liver weight and bile flow were investigated. The drugs used were as follows: nonspecific alpha-adrenergic antagonists (DH-ergocristine, dibenamine, phenoxybenzamine), vasodilators with a direct miscellaneous action (theophylline, papaverine, dipyridamole, glucagon, Aiu-cor by Instituto Gentilli, Italy [inosine, ATP, IPI, UTP]) and antispasmodics (piperylone, tropenziline, noraminophenazone). Adrenaline increased arterial and portal venous resistance followed by a diminution of oxygen consumption, liver weight and bile flow. alpha-Adrenergic antagonists inhibited the effects of adrenaline on portal venous resistance and oxygen consumption and especially the effects on hepatic arterial resistance. The most potent agent was phenoxybenzamine. In contrast to alpha-adrenoceptor blockade, the effects of other vasoactive agents were without a sustained influence on hepatic arterial resistance (excepting those of glucagon and dipyridamole). Some of them were effective as antagonists on responses in the portal venous bed (papaverine, Aiu-cor). Moreover, there were drugs exerting an enhancement of the vasoconstrictor responses of hepatic artery to low concentrations of adrenaline with no effect on the portal venous bed (piperylone, tropenziline). Theophylline and noraminophenazone exerted no effect either on the arterial or portal venous bed. No vasodilator agent antagonized the changes of the bile flow after adrenaline administration.

Animals↗
PubMed1979

13C-NMR spectra of alpha-adrenergic blocking agents.

The natural abundance 13C-NMR spectra of five alpha-adrenergic blocking agents, tolazoline, dibenamine, azapetine, phenoxybenzamine, and phentolamine, are reported. The chemical shifts of various carbon resonances were assigned on the basis of chemical shift theory, multiplicities observed in single-frequency off-resonance-decoupled spectra, relaxation times, and comparisons with the chemical shifts of model compounds.

Adrenergic alpha-Antagonists↗
PubMed1976

Autonomic and pharmacological control of oxygen autoregulation mechanisms in brain tissue.

The effect of several agents active on autonomic nervous system functions was tested on brain oxygen autoregulation parameters. It was found that atropine, propranolol and isproterenol had no influence on the measured parameters. Phenoxybenzamine, tolazoline and dibenamine all suppress autoregulation. In an additional experimental series, a phenoxybenzamine infusion was given during O2 breathing. The infusion induced a marked rise in TpO2. It is concluded that an alpha-adrenergic mechanism is part of the autoregulation process, and its pharmacological blockade could be used to raise TpO2 levels in brain with O2 breathing at normal atmospheric pressure. Also, the increase in brain TpO2 induced by 95% O2 - 5% CO2 breathing seems to be blocked by alpha-adrenolytic drugs.

Animals↗
PubMed1988

Involvement of the sympathetic nervous system in the cardiovascular effects of ACTH-(1-24) during hemorrhagic shock in rats.

In urethane-anesthetized rats, removal of about 50% of the total blood volume over a period of 25-30 min caused hypovolemic shock, with extreme hypotension (MAP = 18-25 mm Hg and death of all animals within 22 +/- 5 min. The i.v. injection of ACTH-(1-24) in the dose range of 40-160 micrograms/kg induced a sustained, dose-dependent, and, at the highest dose used, an almost complete recovery of blood pressure, and 100% survival, at least for 2 h after treatment. The effect of ACTH-(1-24) was completely prevented by reserpine (5 mg/kg) and clonidine (0.1 mg/kg), significantly reduced by prazosin (0.1 mg/kg), dibenamine (15 mg/kg) and i.v. yohimbine (1 mg/kg) and unaffected by i.c.v. yohimbine (0.2 mg/kg) and i.v. practolol (15 mg/kg). These data suggest that the effect of ACTH-(1-24) in hypovolemic shock depends on the functional integrity of the sympathetic nervous system and is mediated through an activation of peripheral alpha-adrenoceptors.

Animals↗
PubMed1981

Further studies on dimethylnitrosamine metabolism, activation and its ability to cause liver injury.

Effects were studied of aminoacetonitrile (AAN), dibenamine (DB) diethyldithiocarbamate (DDTC) dimethylformamide (DMF), disulfiram (DS), and 2-mercapto-1-methylimidazole (MMI) on the in vitro dimethylnitrosamine (DMN) metabolism to CO2, covalent binding (CB) of DMN metabolites to nucleic acids in liver slices, DMN demethylase (DMNase) in male rat liver microsomes or 9,000 g supernatants and CB to microsome of 9,000 g supernatant proteins. Effects of those chemicals on DMN-induced rat liver necrosis were also studied, except for DS whose preventive effect was previously reported by our laboratory. All the chemicals significantly prevented DMN-induced liver necrosis, except for MMI that had no effect. All these compounds when added to incubation mixtures containing liver slices from Sprague-Dawley rats, significantly inhibited transformation of DMN to CO2 and CB to nucleic acids and when they were injected into animals and liver slices prepared afterwards, they did so except for MMI and DMF that had no effect. None of the chemicals tested except DDTC and MMI modified CB to microsome proteins whereas the CB to 9,000 g supernatant proteins was significantly decreased by all the chemicals except MMI. DMNase activity either in microsomes or 9,000 g supernatants was significantly inhibited by all the compounds except MMI.

Animals↗
PubMed1976

Release of creatine kinase by antigen, histamine, and catecholamines.

In mepyramine treated, ovalbumin sensitized anaesthetized guinea pigs protracted anaphylactic shock was produced by i.p. injection of antigen, and serum creatine kinase (CK) activities were determined 4, 6, or 17 hrs thereafter. Significant increases above nonsensitized controls were obtained. In nonanaesthetized guinea pigs shock course and serum CK increase were considerably accelerated. Histamine increased the serum CK only when given in high amounts (10 mg/kg) s.c., in the presence or absence of mepyramine. I.p. injection of histamine in mepyramine treated animals had no effect. Adrenaline (1 or 10 mg/kg) given as a s.c. depot in oil produced a significant increase of serum CK, as well as noradrenaline (0.1, 1, or 10 mg/kg). Dibenamine reduced the effect of adrenaline. In isolated perfused guinea pig hearts a significant CK liberation occurred already within the first hour after eliciting anaphylaxis. Nonanaphylactic hearts released CK too, but significant amounts were obtained only in the total 4 hrs after ovalbumin administration. Isolated anaphylactic hearts incubated in Tyrode solution liberated significantly more CK than did nonsensitized control hearts. The findings are discussed in view of a possible myocardial damage in anaphylaxis.

Anaphylaxis↗
PubMed1986

Effects of diethylcarbamazine on the motility of Angiostrongylus cantonensis and Dirofilaria immitis.

Effects of piperazine derivatives, especially of diethylcarbamazine (DEC) on adult Angiostrongylus cantonensis and Dirofilaria immitis were examined. Piperazine (3 X 10(-5)-10(-4) M) paralyzed A. cantonensis and the action was antagonized by picrotoxin. 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (10(-5)-10(-4) M) caused contraction but little effect was produced by strychnine. An inhibitory effect on untreated preparations was caused by lower concentrations (3 X 10(-6)-10(-5) M) of diethylcarbamazine citrate (DEC) and also on the preparations contracted by eserine. A stimulatory effect was also seen when higher concentrations (10(-4)-3 X 10(-4) M) of this drug were applied to both preparations. The inhibitory action of DEC was antagonized by gabergic antagonists such as picrotoxin and bicuculline, but not by alpha-adrenergic antagonists like dibenamine and phentolamine. When the worm preparation was paralyzed by strychnine or hexylresorcinol (inhibitors of the release of acetylcholine in this worm), the stimulatory effect of DEC was blocked, but pyrantel (a nicotinic cholinergic agonist) contracted the paralyzed preparation. However, the effect of DEC on D. immitis (10(-7)-3 X 10(-4) M) was inhibitory, and this action was also antagonized by picrotoxin. These results suggest that the DEC inhibitory and stimulatory action is through the gabergic and cholinergic mechanisms in adult A. cantonensis and D. immitis.

Angiostrongylus↗
PubMed1992

In vitro effects of milbemycin oxime: mechanism of action against Angiostrongylus cantonensis and Dirofilaria immitis.

The neuropharmacological mechanisms underlying the action of milbemycin oxime on the motility of Angiostrongylus cantonensis and Dirofilaria immitis were examined in vitro. In A. cantonensis, milbemycin oxime caused inhibitory effects at low concentrations of > or = 10(-9) g/ml, and paralysis was elicited at 10(-8) - 10(-6) g/ml. The paralysis was antagonized by picrotoxin and bicuculline but not by dibenamine. In addition, stimulatory effects were observed when the antibiotic was used at higher concentrations of 3-5 x 10(-6) g/ml, and the action was antagonized by strychnine. Both effects were also observed in the preparation contracted by eserine or pyrantel. When D. immitis was treated with milbemycin oxime at concentrations of 10(-7) and 3-5 x 10(-6) g/ml, only slight inhibitory and stimulatory effects, respectively, were observed. These effects were partially antagonized by picrotoxin and strychnine, respectively. These results suggest that the inhibitory and stimulatory actions of milbemycin oxime are caused through gabergic and cholinergic mechanisms in A. cantonensis and D. immitis.

Angiostrongylus↗
PubMed1986

Role of adrenergic alpha-receptors in regulation of acetylcholine release evoked by distension of guinea pig ileum.

The significance of adrenergic nerves in the regulation of acetylcholine (ACh) release evoked by distension of the guinea pig ileum was evaluated by pharmacological manipulations. ACh release was measured by bioassay. Release in response to distension was completely abolished by epinephrine and norepinephrine. Tyramine also suppressed the distension-evoked ACh release, while dopamine was ineffective. The release of ACh in the anal segment, adjacent to the distended part, was abolished by epinephrine and norepinephrine. Dibenamine and phentolamine abolished ACh release anal to the distension, but augmented release orally, while dichloroisoproterenol and propranolol were ineffective. The present results give direct evidence that adrenergic nerves modulate cholinergic transmission in the myenteric plexus through alpha-receptors.

Acetylcholine↗
PubMed1985

Carrageenin-induced thrombosis in rats and mice: a model for testing antithrombotic substances?

Among different carrageenins, kappa-carrageenans were found to be thrombogenic, whereas lambda-carrageenins were inactive in this respect, although the latter substances exerted a stronger edemogenic activity. Kappa-carrageenin (Sigma) was the most potent thrombogen. As the consequence of thrombosis tail infarction became visible some minutes after i.v. administration, but it was delayed for about 3 hours after the i.p. route and for about 6 hours after subplantar injection. Infarction frequency as well as extent of infarction was inhibited by heparin, cyproheptadine, phentolamine and dibenamine. Other substances like aspirin and dipyridamole showed no or only weak effects. Advantages of the carrageenin-induced thrombosis model in rats and mice are: (i) simple induction in small laboratory animals, (ii) easy observation and quantification all the time without killing the animals, and (iii) possible external testing of antithrombotic agents by applying substances on the tail.

Animals↗
PubMed1983

Membrane transport in vascular smooth muscle and its relation to normal and altered excitation during hypertension.

Evidence is presented for the operation of Cl-Cl exchange diffusional transport system in rat aortic smooth muscle. The efflux of 36Cl associated with this mechanism is doubled in rats made hypertensive with aldosterone-salt treatment. The residual efflux of Cl is similarly elevated in the hypertensives. This finding supports the hypothesis that increased membrane permeability to Cl is associated with aldosterone hypertension. The agonist-induced increases in aortic effluxes of 42K exhibit a 10-fold reduction in the ED50 to norepinephrine in aldosterone hypertensive rats. The possible contributors to this supersensitivity were studied by means of a pharmacologic analysis of the action of competitive (phentolamine) and non-competitive (dibenamine) antagonism of norepinephrine induced increases in 42K efflux. The dissociation constant for phentolamine, KB= 1 x 10-8M, was relatively unaltered in the hypertensive group, as was the dissociation constant for norepinephrine, KA= 3.4 - 5.8 x 10-7M. A substantial increase in receptor number and/or transduction efficiency (3-12 fold) was derived from the analysis. It is tentatively concluded that supersensitivity to norepinephrine during aldosterone hypertension may be more closely related to changes in receptor number and/or efficiency than in receptor affinity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMedDate not supplied

The effect of alkylating agents on the synaptic transmission in the frog's isolated sympathetic ganglion.

The effect of four alkylating agents, such as dibenamine, phenoxybenzamine, mannomustine and cyclophosphamide, was studied on the isolated sympathetic ganglion of the frog. It has been established that all of these agents were able to bind to the nicotinic receptors through the formation of the reactive ethylenimonium ion not only in the frog ganglion but also in the motor end-plate of the rat skeletal muscle. The binding to the ganglionic receptors showed reversible and irreversible phases being dependent not only on the drug concentrations and the incubation time used but the temperature of the medium as well.

Action Potentials↗
PubMed1999

Experimental and theoretical comparisons between the classical Schild analysis and a new alternative method to evaluate the pA2 of competitive antagonists.

The Schild analysis is undoubtedly the most frequently used powerful diagnostic tool to investigate the nature of an antagonist and, consequently, to evaluate its potency, often expressed as pA2. Nevertheless, different reasons often prevent the experimenter from applying this analysis, leading to use an inhibition curve for the antagonist and to evaluate its potency by means of several approaches, which are generally considered theoretically invalid. In a recent work, a new theoretical approach, mathematically analogous to the Schild one, has been shown. By means of a simplified experimental protocol based on an antagonist inhibition curve (following a control concentration-response curve for the agonist), this method allows a linear regression analysis, giving a slope value absolutely equivalent to the Schild slope and a reliable estimation of the pA2 of a competitive antagonist. In this paper, this new method has been compared with the Schild analysis, to determine the parameters of potency relative to well-known competitive antagonists, on different in vitro isolated preparations. In strips of guinea pig isolated gastric smooth muscle, pirenzepine antagonised the effects of bethanechol. In guinea pig isolated ileum, atropine blocked the contracturant effects of carbamylcholine, while in electrostimulated ileum segments, the inhibitory responses to alpha-methylnoradrenaline were reduced by idazoxan. Finally, in guinea pig isolated spontaneously beating atria, the negative inotropic effects of 5'-N-ethylcarboxamidoadenosine were antagonised by 8-cyclopentyl-1,3-dipropylxanthine. The parameters of potency, relative to all the above competitive antagonists and expressed as pA2, resulted almost equivalent, when calculated by the Schild analysis or by the alternative method. Furthermore, when tested also for the well-known irreversible alkylating agent dibenamine in rat aortic rings stimulated by noradrenaline, the alternative method furnished a profile of clear nonlinearity, unmasking the nature of the antagonism. Finally, the relationships between the results calculated by the alternative analysis or by the Schild analysis and different levels of computer-generated "random noise" (affecting the shape and the position of theoretical curves) were also evaluated, in order to know the robustness of the new method. The two methods proved reliable and almost equivalent in robustness, when applied with different levels of "random noise". These results confirm the Schild analysis as the most accurate tool to study antagonists, since this analysis can furnish the highest number of information and observations on the behaviour of an antagonist. Nevertheless, when limiting conditions prevent a classical Schild analysis and impose the use of an inhibition curve, the new method probably represents the most preferable experimental approach. Indeed, it allows to calculate the antagonist potency, after the evaluation of a slope parameter giving an important information about the possible nature of the antagonism.

Animals↗
PubMed1975

Differences between the effects of dopamine and apomorphine on rat aortic strips.

Dopamine and apomorphine have been compared with regard to contraction and relaxation of aortic strips prepared from rats of different ages. Both dopamine and apomorphine contracted aortic strips from older (9-12 weeks) rats to greater maximal tension than preparations from younger (3--5 weeks) animals. Contraction in response to both agonists could be blocked by the alpha-blocker, Dibenamine. In contrast to dopamine contraction by apomorphine was associated with the development of tachyphylaxis. Both apomorphine and dopamine relaxed the aorta after alpha blockade, however, the relaxation produced by these drugs differed in two major aspects. First, dopamine-induced relaxation was greatest in aortic strips from young rats compared to older rats whereas relaxation with apomorphine was not age dependent. Second, dopamine-induced relaxation was abolished by propranolol but not haloperidol whereas apomorphine relaxation was only blocked by haloperidol. These data establish that the aortic relaxation caused by dopamine is most likely a beta-adrenergically mediated response whereas that produced by apomorphine is not. Moreover, only dopamine was able to increase the concentration of rat aortic cyclic AMP. Should these data be applicable to other vascular beds or species, it is possible that the vascular effects of dopamine will be influenced by age and drugs which impinge on cyclic nucleotide disposition.

Age Factors↗
PubMed1976

Cocaine cue in rats as it relates to subjective drug effects: a preliminary report.

Using a food-reinforced two-lever operant method, rats (n=5) could be trained to discriminate 10 mg/kg cocaine from saline. Stimulus generalization experiments with lower doses (0.31-5.0 mg/kg) revealed that the cocaine cue is a dose-related phenomenon. Neuroleptic drugs were found relatively ineffective as possible antagonists of the cocaine cue, and no antagonistic effect whatsoever was obtained with dibenamine, propranolol, cyproheptadine and methysergide. iamphetamine (1.25 mg/kg) and apomorphine (0.31 mg/kg) were generalized with cocaine, and a dopaminergic involvement is discussed.

Amphetamine↗
PubMed1982

Muscarinic activity in the isolated guinea pig ileum of some carboxamides related to oxotremorine.

A series of structural analogues of the potent oxotremorine-like agent N-(4-pyrrolidino-2-butynyl)-N-methyl-acetamide (1) was investigated for muscarinic activity in the isolated guinea pig ileum. Substitution of larger alkyl groups for the acetyl methyl group of 1 results in an attenuation of muscarinic potency. The observation that the agonist N-(4-dimethylamino-2-butynyl)-N-methylpropionamide (6) has a dissociation constant (KA = 5.1 X 10(-5) M), estimated after elimination of spare receptors with dibenamine, similar to that of the antagonist N-(4-dimethylamino-2-butynyl)-N-methyl-2,2-dimethylpropionamide (11) suggests that the decrease in muscarinic agonist activity with increasing substitution is due mainly to a loss of efficacy. The N-methyl group of 1 is essential for muscarinic activity since its replacement by a hydrogen atom or an ethyl group yields antagonists.

Animals↗
PubMed1989

The effect of strontium on the drug-receptor interaction on cholinergic drugs.

The effect of replacing calcium with strontium in the perfusion fluid was qualitatively and quantitatively studied in the isolated longitudinal muscle of the guinea-pig ileum. In the presence of strontium hyoscine could be considered a competitive antagonist of acetylcholine for the acetylcholine receptor of the longitudinal muscle of the guinea-pig ileum; dibenamine still blocked this receptor in an irreversible way. The equilibrium constants for acetylcholine (KA) and hyoscine (KI) were obtained in the presence of calcium (KA = 3.16 +/- 0.63 microM; KI = 0.38 +/- 0.07 nM), and strontium (KA = 7.00 +/- 0.89 microM; KI = 0.93 +/- 0.16 nM). The results show a decrease in the affinity of both drugs for the muscarinic receptor in the presence of strontium.

Acetylcholine↗
PubMed1990

Characterization of alpha-adrenoceptors in the late pregnant ovine uterine artery.

Ring segments of uterine artery from pregnant ewes within two weeks of term were used to study alpha-adrenoceptor-mediated contractions in vitro. The order of potency for the agonists giving the same maximum contractile effect was norepinephrine greater than epinephrine greater than phenylephrine much greater than methoxamine; whereas the maximum contraction to clonidine was about 42% of that to norepinephrine. Medetomidine caused inconsistent responses and B-HT 920 was ineffective. Phentolamine (10(-7) M) and prazosin (10(-7) M), significantly (P less than 0.005) inhibited epinephrine-induced contractions, whereas yohimbine (10(-7) M) was ineffective. Clonidine-induced contractions were blocked by prazosin (10(-8) and 10(-7) M) but were insensitive to yohimbine (10(-7) M). The dissociation constant (KB) of the competitive antagonist prazosin was determined with phenylephrine. The slope of the Schild plot was not significantly different from unity. The pA2 value of prazosin with phenylephrine was 9.1 +/- 0.2. The dissociation constant (KA) and the relationship between receptor occupancy and response for the full agonists norepinephrine and phenylephrine were analyzed using the irreversible antagonist dibenamine. The KA values of norepinephrine and phenylephrine were 1.5 +/- 0.4 x 10(-6) M and 2.5 +/- 0.8 x 10(-6) M, respectively. The occupancy response relationship was nearly linear and the half-maximal response to norepinephrine or phenylephrine was obtained with a 50% receptor occupancy. These results suggest that contraction to alpha-adrenoceptor agonists in the late pregnant ovine uterine artery is mediated primarily by alpha 1-adrenoceptors, and there appears to be no substantial alpha 1-adrenoceptor reserve in this tissue. The mediation of contraction via alpha 2-adrenoceptors is not prominent in this tissue.

Adrenergic alpha-Agonists↗