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Biomedical subjects

E Malta

Publications and source records attributed to E Malta.

At least 37 records · Page 2Linked to original sources
PubMed1985

The sympathomimetic activity of (+/-)-pindolol at beta 1- and beta 2-adrenoceptor sites.

In isolated right atrial and stilboestrol-pretreated uterine preparations from both guinea-pigs and rats, pindolol elicited propranolol-sensitive positive chronotropic and smooth muscle relaxant actions. Although the pD2 values for pindolol (8.4-9.2) and (-)-isoprenaline (ISO, 8.4-8.7) fell within the same range in these preparations, the maximum responses to pindolol were less than 15% of those to the catecholamine. Thus, pindolol did not display any selectivity for agonistic actions at beta 1- or beta 2-adrenoceptors. In uteri taken from progesterone-pretreated rats, the pD2 value for (-)-isoprenaline was 9.5 and that of pindolol 8.5. In these preparations the maximal relaxant effect of pindolol (approximately 50% Emax ISO) was greater than that found in oestrogen-pretreated uteri. Thus, it appears that the maximal response of pindolol in vitro can be related to the pD2 value for (-)-isoprenaline. In anesthetized cats, intravenous pindolol elicited non-beta-adrenoceptor-mediated increases in heart rate and decreases in soleus muscle contractility. The mechanism(s) underlying the latter actions are unknown.

Anesthesia↗
PubMed1985

The influence of molecular structure on the affinity and efficacy of some beta-adrenoceptor agonists.

The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective beta 1-adrenoceptor agonist RO363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pKD) was calculated from their ability to displace the radioligand [125I]iodocyanopindolol ([125I]CYP) from beta-adrenoceptor sites in left atrial (beta 1) and uterine (beta 2) membrane homogenates. These pKD values were used to calculate efficacy from the positive inotropic and uterine relaxant responses elicited by the drugs in organ bath experiments. The drugs studied were either arylethanolamines i.e., (-)-isoprenaline (ISO), p-hydroxyisoprenaline (pOH-ISO), compounds XIV and XVI or aryloxypropanolamine-derivatives, i.e., oxymethylene-isoprenaline (OM-ISO), prenalterol and Compound XI which possessed a p-phenol or catechol ring and an isopropyl or a homoveratryl amine substituent. Only ISO, OM-ISO, pOH-ISO and Compound XVI were active as agonists in both tissue preparations. These drugs were partial agonists which exhibited a wide range of pD2 values and did not display any marked selectivity for either beta-adrenoceptor subtype. Compound XI and prenalterol were inactive as agonists and together with the partial agonists behaved as competitive antagonists to ISO in the two preparations. All drugs tested displaced [125I]CYP from beta-adrenoceptor sites, however, there was also a wide range of potency amongst the drugs. Analysis of the structure-affinity and structure-efficacy relationships indicated that removal of the 3-hydroxyl group from the catechol ring reduces both affinity and efficacy without altering the selectivity of the drug for either beta-adrenoceptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1985

The in vitro pharmacology of xamoterol (ICI 118,587).

The effect of xamoterol and (-)-isoprenaline have been compared for their activity at beta-adrenoceptor sites in a number of in vitro cardiac and smooth muscle preparations. Xamoterol produced weak positive chronotropic effects in guinea-pig, rat and cat atria (intrinsic activity less than 0.55, (-)-isoprenaline = 1). Positive inotropic effects were obtained in driven left atria of the cat but were absent in guinea-pig left atrial and right ventricular strip preparations. Agonistic effects were due to beta 1-adrenoceptor stimulation. Xamoterol was without beta-adrenoceptor-mediated inhibitory effects in guinea-pig ileal, tracheal and uterine preparations and in the rat vas deferens and oestrogen-primed uterus. Weak beta 2-adrenoceptor-mediated relaxation was obtained in progesterone-primed rat uteri. Xamoterol produced non-specific inhibitory effects in guinea-pig ileal and tracheal preparations. Xamoterol acted as a competitive antagonist at beta 1-(pA2 range = 7.4 to 7.8) and beta 2-adrenoceptors (pA2 range 5.2 to 6.2) and displaced [125I]-iodocyanopindolol from guinea-pig left atrial (pKD = 7.25) and uterine (pKD 5.24) membrane preparations. It is concluded that xamoterol displays a selective affinity for beta 1-adrenoceptors. Although its partial agonistic actions are more evident at beta 1-adrenoceptor sites, like prenalterol, xamoterol displays a degree of tissue rather than receptor-dependent selectivity.

Adrenergic beta-Agonists↗
PubMed1985

The affinity and efficacy of naturally occurring catecholamines at beta-adrenoceptor subtypes.

The contribution of affinity and efficacy to the agonistic actions of the naturally occurring catecholamines, (-)-noradrenaline and (-)-adrenaline at beta-adrenoceptor sites were assessed in guinea-pig driven left atrial (beta 1) and K+-depolarized uterine (beta 2) preparations. The dissociation constants of each agonist, required in these calculations, were calculated using radioligand binding techniques. [125I]Iodocyanopindolol bound to sites in membrane preparations of each tissue which have been shown to represent beta 1-(atria) and beta 2-(uterus) adrenoceptors. It was found that (-)-noradrenaline was approximately 10-fold more selective for the beta 1- as opposed to the beta 2-adrenoceptor in the pharmacological studies. Affinity/efficacy calculations indicated that this selectivity was entirely due to a selective affinity for the beta 1-adrenoceptor subtype. (-)-Noradrenaline, (-)-adrenaline and the reference compound (-)-isoprenaline all had approximately the same efficacy at either beta-adrenoceptor subtype.

Animals↗
PubMed1985

Comparison of the Arrhythmogenic Actions of (-)-Isoprenaline, Dobutamine and the selective beta 1-adrenoceptor agonist, (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxy phenethylamino]-propane)-oxalate (Ro 363).

In guinea-pig left atrial preparations, concentrations of (-)-isoprenaline and (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxyphenethylamino]-propane)-oxalate (Ro 363) causing maximal inotropic responses produced small reductions in effective refractory period. Dobutamine had little effect on the refractory period except at supramaximal inotropic concentrations, when increases in effective refractory period were produced. Isolated perfused heart preparations from guinea-pigs developed arrhythmic contractions following the administration of (-)-isoprenaline, Ro 363 and dobutamine in doses producing 70-100% of their maximal chronotropic responses. The arrhythmogenic activity of the three agonists paralleled their respective beta 1-receptor stimulant properties. In chloralose-anaesthetized cats, the 3 agonists, (-)-isoprenaline, Ro 363 and dobutamine, when compared to epinephrine (adrenaline), were essentially devoid of arrhythmogenic activity in animals in which cardiac sensitization was induced by 3-dimethylamino-2-methyl-2-phenoxypropiophenone hydrochloride (U-0882) or halothane. However, all 3 agonists elicited ventricular arrhythmias following the administration of subarrhythmic doses of ouabain and increased the number of subauricular escape beats which occurred during vagal nerve stimulation in non-ouabain treated animals. In all cases the arrhythmogenic activity of the drugs paralleled their relative activity for eliciting rises in heart rate.

Adrenergic beta-Agonists↗
PubMed1985

Comparison of beta-adrenoceptor populations in cat and guinea-pig left atria.

The subtypes of beta-adrenoceptor present in left atrial preparations from the guinea-pig and cat have been assessed using both responses obtained in organ bath experiments and radioligand binding studies. From the positive inotropic responses to procaterol, the pKB values for practolol using a variety of agonists, and from displacement of [125I]cyanopindolol from left atrial membrane homogenates by the selective beta 1- and beta 2-adrenoceptor antagonists L643,717-01J10 and ICI 118,551, it was concluded that guinea-pig left atria possess only beta 1-adrenoceptors, whilst cat left atria possess both beta 1- and beta 2-adrenoceptor subtypes.

Adrenergic beta-Antagonists↗
PubMed1984

Is Ro 03-7894 an irreversible antagonist at beta-adrenoceptor sites?

Ro 03-7894 (0.6 mM) produced a non-parallel shift to the right of dose-response curves to (-)-isoprenaline in K+ depolarized uterine preparations from the guinea-pig. The displacement of the curves was readily reversed by washing. A rightward shift of similar magnitude was also produced by Ro 03-7894 in transmurally stimulated ileal preparations. The relaxant effects of fenoterol in carbachol-contracted guinea-pig tracheal preparations (in the presence of 2 microM atenolol) were not altered by 0.6 mM Ro 03-7894. In the three tissues there was no evidence of a reduction in the maximal inhibitory response to the agonists. In uterine and tracheal preparations, Ro 03-7894 (0.6 mM) depressed contractile responses to exogenous calcium. The depression of responses was enhanced after washout of Ro 03-7894 for 80 min. Contractile responses of ileal preparations to transmural stimulation were also depressed by Ro 03-7894. Concentration-effect curves for the positive inotropic effects of (-)-isoprenaline in guinea-pig left atrial preparations were markedly shifted to the right and the maximum response depressed by 0.6 mM Ro 03-7894. Although the rightward shift of the curves was fully reversed during the 120 min washout period, the maximal responses remained depressed. In similar experiments, Ro 03-7894 produced a washout-resistant depression of inotropic responses to histamine and calcium. The results of radioligand binding studies in left atria using (-)-[125I]-iodocyanopindolol indicated that, when compared to the untreated atria, there was no reduction in the maximal density of binding sites 120 min after washout of 0.6 mM Ro 03-7894. 5 On the basis of the present results it is concluded that Ro 03-7894 induces a non-specific depressant effect on smooth and cardiac muscle preparations during exposure to the drug. This depressant effect persists following washout of the drug. There is no evidence for an irreversible effect of Ro 03-7894 at beta-adrenoceptor sites.

Adrenergic beta-Antagonists↗
PubMed1984

The affinity and efficacy of the selective beta 1-adrenoceptor stimulant RO363 at beta 1- and beta 2-adrenoceptor sites.

(-)-Isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were tested for their inotropic effects in left atrial (beta 1) and relaxant effects in K+-depolarized uterine (beta 2) preparations from the guinea-pig. The drugs had similar activities as positive inotropic agents but RO363 was approximately 400 times less active than (-)-isoprenaline as a uterine relaxant. RO363 had intrinsic activities of 0.8 and 0.25 ((-)-isoprenaline = 1) in atrial and uterine preparations, respectively. Apparent dissociation constants (KD values) determined from the ability of the agonists to displace (-)-[125I]-iodocyanopindolol ([125I]-CYP) bound to membranes prepared from both tissues were used as a measure of affinity. The [125I]-CYP binding sites possessed the characteristics of homogeneous populations of beta 1-adrenoceptors in atrial and beta 2-adrenoceptors in uterine membrane preparations. The pKD values for (-)-isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for RO363 the atrial value (7.8) was considerably greater than that for the uterus (6.0). The latter value is very similar to the pKB value determined from shifts in (-)-isoprenaline curves produced by RO363 in uterine preparations. Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (-)-isoprenaline with respect to RO363 was calculated to be 25 in atrial and 2633 in uterine preparations. The selective beta 1-adrenoceptor stimulant actions of RO363 are a reflection of both its greater affinity and efficacy for beta 1- as opposed to beta 2-adrenoceptor sites. The potent actions of (-)- isoprenaline in both tissues are largely dependent on efficacy.

Adrenergic beta-Agonists↗
PubMed1984

An homogeneous population of beta 1-adrenoceptors subserves inhibitory responses in guinea-pig ileal preparations.

In transmurally stimulated guinea-pig ileal preparations, the pA2 values obtained with the selective beta 1- and beta 2-adrenoceptor antagonists atenolol and ICI 118,551 were independent of the beta-adrenoceptor agonist used [-)-isoprenaline or fenoterol) and were similar to values reported in isolated cardiac tissue. On the basis of these results, the relaxant responses to beta-adrenoceptor agonists in guinea-pig ileal preparations appear to be mediated by an homogeneous population of beta 1-adrenoceptors.

Animals↗
PubMed1983

Analysis of dose-response curves and calculation of agonist dissociation constants using a weighted nonlinear curve fitting program.

The KA value of a full agonist (Furchgott, 1966) is usually calculated following the transformation of a rectangular hyperbolic relationship between equiactive concentrations into a linear relationship via a double reciprocal plot. Such a transformation will introduce error into the value of KA unless the pre- and postinactivation dose-response curves are also rectangular hyperbolas. Nonlinear curve fitting computer programs, which have been developed to evaluate radioligand binding data, fit data to rectangular hyperbolas and, thus, can be used to fit concentration-response data for pre- and postinactivation curves. Examination of (-)-isoprenaline concentration-response curves for positive inotropic effects in left atrial preparations from the guinea pig, established before and after treatment with the irreversible antagonist Ro 03-7894, indicated a marked deviation from the theoretical rectangular hyperbola (Hill coefficient greater than 1). This was accounted for by the presence of a threshold effect. The present study reports on the use of the computer program LIGAND to fit a rectangular hyperbola to the pre- and postinactivation curves for an agonist, while simultaneously calculating and allowing for the presence of a threshold phenomenon. Since both curves are fitted to rectangular hyperbolas, the KA values can be calculated with greater precision than that possible from double reciprocal plots constructed from uncorrected concentration-response curves.

Adrenergic Agonists↗
PubMed1982

Comparison of guinea pig uterine and rat vas deferens preparations for assessment of beta 2-adrenoceptor-mediated activity.

In the present study, investigations were performed to determine the subtype(s) of beta-receptor-mediating relaxation in K+-depolarized guinea pig uterine preparations, and inhibition of twitches in field-stimulated rat vas deferens preparations. The relative activities of (-)-isoprenaline, salbutamol, terbutaline, noradrenaline, and RO363, and the affinity constants determined for the beta 1-receptor antagonist atenolol, and the beta 2-receptor antagonist lCl 118551, indicated that all the inhibitory responses in both preparations were mediated solely through beta 2-adrenoceptor stimulation. In the uterine preparations there was a small population of alpha-receptors which were of little consequence when assessing beta 2-receptor-mediated activity. During K+-induced contractures, both neuronal and extraneuronal uptake systems were inactivated. In rat vas deferens preparations, it was necessary to pretreat the tissues with phenoxybenzamine in order to prevent alpha-receptor actions and neuronal and extraneuronal uptake systems interfering with beta-receptor-mediated activity. In both tissues, 6-8 highly reproducible concentration-effect curves to (-)-isoprenaline could be established. However, the uterine preparation responded more robustly to repeated washings, required less sensitive recording apparatus, and showed responses to individual concentrations of drugs that were more readily quantified. However, in general, both preparations appear to be suitable as tissues for assessing the beta 2-adrenoceptor actions of drugs.

Adrenergic beta-Agonists↗
PubMed1981

Pre- and postjunctional effects of clonidine- and oxymetazoline-like compounds in guinea-pig ileal preparations.

1 Noradrenaline and 28 imidazolidine (clonidine-like) and imidazoline (oxymetazoline-like) compounds with various phenyl ring substituents have been examined for their ability to inhibit responses to transmural stimulation and exogenous acetylcholine in ileal preparations from reserpine-treated guinea-pigs.2 The bathing solution contained propranolol, mepyramine, cimetidine and desipramine to preclude interference with the responses by other than the alpha-receptor-mediated actions of the compounds.3 In transmurally stimulated preparations the inhibitory response to noradrenaline is due to a combination of prejunctional alpha-adrenoceptor stimulation and a postjunctional depressant effect that does not involve adrenoceptor activation.4 Of the 28 imidazolidines and imidazolines studied, 21 inhibited transmurally elicited responses. In the various compounds studied this effect involved actions at pre- or postjunctional sites as indicated by (a) the frequency-dependence of the inhibitory response, (b) its susceptibility to blockade by alpha-receptor antagonists and (c) the relative concentrations required to inhibit responses to transmural stimulation and exogenous acetylcholine.

Acetylcholine↗
PubMed1980

Structure-activity relationships of clonidine- and tolazoline-like compounds at histamine and alpha-adrenoceptor sites.

1 Thirty clonidine- and tolazoline-like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1-receptors (guinea-pig ileum), histamine H2-receptors (guinea-pig driven right ventricular strips), post-junctional alpha-adrenoceptors (rat desheathed was deferens) and pre-junctional alpha-adrenoceptors (inhibition of sympathetic stimulation in guinea-pig driven left atria). 2 All compounds were inactive at histamine H1-receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2-receptors. 3 At post-junctional alpha-receptors all 30 compounds produced stimulant actions, whereas at prejunctional alpha-receptors the compounds displayed either agonistic or antagonistic actions. 4 Thus structure-activity-relationships (SAR) could only be validated for histamine H2- and post-junctional alpha-receptor effects. These studies show that the most potent compounds are those with 2,6-phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2- than at alpha-receptors. 5 The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2-receptors, while alpha-receptor stimulant activity is retained.

Animals↗
PubMed1980

In vitro activity of RO363, a beta1-adrenoceptor selective agonist.

1 The beta-adrenoceptor stimulant effects of RO363 and (--)-isoprenaline have been compared in a variety of isolated tissue preparations. 2 RO363 is approximately half as potent as (--)-isoprenaline in tissues where actions are due to beta1-receptor activation (guinea-pig atrial and ileal preparations and ventricular strips from the rabbit, rat and guinea-pig. 3 In uterine and lung strip preparations from the guinea-pig, where responses are due to beta2-receptor stimulation. RO363 is 100 to 350 times less active than (--)-isoprenaline and has a low intrinsic activity. 4 In spontaneously contracted tracheal preparations from the guinea-pig, RO363 is a full agonist and is approximately half as potent as (--)-isoprenaline. These effects of RO363 are due to the activation of a population of beta1-receptors in the tissue since RO363 and (--)-isoprenaline have the same relative potencies in trachea, cardiac and ileal preparations. In addition the Kb values for practolol are similar in all these preparations when RO363 is used as the agonist. 5 The results show that RO363 is a potent and highly selective beta1-receptor agonist.

Adrenergic beta-Agonists↗
PubMed1980

Phenoxypropanolamines as selective beta 1-receptor agonists.

The introduction of an oxymethylene link between the ring and the ethanolamine side chain of some beta-receptor agonists produces compounds with beta 1-receptor stimulant actions coupled with weak beta-receptor antagonistic activity.

Adrenergic beta-Agonists↗
PubMed1979

Comparison of pre-junctional alpha-adrenoceptors at the neuromuscular junction with vascular post-junctional alpha-receptors in cat skeletal muscle.

1 Activation of pre-junctional alpha-adrenoceptors at the skeletal neuromuscular junction enhances acetylcholine release whereas activation of such receptors at autonomic nerve endings inhibits transmitter output. In the present study the characteristics of pre-junctional alpha-adrenoceptors at motor nerve terminals have been compared with post-junctional (vascular) alpha-adrenoceptors in the cat hind limb.2 Reversal of partial (+)-tubocurarine blockade of contractions of the tibialis anterior muscle was used to monitor pre-junctional activity and increases in hindlimb vascular resistance to assess post-junctional actions at alpha-adrenoceptors.3 Responses to intra-arterial injections of noradrenaline, adrenaline, phenylephrine, oxymetazoline, methoxamine and clonidine were monitored. Dose-response lines for all the compounds except clonidine were parallel. The latter agent produced only weak and inconsistent effects.4 Ratios of the doses of the agents required to produce pre- and post-junctional effects indicated that oxymetazoline and adrenaline possessed some preferential activity at post-junctional sites, whereas the remaining agents were non-selective in their actions. If dose-ratios with respect to noradrenaline were compared at the two sites none of the compounds possessed a marked degree of selectivity.5 In the presence of phentolamine or tolazoline, dose-response curves to the pre- and post-junctional effects of phenylephrine were shifted to a similar extent. Thymoxamine showed preferential activity as a pre-junctional alpha-receptor antagonist.6 In comparing the results of this study with those of other authors, it is apparent that there are marked differences in the characteristics of pre-junctional alpha-receptors at the skeletal neuromuscular junction and at autonomic nerve endings. The pre- and post-junctional alpha-receptors in skeletal muscle show less divergence.

Animals↗