Biomedical subjects

J L Wale

Publications and source records attributed to J L Wale.

3 recordsLinked to original sources

PubMedDate not supplied

A study of the relationship between cardiac beta-adrenoceptor blockade and intrinsic sympathomimetic activity in rats depleted of catecholamines.

1. The intrinsic sympathomimetic activity of a range of beta-adrenoceptor antagonists and its relationship to beta-adrenoceptor blockade was studied in pentobarbitone-anaesthetized, vagotomized rats which had been depleted of catecholamines by pretreatment with syrosingopine. Dichlorisoprenaline, practolol, oxprenolol, pindolol and acebutolol, produced dose-dependent positive chronotropic responses in this preparation. 2. The relationship between the dose requirements for this intrinsic sympathomimetic activity and beta-adrenoceptor-blocking activity was not the same for all drugs: (i) dichlorisoprenaline and practolol had intrinsic activity at all beta-adrenoceptor-blocking doses; and (ii) oxprenolol, pindolol and acebutolol had predominantly beta-adrenoceptor blockade at the lower dose levels and agonist activity only became significant at high doses relative to those producing beta-adrenoceptor blockade. 3. The positive chronotropic response to both practolol and pindolol was observed in rats which had been pithed and was antagonized by propranolol (0.1-3.0 mg/kg, i.v.), indicating that beta-adrenoceptors were involved. 4. It was concluded that the intrinsic sympathomimetic activity of beta-adrenoceptor antagonists was not a simple property as it was described by the relationship between the dose requirements for intrinsic sympathomimetic activity and for beta-adrenoceptor blockade as well as the degree of partial agonist activity.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

The influence of the intrinsic sympathomimetic activity of beta-adrenoceptor antagonists on haemodynamic effects in anaesthetized dogs.

1. The effects of propranolol, atenolol (ICI 66,082), practolol and pindolol on heart rate and maximal left ventricular dp/dt, atrioventricular conduction time, mean aortic flow and diastolic blood pressure during cardiac pacing were investigated over a wide dose range (0.025-4.0 mg/kg, i.v.) in dogs anaesthetized with pentobarbitone.2. Propranolol and atenolol produced similar reductions in haemodynamic parameters. Propranolol had no further effect in dogs pretreated with atenolol. 3. Practolol tended to cause smaller reductions in the haemodynamic parameters than either propranolol or atenolol. Subsequent administration of propranolol still had some depressant activity. 4. Pindolol produced a biphasic response, with depression of cardiac function at the low doses (0.025 and 0.1 mg/kg), but a reversal of effect as the dose was increased. 5. It is therefore concluded that, in anaesthetized dogs, the intrinsic activity of practolol and pindolol limits the fall in heart rate, cardiac conduction, aortic flow and maximal dp/dt observed with beta-adrenoceptor blockade. With pindolol, however, the influence of intrinsic activity is observed only in high doses related to beta-adrenoceptor blockade.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

An application of receptor models to the analysis of data on beta-adrenoceptor blockade.

1. The classical single receptor competitive occupancy model accurately describes the joint action of an agonist (isoprenaline) and a beta-adrenoceptor antagonist (propranolol) or some partial agonists (dichlorisoprenaline, practolol) on the positive chronotropic response in rats which have been depleted of catacholamines. 2. The mathematical form of the model suggests that the dissociation constants of classical competitive partial agonists may be assessed using dose ratios by exactly the same method as that currently used for agonist-antagonist interactions, provided that the log dose-response curves are first suitably normalized. 3. Close agreement between the theoretical mathematical models and the experimental data can be demonstrated by statistical fitting for certain beta-adrenoceptor antagonists (propranolol, dichlorisoprenaline, practolol). 4. The model fails to describe the behaviour of other beta-adrenoceptor antagonists (oxprenolol, pindolol). A possible extension of the model to include these drugs is proposed.

Adrenergic beta-Agonists↗