C. Raper

Cardiac arrhythmias produced by interaction of ouabain and β-receptor stimulation

Abstract Low doses of propranolol having specific β-receptor blocking activity abolished arrhythmias induced by ouabain in 7 out of 21 cats. In 9 of the remaining experiments, propanolol abolished arrhythmias only after it was given in higher doses which had quinidine-like activity. In the presence of sub-arrhythmic doses of ouabain, stimulation of the cardiac sympathetic nerves precipitated arrhythmias in 13 out of 16 experiments. In 8 of these, arrhythmias lasted for less than 5 min and could be reproduced regularly. This effect of sympathetic stimulation was abolished by low doses of propanolol. When persisting arrhythmias were produced, low doses of propanolol abolished them in some experiments but in others quinidine-like doses were necessary. Injection of isoprenaline in the presence of sub-arrhythmic doses of ouabain also precipitated arrhythmias but injections of phenylephrine generally did not, although it increased the severity of an existing arrhythmia.

Cholinomimetic activity of dimethylamino-ethanol, and -propanol and related compounds

Abstract Dimethylaminoethanol (DMAE) and dimethylaminopropanol (DMAP) possess indirect cholinomimetic activity in the isolated guinea pig ileum preparation. This activity does not involve the stimulation of nicotinic receptors. Their ability to release acetylcholine was indicated by lack of stimulant activity in tissues pretreated with morphine or tetrodotoxin and in cooled tissues, and was confirmed by assay of released acetylcholine. The closely related cholinomimetic compounds choline and dimethylaminoethane (DME) acted predominantly through muscarinic and nicotinic receptor stimulation respectively. Isoamylalcohol was devoid of stimulant activity. Indirect cholinomimetic activity appears to be dependent on the presence of a tertiary nitrogen group (as in DMAE, DMAP and DME). The absence of an hydroxyl group results in direct stimulation of nicotinic receptors (DME) while in the presence of an hydroxyl group (DMAE, DMAP), acetylcholine release is ‘aganglionic’. Quaternisation of the nitrogen (choline) results in direct stimulant actions on post-junctional cholinergic receptor sites.

Influence of N-alkyl substitution on antagonism at β1- and β2-receptor sites

Abstract 1-Alkylamino-3-(2-nitrilophenoxy)-2-propanols with the N-alkyl substituents -H, -CH 3 , -C 2 H 5 , -CH(CH) 3 ) 2 and -C(CH 3 ) 3 have been tested for their β-antagonistic activity in isolated tracheal ( β 2 ) preparations. Results were compared with those previously found in atrial ( β 1 ) preparations. Increasing substitution produces an enhancement of potency and increasing selectivity towards β 2 - as opposed to β 1 -antagonistic effects.

Anti-fibrillary and anti-adrenaline activity of β-receptor blocking drugs

Abstract The anti-adrenaline and anti-fibrillary activities of the β-receptor blocking drugs, dl-propranolol, d-propranolol, pronethalol, DCI, MJ 1999 (4-(2-isopropylamino-1-hydroxyethyl)-methanesulphonanilide), methaxamine, isopropylmethoxamine and butoxamine have been compared with quinidine, procainamide, procaine and lignocaine using isolated rabbit auricles and spontaneously fibrillating chronically denervated skeletal muscle. Anti-adrenaline activity was assessed against the chronotropic action of the amine in rabbit auricles and against the increase in tension and fibrillation produced in denervated muscle. Anti-fibrillary activity was determined directly against the spontaneous fibrillation in denervated muscle, while prolongation of the effective refractory period gave a measure of anti-fibrillary activity in isolated auricles. The order of relative potencies of the drugs as anti-adrenaline and anti-fibrillary agents was similar in both tissues. However, there was no correlation between the doses of the β-receptor blocking drugs required to produce anti-adrenaline and anti-fibrillary effects in either tissue. β-Receptor blockade could be distinguished from anti-fibrillary activity by differences in the duration of the two effects in denervated muscle.

Beta-receptor blocking and cardiodepressant actions of 2-nitrilophenoxypropanolamines

Abstract The β-adrenoreceptor blocking and cardiodepressant activities of a series of 1-alkylamino-3-(2-nitrilophenoxy)-2-propanols have been studied in isolated rabbit atria. Increasing the amine substituent through the series -H, -CH 3 , -C 2 H 5 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3 increases both the β-receptor blocking and the cardiodepressant activity of the compounds. In the above series p A 2 values against isoprenaline ranged from 5.83 to 8.65. Cardiodepressant activity, as judged by negative inotropic and chronotropic actions and by increases in effective refractory period, occurred at much higher concentrations than those required for β-receptor blockade. The potency ratio of the -C(CH 3 ) 3 to the -H derivative was 661 for β-receptor blockade, and ranged from 7 to 14 for the cardiodepressant actions. Despite the same rank order of potency of the compounds in producing cardiodepressant actions and β-receptor blockade, no correlation exists between the two effects.

Specificity of β-receptor antagonists

Abstract pA2 values and changes in the effective refractory period of atria have been studied using β-receptor antagonists and procainamide. Propranolol had the highest specificity for β-receptors. Pronethalol and Ciba 39089 Ba (1-isopropylamino-2-hydroxy-3-(0-allyloxy-phenoxy)-propane) showed high anti-histaminic activity, and MJ 1999 (4-(2-isopropylamino-1-hydroxyethyl)-methanesulphonanilide) high anti-muscarinic activity in relation to their β-receptor blocking actions. Procainamide appeared to be non-specific.

Pyrrolizidine aminoalcohols: Indirect cholinomimetic activity in guinea-pig ileum

Abstract The pyrrolizidine aminoalcohols supinidine, hydroxyheliotridane, isoretronecanol, heliotridine, retronecine, desoxyretronecine and retronecanol possess stimulant actions in the guinea-pig ileum preparation at 37°C, while platynecine and hastanecine lack this activity. Contractions induced by the aminoalcohols are unaffected by hexamethonium and occur in nicotine-depolarized and in ganglion-free preparations. The stimulant activity is abolished by atropine and potentiated after cholinesterase inhibition with physostigmine. Stimulant activity is abolished by procaine, excess magnesium, morphine, tetrodotoxin and cooling to 25°C. These results suggest that the cholinomimetic action of the aminoalcohols involves the release of acetylcholine from post-ganglionic sites, and this was confirmed in experiments in which acetylcholine release was assessed in the presence of the aminoalcohols. When the temperature is lowered to 25°C weak anticholinergic and antihistaminic actions are unmasked. No correlation exists between the stimulant and the anticholinergic actions of the compounds.

Sympathetic involvement in vagal escape and the effects of β-receptor blocking drugs

Abstract Vagal escape was initiated in chloralose anaesthetised cats. A sympathetic component is involved in vagal escape. Concomitant β-receptor stimulation produced by sympathomimetic amines or cocaine increased, and blockade of sympathetic effects with β-receptor antagonists or with St-155 (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride) decreased the rate of vagal escape. Low doses of the β-receptor antagonists propranolol, pronethalol and MJ-1999 which produced specific β-receptor blockade resulted in a decrease in the number of ectopic vagal escape beats. With higher doses there was a further decrease in the number of ectopic escape beats which was associated with the appearance of beats initiated from the sino-atrial node. The latter effects are due to a combination of cardio-depressant and atropinic activities of the drugs. Muscarinic receptor blockade with cumulative doses of atropine produced a reduction in the number of ectopic beats, and a rise in the number of sinus beats during vagal stimulation. Similar results with procainamide are due to a combination of cardio-depressant and ganglion blocking actions.

Effects of catecholamines on the gastrocnemius muscle of the domestic fowl.

Abstract The effects of adrenaline, noradrenaline and isoprenaline on contractions of the nonfatigued gastrocnemius muscle have been studied in anaesthetized fowls. The amines did not appear to affect the muscle by a direct action on the contractile elements, but both facilitatory and inhibitory effects on neuromuscular transmission were evident. Facilitation of transmission, as evidenced by an initial reversal of the blockade produced by tubocurarine and a slight increase in the twitch tension of the indirectly stimulated muscle, was mediated through α -adrenoreceptors. Hyperpolarization of the muscle fibres, mediated through β -adrenoreceptors, accounted for the depressant effect on contractures produced by depolarizing drugs, for the secondary potentiation of blockade produced by tubocurarine, and for the small decrease in twitch tension produced in the indirectly stimulated muscle. The results are discussed with reference to the action of the amines in amphibian and mammalian muscles.

Effects of atropine on responses to directly and indirectly acting cholinomimetics

Abstract In the isolated guinea-pig ileum atropine delayed the onset and slowed the rate of contraction of responses to indirectly acting cholinomimetics (nicotine, dimethylphenylpipezinium, dimethlaminoethanol, dimethylaminopropanol and supinidine), while response heights were little affected. In contrast, atropine had little effect on the time taken for acetylcholine to produce its peak response, while contraction height was reduced. The competitive action of atropine on concentration-effect curves to acetycholine was not apparent with indirectly acting cholinomimetics. Nevertheless analysis of time-effect rather than concentration-effect curves showed that atropine competitively antagonized responses to acetylcholine released by the latter agonists. Atropine antagonism of exogenously administered and endogenously released acetylcholine was similar. The extent and offset of acetylcholine antagonism by atropine was unaffected by indirectly acting compounds. With indirectly acting cholinomimetics, the atropine resistance may be explained on the basis of the differing mechanisms by which exogenous and endogenous acetylcholine elicit responses, rather than a difference in the receptors involved or limited access of atropine to endogenous sites.