Sympatholytics

Abstract: Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare-like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. A drenergic. nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5-hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea-pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.

Abstract: Sm,-The in vivo studies of Axelrod, Whitby & Hertting (1961), Hertting, Axelrod & Whitby (1961), Hertting, Axelrod & Patrick (1962) and Axelrod, Hertting & Potter (1962) and the in v i m studies of Dengler, Spiegel & Titus (1961) showed that the uptake of noradrenaline into sympathetically innervated tissues can be inhibited by a wide variety of drugs. Among the compounds reported to act as inhibitors of noradrenaline uptake were cocaine, reserpine, guanethidine, imipramine, chlorpromazine and the adrenergic blocking agents dichloroisoprenaline (DCI), ergotamine and phenoxybenzamine. The present study was undertaken as a quantitative investigation of the potencies of these and certain other drugs as inhibitors of noradrenaline uptake. In previous reports from this laboratory the kinetics of noradrenaline uptake in the isolated perfused rat heart and the inhibition of this process by a group of sympathomimetic amines have been described (Iversen, 1963 ; 1964). The methods used in the present experiments are described in these papers. Drugs were added to the perfusing medium, which also contained 14C-noradrenaline. The uptake of noradrenaline was measured by analysing the '*C-noradrenaline content of the heart at the end of a 10 min. perfusion. Each drug concentration was tested on a group of four hearts and the results were expressed as the mean percentage inhibition of noradrenaline uptake in the drug-treated group when compared with the uptake in drug-free controls. When sufficient data were available the drug concentration required to produce a 50% inhibition of noradrenaline uptake (ID50) was calculated.

Abstract: The adrenergic ß‐receptor blocking drugs currently undergoing clinical evaluation are classified in relation to their pharmacological properties. Particular consideration is given to those pharmacological properties that may be of importance in the clinical application of these drugs. The present evidence on the role in the ß‐blocking action of propranolol in angina pectoris and arrhythmias is reviewed, and it is concluded that this property is of major significance in these indications. Finally, recent advances in this field are summarized and possible future areas for research described.