The actions of bretylium: adrenergic neurone blocking and other effects. 1959

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.

Fig. 5

Contractions of the nictitating membranes of a cat under chloralose anaesthesia during stimulation of the postganglionic cervical sympathetic nerves at various frequencies by supramaximal rectangular pulses. Each point represents the mean of five responses on each of the two membranes. I, Initial; B2, after 2 mg./kg. of bretylium intravenously; B6, after a total of 6 mg./kg.; B10, after a total of 10 mg./kg.; C, after 1 mg./kg. of cocaine in addition. The vertical lines represent the heights of the sustained contractions of the membranes caused by 6 and 10 mg./kg. of bretylium respectively in the absence of nerve stimulation.

Fig. 1

The effect of adrenergic nerve simulation decreasing motility of isolated rabbit ileum. Supramaximal stimulation at white dots (50 pulses/sec. for 20 sec. every 3 mm.), a, Bretylium was added to the organ bath in a concentration of 1 μg./ml. (at B1). b, Bretylium was applied to the nerve only in concentrations of 3 and 10 μg./ml. (83 and B10 respectively). P, Stimulation proximal to and D distal to the nerve bath. Between records b1 and b2, 15 min., and between b2 and b3, 30 min.

Fig. 2

Contractions of isolated rabbit uterus caused by stimulation of the hypogastric nerve. The vertical lines indicate supramaximal stimulation (30 pulses/sec. for 1 min.). From B10, the nerve bath contained bretylium at 10 μg./ml. and from B50 it contained 50 μg./ml. Time, 1 min.

Fig. 3

Venous outflow from a perfused rabbit ear, recorded with a Thorp impulse counter. The horizontal bars indicate supramaximal stimulation of medial nerve (50 pulses/sec. for 1 min.). At N, 0.2 μg. of noradrenaline, and at A, 0.1 μg. of adrenaline were injected into the arterial cannula. At B30, E50, B200, B600, and B300, 30, 50, 200, 500, and 300 μg. of bretylium respectively were injected into the arterial cannula. Records a and b were made from different ears. Time, 5 min.

Fig. 4

Relaxation of the nictitating membrane after bretylium in the unanaesthetized cat. Each point is the mean of observations on four animals. The higher oral and subcutaneous doses were maximal in effect for the method of administration. ○——○, 10 mg./kg. subcutaneously. •——•, 2.5 mg./kg. subcutaneously. □——□, 50.0 mg./kg. orally. ▪——▪. 12.5 mg./kg. orally.

Fig. 6

Contractions of the nictitating membrane of a cat anaesthetized with chloralose. Supramaximal rectangular pulse stimuli 25 sec. were applied to the postganglionic nerve for 30 sec. at the white dots. A, 50 μg. of adrenaline intravenously; B5, 5 mg./kg. of brctylium intravenously; C1, 1 mg. kg. cocaine intravenously. Time, 10 min.

Fig. 7

The effect of bretylium added to the fluid perfusing the isolated superior cervical ganglion of the cat. Record of the nictitating membrane responses caused by supramaximal stimulation of the preganglionic cervical sympathetic nerve (10 pulses/sec.). The presence of continuous stimulation is indicated by the horizontal lines. a, Contraction before the drug. b to e, contractions during the perfusion with Tyrode solution containing 100 μg./ml. of bretylium started at B; the numerals give the time in minutes from changing to this solution. f, Contraction 8 min. after returning to normal Tyrode solution. Time, 1 min.

Fig. 8

Postural hypotension after bretylium in a cat anaesthetized with chloralose. The cat was supine except when tilted through 75°, for the periods indicated by the horizontal white lines. Saline was injected intravenously at 3 and 3 mg./kg. of bretylium at B3. The numerals 10 to 50 indicate the time in min.

Fig. 9

The heart rate of a cat anaesthetized with chloralose recorded with a Thorp impulse counter. Bretylium (0.3, 1.0, and 3 mg./kg.) was injected intravenously at B0.3, B1, and B3 respectively. It abolished the cardioacceleration caused by supramaximal stimulation of the inferior cardiac nerve for 30 sec. with 20 pulses/sec. (at white dots), but not the responses to vagal stimulation for 20 sec. at 20/sec. (at V). The response to 5 μg. of adrenaline intravenously (at A) was unchanged. Time, 1 min.

Fig. 10

The effect of bretylium on the noradrenaline content of the venous blood from the spleen during stimulation of the splenic nerve. Stimuli were applied to the nerve at the rate of 25/sec. for 10 sec. in Expt. No. 1 and for 60 sec. in Expt. No. 2. The venous blood was collected for 30 sec. from the beginning of stimulation in Expt. No. 1, and for 2 min. in Expt. No. 2. The output of noradrenaline, assayed in the pithed rat, is expressed in pg./stimulus. The arrows indicate the intravenous injection of 10 mg./kg. of bretylium in Expt. No. 1 and 5 mg./kg. in Expt. No. 2.

Fig. 11

Records of the blood pressure of cats anaesthetized with chloralose. The first group shows the pressor responses to supramaximal stimulation of the splanchnic nerve at 15/sec. for 40 sec. (horizontal bars), a, Before the drug; b and c, 50 min. after 3 and 10 mg./kg. of bretylium intravenously respectively; d, 8 min. after 1 mg./kg. pentacynium intravenously. The second group shows the pressor responses to 20 μg. dimethylphenylpiperazinium intravenously in another cat (at arrows), e, Before the drug; f, 35 min. after 3 mg./kg.; and g, 45 min. after 10 mg./kg. of bretylium. Time, 1 min.

Fig. 12

Record of the blood pressure of an adrenalectomized cat anaesthetized with chloralose. Adrenaline (10 μg.) was injected intravenously at A and 100 μg. of dimethylphenylpiperazinium at D. Bretylium was injected intravenously, 1 mg./kg. at B1 and 3 mg./kg. at B3. S represents an injection of saline. Time. 1 min.

Fig. 13

Record of twitch responses of an isolated rat diaphragm. Stimuli (5/min.) were applied to the phrenic nerve except at M which is a response to direct muscle stimulation. Bretylium was added to the organ bath to give 400 μg./ml. at BM and to the nerve only to give 10 mg./ml. at BN. The bath fluid was changed at white dots. Time, 1 min.

Fig. 14

Local anaesthesia after the intradermal injection of bretylium and cinchocaine hydrochloride in guinea-pigs. Ordinate: the % of negative responses to six pricks on four wheals in each of three guinea-pigs (total of 72 responses). × and □. Bretylium 10 and 30 mg./ml. respectively; ○ and •. Cinchocaine hydrochloride 0.5 and 1.5 mg./ml. respectively.