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1 Graded motor responses were elicited in isolated, desheathed, thin strips of dog, horse, pig and sheep retractor penis (RP) muscles by field stimulation with trains of 0.2 ms pulses at 10 hertz. These twitches were shown to be neurogenic in all four species, by their prompt extinction in tetrodotoxin. 2 α-Adrenoceptor blocking drugs abolished the contractile response to noradrenaline and to tyramine in all four species. 3 Motor transmission was wholly adrenergic in the horse as in the dog RP because phentolamine rapidly abolished the electrically induced twitches in both these species; but in the pig and in the sheep RP a large proportion of the motor transmission was unaffected by phentolamine given in many times the concentration required to abolish matching noradrenaline-induced contractions. 4 Because of the occurrence of periodic spasms in sheep preparations, further investigation of the phentolamine-resistant transmission was confined to the pig RP. Its responses were shown to be entirely postganglionic in origin because they were unaffected by pentolinium. 5 In the pig RP a considerable proportion of the phentolamine-resistant motor transmission persisted after combined blockade of α- and β-adrenoceptors by phenoxybenzamine plus propranolol and was more resistant to guanethidine and bretylium than the motor transmission to the dog RP; it was not extinguished after reserpine treatment. 6 The pig RP is contracted by histamine but is rather insensitive to acetylcholine, 5-HYDROXYTRYPTAMINE and adenosines-triphosphate. The motor transmission remained unaffected after responses to these substances were blocked by the following antagonists, given alone or in combination: mepyramine, burimamide, atropine, (+)-tubocurarine, methysergide and 2–2′-pyridylisatogen tosylate.

1 The prevention by guanethidine and related agents of the output of noradrenaline induced by low sodium was investigated in rabbit ventricular slices. When external NaCl was reduced, the output of noradrenaline into the medium collected at 30 min intervals, increased and the endogenous levels decreased. These changes induced by replacing sodium with sucrose or choline were not affected either by the omission of calcium and addition of 0.5 mM ethylene glycol-bis(aminoethylether)N,N,N′,N′ tetra-acetic acid (EGTA) or by an increase in the calcium concentration to 10 mM 30 min before sodium deprivation. 2 Guanethidine 4 × 10-6 and 4 × 10-5 M and 4-7-exo-methylene-hexahydroisoindoline-ethyl guanidine (No. 865-123) 4 × 10-5 to 8 × 10-4 M inhibited, in a dose-dependent manner, increases in output of noradrenaline induced by reduction of sodium to 18 mM, while guanethidine 8 × 10-5 M and high doses of bretylium produced no inhibition: the latter two released noradrenaline. 3 The inhibitory actions of guanethidine 4 × 10-5 M and No. 865-123 4 × 10-4 M were prevented by tetracaine 3.3 × 10-4 M, which per se did not modify the output of noradrenaline induced by 18 mM sodium. 4 Accumulation of guanethidine and No. 865-123 in ventricular slices was greater than that noted in striated muscle slices and was dose-, time- and temperature-dependent. Tetracaine 3.3 × 10-4 M did not prevent the accumulation of guanethidine 4 × 10-5 M and No. 865-123 1.1 × 10-6 to 4 × 10-4 M. 5 The guanidine derivatives appear to increase the permeability of adrenergic nerve endings to sodium ions.

1 Responses of isolated ductus arteriosus preparations from near term guinea-pigs and lambs to transmural electrical stimulation and drugs were studied in a low oxygen medium (Po2 19 to 28 mmHg). 2 Acetylcholine and noradrenaline contracted both vessels in a dose-dependent manner, their threshold being between 10-8 and 10-7 M. Transmural stimulation (pulse width 0.2 to 0.6 ms, typically 20 Hz) also contracted the vessels. 3 Atropine and phentolamine or dibenzyline selectively blocked responses to acetylcholine and noradrenaline, respectively. 4 In the guinea-pig ductus, part of the response to transmural stimulation was due to activation of intrinsic adrenergic nerves since the responses were reduced by α-adrenoceptor antagonists, bretylium or prior reserpine treatment, but not by atropine. The response of the lamp ductus to transmural stimulation varied greatly in magnitude and was inconsistently affected by α-adrenoceptor blocking drugs. 5 There was no evidence that transmural stimulation activated cholinergic nerves in either species. 6 After inactivation of α-adrenoceptors with dibenzyline, noradrenaline caused a β-adrenoceptor-mediated relaxation. Both this effect and isoprenaline-mediated relaxation were blocked by propranolol. β-Adrenoceptor activity was more prominent in the ductus of the guinea-pig than of the lamb. 7 Raising the Po2 from 19-28 to 92-98 mmHg increased the response of the guinea-pig ductus to transmural stimulation suggesting that, in this species, physiological elevation of oxygen tension at birth may increase transmitter release from intrinsic adrenergic nerves. Whether this mechanism would contribute to ductus closure remains an open question. 8 We postulate that β-adrenoceptor-mediated relaxation has a role in maintaining ductus patency in the guinea-pig foetus.

Ten years ago, in papers on medical sympathectomy and the clinical use of methonium compounds, early experience in this unit with ganglion-blocking drugs was recorded (Turner, 1950, 1951). Recently the indications for treatment, method of administration, and the problems of tolerance and side-effects were reviewed (Turner, 1959). At an early stage it was decided that to initiate life long treatment with potent and potentially dangerous drugs was a major decision and that it was best first to make a detailed and standardized assessment of each patient in hospital. If treatment was indicated we tried to achieve a steady state with the appropriate drug, and then further treatment was supervised on a long-term basis in a special clinic organized for the purpose. This procedure has helped to ensure the proper and uniform selection of patients suitable for treatment, has facili tated the maintenance of good control over the blood pressure as well as the collection and correlation of data, and has made possible comparative assessments of different drugs. Numerous ganglion-blocking agents have been investigated, all potent in lowering the blood pressure, but none free from difficulties of administra tion, particularly as regards tolerance and side-effects. None, in fact, has been satisfactory. Although the blood-pressure can be reduced to almost any desired level this can rarely be achieved without troublesome side-effects from concomitant parasympa thetic blockade. Some improvement results from combining the ganglion-blocking drug with chloro thiazide or rauwolfia, but in some degree most patients complain of constipation, dryness of the mouth, diffi culty with accommodation, delay in micturition, or impotence. In many individuals these effects are asso ciated with a feeling of general malaise. Because of all this, physicians have looked forward to the day when research workers would be rewarded by the finding of a compound with selective blocking action on the sympathetic nervous system. Recently, in the laboratories of the Wellcome Founda tion in England and the Ciba Foundation in Switzer land, compounds have been isolated which do selectively block the peripheral sympathetic nervous system by accumulating in sympathetic ganglia and post-ganglionic fibres. The first of these has been given the name of bretylium tosylate (" darenthin "), and has the formula N-o-bromobenzyl-N-ethyl : N : N-dimethylammonium p toluenesulphonate. The second substance has been given the name of guanethidine (" ismelin ") and has the formula 2-(octahydro-L-azocinyl-ethyl) guanidine sulphate. This paper is principally concerned with a clinical trial of bretylium, which we have used for 15 months in the treatment of 43 patients with hypertension.

The simultaneous i.v. administration of equimolar doses of bretylium and hexylsalicylic acid results in an increase in plasma area under the curve value of both substances in comparison with their separate administration. The higher plasma levels of both compounds were associated with a reduced renal excretion and an increased biliary elimination. However, the increase in biliary excretion did not compensate for the reduced elimination of bretylium and hexylsalicylic acid via the kidney. The results presented in this paper give further evidence that ion-pairing in-vivo may result in altered pharmacokinetics of drugs particularly due to changes in biliary or renal excretion.