Pharmacological experiments on the release of the sympathetic transmitter

Abstract

(1960) and by Brandon & Rand (1961). These authors used the contractile response of the effector organ as an index ofthe amount of transmitter liberated. Interpretation of their results is, however, difficult because not only are we ignorant of the relation between transmitter liberation and effector response, but, as Vane (1962) has pointed out, many drugs alter non-specifically the tissue response to catechol amines. We have therefore done our experiment by collecting venous blood from the spleen of the cat and estimating the noradrenaline liberated by stimulation of the nerves.Cocaine, anticholinesterases and hexamethonium do not appear to affect the liberation of noradrenaline by the nerves or its uptake by the tissues of the spleen. METHODSCats were anaesthetized with ethyl chloride, ether and intravenous chloralose 80 mg/kg. The spleen, its nerve supply, arteries and venous drainage were prepared as described by Brown & Gillespie (1957), except that instead of tying the splenic nerve early in the preparation, we left ligation as late as possible in order to prevent those effects of neuronal rest that may appear after 1-2 hr (Brown, Davies & Ferry, 1961). In some experiments the spleen was perfused with the cat's own blood through a constant-output perfusion pump. This consisted of a tube of silicone rubber compressed by three plates. The two outer plates were input and output valves, the larger, middle or ventricular plate compressed most of the tubing between the valves. The valves and ventricles were operated by pulses of air produced in three coupled compressors which ran at 90 c/min. The output of the pump could be varied by altering the stroke volume. In most experiments the stomach and duodenum were removed in order to gain better access to the arterial supply of the spleen. Blood was taken from the cat through a polythene cannula placed in the stump of the superior mesenteric artery and, after passing through the pump, was ejected into the coeliac axis through a cannula placed in the hepatic artery. The coeliac axis was tied between the aorta and the hepatic artery after the pump hadbeenconnected and had begun to pump blood into the coeliac axis; there was thus no interruption of the blood supply to the spleen. Experiments showed that, if the splenic blood supply was interrupted, the resistance to * M.R.C. Scholar.

Further Observations on the Pressor Action of Propranolol

“…In that case, the former mechanism was rendered already ineffective by the blockade of the a-adrenergic receptors. The a-adrenergic blocking agents were shown to raise the output of the sympathetic transmitter in the venous blood from the spleen when the splenic nerves are excited (Blakeley, Brown & Ferry, 1963). By such an action, the infusion of phentolamine which blocks the a-adrenergic receptors might make available more transmitter to activate the nearby /3-adrenergic receptors and consequently might exaggerate the possible vasodilator influence.…”

Drug‐induced changes in the release of [3H]‐noradrenaline from field stimulated rat iris

“…This fraction is not identical with the total release from the nerves and the 'true' release is not easily determined. To obtain a more valid estimation of the 'true' release from the nerve terminals, attempts have been made to obtain a drug-induced increase of the fraction of NA overflowing into the circulation, for example by inhibition of the enzymatic destruction (Brown, 1965;Folkow et al, 1967), inhibition of the membrane pump (Trendelenburg, 1959;Blakeley, Brown & Ferry, 1963;Kirpekar & Cervoni, 1963;Thoenen, Hurlimann & Haefely, 1964a;Geffen, 1965;Boullin, Costa & Brodie, 1967) or a-adrenoceptor blockade (Brown & Gillespie, 1957;Kirpekar & Cervoni, 1963;Rosell, Kopin & Axelrod, 1963;Thoenen, Hiirlimann & Haefely, 1964b;Boullin et al, 1967;Kirpekar & Wakade, 1970). However, great care must be taken when evaluating these results as the drugs used may also change the true release.…”

The effects of bretylium on C fibre excitation and noradrenaline release by acetylcholine and electrical stimulation

“…This observation confirmed the original finding of Daly & Scott (1961) on the spleen of the dog. Ferry (1963) and Blakeley, Brown & Ferry (1963) concluded that their results suggested a different interpretation of some of the evidence advanced in support of a " cholinergic link " in the post-ganglionic adrenergic sympathetic pathway. More recently Hertting & Widhalm (1965) and Fischer, Weise & Kopin (1966) reported that bretylium blocked the liberation of 3H-noradrenaline produced by electrical stimulation of the splenic nerves at dose levels that did not alter the release of noradrenaline by acetylcholine in the Krebs perfused cat spleen.…”

“…Ferry (1963) concluded, on the basis of his experimental results, that acetylcholine excited the sympathetic postganglionic nerves of the spleen somewhere near their endings. Blakeley, Brown & Ferry (1963) found that the anticholinesterases eserine and neostigmine did not affect the liberation by the nerves of the sympathetic transmitter. Furthermore, hexamethonium had no effect on the output of noradrenaline produced by electrical stimulation of the splenic nerves, whereas the release of noradrenaline by arterial injection of acetylcholine was prevented by hexamethonium.…”