SK&F 29661 (1,2,3,4-tetrahydro-7-isoquinoline-sulfonamide) is a potent and selective in vitro and in vivo inhibitor of adrenal phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). Its Ki value for in vitro inhibition of rat adrenal PNMT was 133 nM. In vivo, the adrenal conversion of 3H-norepinephrine to 3H-epinephrine was maximally inhibited by a single oral dose of 100 mg/kg. In long term chronic studies in rats, adrenal epinephrine was reduced by SK&F 29661 in a dose dependent fashion to greater than 90%, without substantial increases in norepinephrine. Urinary excretion of epinephrine was significantly reduced by the drug both basally and following 2-deoxy-D-glucose stimulation. No drug related changes were found in plasma corticosterone values and only small effects were observed on adrenal tyrosine hydroxylase and PNMT enzyme levels. The cardiac norepinephrine pool and its turnover time were both significantly reduced; its turnover rate, however, was only slightly increased. Our studies indicate that SK&F 29661 is a highly effective, non-toxic and novel pharmacological tool which is useful in depleting adrenal epinephrine stores via inhibition of its biosynthesis.

Continuous stimulation of the right vagus nerve in anaesthetized animals can produce cardiac asystole, followed by a reinitiation of the heart beat. The latter is commonly referred to as " vagal escape " (Bard, 1956a). Although the mechanism of the escape phenomenon is unresolved, evidence has accumulated which indicates that adrenergic factors may be involved, possibly through a local release of catecholamines by acetylcholine (Campos & Freidman, 1963;Moore, 1967).To evaluate the local release hypothesis, the effects of beta adrenergic and postganglionic parasympathetic blockade on the chronotropic action of the vagus were determined in this study. In the course of our experiments, interesting data were obtained on the effect of stimulation frequency on the duration of vagally induced cardiac asystole and the intracardiac origin of the ensuing vagal escape. The cat was used in all experiments because the vagus and cervical sympathetic nerves can be easily separated in this species (Liddell & Sherrington, 1929). METHODSCats of either sex, weighing between 2 and 5 kg, were anaesthetized intraperitoneally with a-chloralose, 85 mg/kg, and placed on a heated cat board. A tracheotomy was performed, and the exposed part of the cannula was covered with non-conducting electrical tape. Arterial blood pressure was recorded from the right femoral artery with a cannula leading to a Statham P 23 Db transducer and Sanborn Model 296 recorder. The right femoral vein was cannulated for injection of drug solutions. The Lead II electrocardiogram was recorded from subcutaneous needle electrodes with a Sanborn Model 100 Viso-Cardiette recorder. The left vagosympathetic trunk was isolated and cut. The corresponding right trunk was isolated, the cervical sympathetic section was isolated and severed, and the vagus was tied with suture and crushed central to the tie. Throughout the experiments, the right vagus was kept warm (-37' C) and moist with Locke-Ringer solution.The vagus was stimulated with bipolar platinum electrodes leading from American Electronics Laboratory stimulus isolation and stimulator units. Supramaximal voltage was determined for each preparation by selecting the voltage required to produce a maximal slowing of the heart rate at a stimulation frequency of 5 c/s.

Desrnethylimiprarnine (DMI) and atropine were compared in a variety of organ system tests in rats involving parasympathetic function in order to evaluate the specificity of these compounds as gastric antisecretory agents. DMI was similar to atropine in its effects on the stomach; each markedly inhibited gastric acid secretion and stomach emptying and protected against restraint-induced gastric ulceration. However, unlike atropine, DMI did not substantially increase pupil size, reduce fecal pellet output, cause urinary retention, or increase heart rate. From these data, it is possible that at least certain antidepressant type drugs could be developed for the treatment of peptic ulcer disease.