1 Two studies were performed each in six normal volunteers in order to find evidence of either a physiological or pharmacological role of presynaptic ax-and presynaptic P-adrenoceptors in man.2 In Study 1 subjects received a 60 min infusion of guanfacine 3 mg (a2-adrenoceptor agonist) preceded by either idazoxan (oL2-adrenoceptor antagonist) or vehicle. 3 Guanfacine reduced plasma noradrenaline concentration by approximately 30% and this fall was not antagonised by the a2-receptor antagonist. The 30-fold increase in plasma growth hormone, measured as a marker of the central action of guanfacine, was almost completely blocked by idazoxan. 4 A comparison of the drug concentrations of idazoxan and guanfacine, together with their relative affinities for c.2-adrenoceptors, suggested that the idazoxan could not block the peripheral actions of guanfacine and that these were responsible for the fall in plasma noradrenaline concentration. 5 In Study 2 adrenaline 0.05 ,ug kg-1 min--was infused for 80 min preceded by either idazoxan or vehicle. 6 After vehicle, adrenaline caused no change in plasma noradrenaline concentration whereas it rose approximately 25% after administration of idazoxan. This was probably due to unmasking of presynaptic f-adrenoceptor stimulation by adrenaline when the opposing inhibitory autoreceptor was blocked.

The adrenergic nervous system plays an important role in the control of insulin release and animal work suggests that this is mediated by way of alpha 2 adrenoceptors. A specific alpha 2 adrenoceptor antagonist (idazoxan) is now available for use in man and we have studied its effects on insulin release in normal volunteers (a) during the infusion of adrenaline (0.05 micrograms/kg/min) and (b) after an intravenous dose of glucose (20 g). The infusion of adrenaline alone had no significant effect on insulin release while in the presence of idazoxan, insulin release was markedly stimulated by adrenaline. Despite this, adrenaline-induced hyperglycaemia was unaffected by pretreatment with idazoxan. In the second study, pretreatment with either idazoxan or a specific alpha 1 antagonist (prazosin) had no significant effect on either glucose tolerance, glucose-induced insulin release or glucose-induced suppression of glucagon. Intravenous glucose also had no significant effect on pancreatic polypeptide levels. Therefore the effect of adrenaline on insulin release is mediated by way of inhibitory alpha 2 adrenoceptors in the pancreas, while the release of insulin in response to glucose in a resting subject is independent of the alpha-adrenergic system.

Six healthy volunteers received a 60 min infusion of guanfacine (alpha 2-agonist) on two occasions, preceded by either idazoxan (alpha 2-antagonist) or vehicle. Idazoxan elevated blood pressure by 8/7 mmHg, but there was no change on either day during guanfacine infusion. Guanfacine reduced plasma noradrenaline by approximately 30%, and this was not antagonized by idazoxan. By contrast, the 30-fold increase in plasma growth hormone caused by guanfacine was almost completely blocked by idazoxan. Guanfacine caused a two- to three-fold increase in plasma glucagon and a similar reduction in plasma insulin. Only the latter was antagonized by idazoxan. No consistent changes in plasma ACTH were observed after either idazoxan or guanfacine. Idazoxan itself elevated plasma noradrenaline up to twice baseline values, but did not affect the other metabolic measurements. alpha 2-Adrenoceptor stimulation plays a minor role in control of hormone release but has a greater physiological role in regulating release of the neurotransmitter, noradrenaline.

1 The mechanism of the antihypertensive effect of ot-methyldopa was compared with clonidine by administering equipotent single doses of clonidine (0.2 mg) and amethyldopa (750 mg) to nine hypertensive patients. Plasma noradrenaline was followed for 8 h thereafter as an index of peripheral sympathetic activity. 2 a-Methyldopa and clonidine produced the same hypotensive response at 6 and 8 h after dosing with a similar fall in plasma noradrenaline levels at these times. 3 Linear regression analysis between the systolic blood pressure fall and the corresponding plasma noradrenaline fall, showed that the slopes of the two regression lines were similar for a-methyldopa as for clonidine. 4 Equipotent doses of ao-methyldopa and clonidine produce the same fall in plasma noradrenaline. This supports the current hypothesis that an a-methyldopa metabolite acts centrally, like clonidine, to reduce peripheral sympathetic activity.

In chronic bronchitis, intersubject variability in both theophylline pharmacokinetics and pharmacodynamics must be taken into account if the drug is to be used to its best advantage. Both kinds of variability can be integrated into a model which relates the steady state concentration of theophylline to simultaneously measured ventilatory response (most conveniently, the FVC). In a group of 56 patients with chronic bronchitis, the mean +/- s.d. linear response to increasing steady state concentrations of theophylline was 0.04 +/- 0.012 1 microgram-1 ml, starting from a mean +/- s.d. pretreatment FVC of 1.58 +/- 0.791. Using these population parameter values, with or without a pretreatment FVC and/or one steady state concentration -FVC observation, it was possible to predict the degree of response which would be achieved by a smaller group of 20 similar patients. These estimates were obtained using a mathematical procedure based on Bayesian Probability Theory and Maximum Likelihood Estimation. Estimates of the overall response in individual patients allowed prediction of the response at any steady state concentration. These estimates were unbiased and accurate enough for clinical use when they were based on a pretreatment FVC and/or one paired steady state concentration -FVC observation.