SUMMARY Theophylline is thought to act by inhibiting the activity of phosphodiesterase, with a resultant increase in intracellular cyclic AMP. However, this concept is largely based on in vitro studies using concentrations of theophylline which greatly exceed therapeutic plasma concentrations. To investigate the relationship of the cardiovascular and metabolic effects of theophylline to activation of the sympathetic nervous system, i.v. aminophylline was administered to six healthy males under basal conditions. Each subject received four infusions. Mean theophylline concentrations (±+ SEM) of 4.5 + 0.2, 10.0 0.5, 14.0 + 0.5 and 20.0 + 1.2 ,ug/ml were achieved. Plasma epinephrine increased 262% (from 29 4 to 105 14 pg/ml, p < 0.01) and plasma norepinephrine increased 64% (from 190 1 18 to 312 51 pglml, p < 0.05) during the high-dose infusion. The increases in circulating catecholamines were dose-related (p < 0.001 by analysis of variance). Dose-related increases in heart rate, systolic blood pressure, plasma glucose, free fatty acids and insulin were also observed (p < 0.001 by analysis of variance). Although the duration of total electromechanical systole (QS2) and left ventricular ejection time adjusted for heart rate fell during the aminophylline infusions, this positive inotropic response was not influenced by dose, except possibly the high dose. Echocardiographic ejection fraction was not changed by the aminophylline infusions. We conclude that the acute cardiovascular and metabolic effects of theophylline may be mediated in part by stimulation of the sympathetic nervous system. AMINOPHYLLINE (theophylline ethylenediamine) is a methylxanthine derivative that is widely used in the treatment of cardiovascular and respiratory disease. Although ethylenediamine has been implicated in allergic reactions to aminophylline, it is otherwise thought to be therapeutically inactive. Theophylline and other methylxanthines are known to exert a variety of important physiologic and biochemical effects. ' Although the dose-response relationship between plasma concentrations of theophylline and improvement of pulmonary function during bronchospasm is well established,2' I a similar relationship for its cardiovascular and metabolic effects has only recently been examined in human studies." Despite the evidence that the acute administration of methylxanthine derivatives stimulates the release of epinephrine and norepinephrine from the sympathoadrenal system in man,7' 8 the extent to which this response may be dose-or concentration-dependent has only been studied in an in vitro system, the isolated perfused adrenal gland.9' 10 Epinephrine and norepinephrine are known to have chronotropic and inotropic effects on the heart, which, together with vasoconstrictor effects, lead to an increase

Lorcainide is a type I antiarrhythmic drug of the local anesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmia, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable. Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time. Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

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