1 The acute peripheral vascular and diuretic effects of intravenous frusemide 10 mg and 20 mg were compared with those of bumetanide 250 pug and 500 ,ug in a group of 10 salt depleted volunteers. 2 Significant reductions in forearm blood flow (FBF) were observed after frusemide 10 mg (-0.77 ml 100 ml-' min-' P < 0.05) and 20 mg (-0.75 ml 100 m11 minil P < 0.01 at 15 min). No changes were observed after bumetanide. The reductions in blood flow produced by frusemide were significantly different from those of bumetanide (P < 0.05) at 15 min. 3 Increases in venous capacitance (VC) and mean arterial blood pressure (MAP) were observed after frusemide but these differences were not statistically different from placebo or bumetanide. No increases were seen after bumetanide. 4 Plasma aldosterone concentrations were unchanged after either drug but plasma renin activity (PRA) was increased after frusemide 10 mg (4.42 + 1.01 -+ 8.50 + 1.90 ng A I ml-' h'1 P < 0.01) and 20 mg (4.01 ± 0.72 --7.81 ± 2.27 ng A I m[71 h-1 P < 0.05). No increases were observed after bumetanide and significant differences between bumetanide and frusemide were observed (P < 0.01). 5 This study demonstrates that the acute peripheral arterial effects of frusemide are not observed after comparable diuretic doses of bumetanide. The differences appear to be related to the ability of the drugs to stimulate acute renin release from the kidney.

To examine the importance of angiotensin II formation in the production of frusemide's acute peripheral venous and arterial responses, the effect of pretreatment with captopril was studied. Captopril abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by intravenous frusemide. The study provides evidence that angiotensin II formation performs an essential role in the production of the acute vascular effects of frusemide in man.

1 The P-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. 2 Seven subjects received in random order oral doses of ICI 141,29220,50,100,200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. 3 The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 ± 3.7%) and 400 mg (24.3 + 5.2%) were similar to atenolol 50 mg (27.3 + 4.7%) but less than atenodol 100 mg (30.8 + 2.9%) (P < 0.02). 4 Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-'. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. 5 At the 4 ,ug min-' dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P < 0.02). ICI 141,292400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P < 0.02). 6 These results indicate that ICI 141,292 is a cardioselective ,-adrenoceptor antagonist with partial agonist activity.

1 To examine the importance of acute frusemide-induced renin release in the production of the acute peripheral venous and arterial responses to frusemide in man, the effects of two drugs, previously described as inhibitors of acute frusemide-induced renin release, propranolol and digoxin, were examined. 2 Propranolol abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by frusemide. The acute increases in plasma renin activity and plasma aldosterone concentrations were also abolished. 3 Pre-treatment with digoxin had no effect on the acute peripheral vascular responses to frusemide and failed to inhibit the acute increases in plasma renin activity and plasma aldosterone produced by frusemide. 4 The study provides further evidence of a relationship between acute frusemideinduced renin release and the acute peripheral vascular effects of frusemide in man.

The effects of maintenance indomethacin therapy on single dose digoxin pharmacokinetics and dynamics were studied in six healthy volunteers with normal renal function. Indomethacin did not alter the elimination half‐life, systemic clearance or distribution of digoxin. No pharmacodynamic interaction as assessed by changes in the systolic time intervals QA2 and LVET was found. This study does not lend support for a significant digoxin‐indomethacin interaction in man.