1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg metoprolol on the cardiovascular and respiratory responses to progressive exercise in nine healthy men in doubleblind, placebo-controlled experiment. As judged by their effects on exercise heart rate and cardiac output the doses of the two drugs used were equivalent.2 fp-adrenoceptor blockade reduced oxygen consumption by 3.5% over the whole work range with an increase in the respiratory exchange ratio of 0.056 units. Carbon dioxide production and exercise ventilation were unchanged. The two drugs had similar effects. Possible mechanisms for these observations are discussed.3 Perceived exertion during exercise was increased by both the f-adrenoceptor blocking drugs and this may be of relevance to the symptom of fatigue reported by patients on these drugs. Endurance, assessed as either total work done or maximal work achieved, was reduced by 15%.One of the main therapeutic uses of f-adrenergic receptor blocking drugs has been in the management of angina pectoris. Many authors have reported improved exercise tolerance in these patients with delayed onset of both ischaemic pain and ECG abnormalities and reduced dependence on coronary vasodilators- (Comerford & Besterman, 1976). 0-adrenoceptor blocking drugs are also widely used in the control of hypertension, often in patients whose exercise tolerance is presumably normal. As adrenergic mechanisms play a major role in facilitating oxygen transport through their involvement in the control of cardiovascular and respiratory adjustments during exercise, it is important to establish the effect of f-adrenoceptor blockade on exercise tolerance, particularly as there is now evidence that the cardiovascular reserves of untrained but otherwise healthy people are more limited than generaly appreciated (Wasserman, Whipp, Koyal & Beaver, 1973). Using normal individuals we have measured cardio-respiratory variables and the level ofperceived exertion during a standard progressive exercise test. Nine subjects were exercised to exhaustion while taking either metoprolol, propranolol or placebo. In this way the effects of both non-selective and more cardio-selective ,B-adrenergic receptor blockade have been studied. MethedsNine healthy adult male volunteers with normal lung function were used as subjects. They were aged 25 to 42 years (mean + s.d. 35 + 7 years), and gave their informed consent to a protocol which had been approved by the Ethical Committee of the Department of Physiology and Pharmacology.Identical tablets containing either 80 mg propranolol (Inderal, ICI) or 100 mg metoprolol (Betaloc, Astra) or lactose were used, and neither the subjects nor the experimenters were aware of the code used to identify the tablets. Three experiments were performed on each subject and at least 48 h elapsed between experiments on any individual. The order of the drugs was randomized between individuals to reduce bias due to any training effect of the procedure. Each experiment took 1.5 h and it started

The difference between the mean operative delays in the two groups was therefore 43 hours (95% confidence interval 41-35 to 44-45 h; t=6 0 143 df; p

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Summary and conclusionsThe value of beta-blockade for suspected acute myocardial infarction was assessed by determining the sixweek and one-year mortality rates in patients started on propranolol, atenolol, or placebo immediately on entry to a coronary care unit. A total of 388 patients entered this double-blind, randomised study, and when analysed on the basis of the initial, intention-to-treat categories there was no significant difference between the three groups in respect of the mortality rate at one year. There was, however, a high withdrawal rate from the trial; the reasons for this illustrate problems of physician compliance and interpretation of data, which are common to all early-entry trials of haemodynamically active agents in acute myocardial infarction. Introduction Despite many clinical trials the role of beta-blockade in the immediate treatment of patients with acute myocardial infarction is still not clear. '-5 In some of the trials that used propranolol the dosage may have been insufficient to achieve beta-blockade.,

1. Splenic blood flow and splanchnic haemodynamics have been studied in twenty patients with splenomegaly due to blood dyscrasia or diseases involving the reticuloendothelial system. Thirteen of these patients had portal hypertension, three had abdominal collaterals on arteriovenography and one oesophageal varices. 2. Total spleen blood flow was increased in all with values up to 1550 ml/min, and associated with this liver blood flows increased up to 2·61 1 min−1 m−2. In four patients the cardiac output was raised. 3. In five patients a raised wedged hepatic vein pressure was found which was solely related to the increase in liver blood flow, but in two others, in whom hepatic histology was abnormal, there was also an increase in postsinusoidal resistance. Nine patients had a raised hepatic pre-sinusoidal resistance. This was related to a greatly increased liver blood flow with portal tract fibrosis and cellular infiltration as possible additional factors. 4. The haemodynamic findings in these patients were similar to those found previously in patients with tropical splenomegaly. In both groups spleen blood flow in ml 100 g−1 min−1 was inversely proportional to spleen size. There were similar increases in total spleen and liver blood flows and in the percentage of patients with an increased pre-sinusoidal resistance. In contrast, in cirrhosis there was no inverse relationship between flow in 1 100 g−1 min−1, and of spleen size, and for the degree of splenomegaly total spleen blood flow was relatively greater.

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In four patients with cold agglutinins, erythrocyte mean corpuscular volume was increased. Erythrocyte volume histograms showed that in each case macrocytosis was due entirely to doublet erythrocytes counted as single cells. For two of the four patients, macrocytosis was reported intermittently, when the blood had been allowed to cool to room temperature during laboratory processing. For these two patients, macrocytosis due to doublet erythrocytes could be elicited in vitro proportionate to the degree of cooling of the blood and could be abolished to rewarming to 37 C. Two other patients had macrocytosis constantly during the acute illness. Otherwise unexplained macrocytosis may reflect cold agglutinin activity without overt hemolysis, particularly if the macrocytosis is intermittent.

Interventions-Twice daily lipid lowering treatment was given, with the fibrate administered in the morning (either bezafibrate 400 mg (n = 101) or fenofibrate 200 mg (n = 1)) and the statin in the evening (either simvastatin 10 mg (n = 23), 20 mg (n = 72), or 40 mg (n = 2) or pravastatin 10 mg (n = 1) or 20 mg (n = 4)). Treatment continued for 1 (n = 9), 2 (n = 58), or 3 (n = 35) years. Main outcome measures-Selected laboratory variables (total cholesterol concentration and liver (aspartate transaminase (AST)) and muscle enzyme (creatine kinase (CK)) activities) and documented symptomatology. Results-A mean (SD) total cholesterol concentration of 5 2 (0.8) mmolIl was achieved after combined treatment for 1 year which was maintained at annual follow up. Over a maximum 3 year follow up no patient reported myalgic symptoms and none had a measured CK activity > 10 times above nomal. Four men on a simvastatinbezafibrate combination had a CK activity rise to less than three times normal. Fourteen patients with a negative history of alcohol excess (consumption < 21 units/week) had borderline raised AST values. Conclusions-Statin-fibrate combination treatment for up to 3 years in a cohort of patients with coronary artery disease was not associated with serious disturbances in biochemical markers of muscle or liver function. (Br Heart J 1995;74:14-17)