1. The alveolar-arterial oxygen-tension gradient was measured in duplicate, in forty-eight healthy subjects (twenty-four men and twenty-four women) aged from 20 to 74 years, while breathing oxygen concentrations of approximately 14, 21, 40, 60 and 100%. 2. The gradient increased with age and with inspired O2 concentration up to 60%. Above 60%, during normal breathing, there was no significant change in gradient. 3. Breathing 100% O2 in deep breaths decreased the gradient in all age-groups, significantly so in subjects of 50 years and younger. The remaining gradient was due to anatomical venous shunt. 4. When this anatomical shunt was allowed for, the differences in gradient between age-groups were largely abolished at all inspired O2 concentrations. The gradient which was not due to anatomical shunt, when breathing air, remained higher in subjects over 60 years than in the younger subjects. 5. The results can be interpreted to mean that three components contribute to the normal gradient: (a) irreversible anatomical shunt; (b) closed, unventilated alveoli which can only be inflated by deep breaths; and (c) cyclical airway closure during normal breathing in subjects over 60 years. Diffusion disequilibrium may contribute a gradient of up to 3 mmHg during the breathing of low O2 concentrations.

The effects of verapamil on epicardial ST segment elevation, regional myocardial metabolism and collateral blood flow were studied in open-chest anesthetized dogs following left anterior descending coronary artery occlusion. Collateral blood flow was measured by radioactive microspheres (15 +/- 5 micron diameter) and regional metabolism was studied by measuring lactate concentration in venous blood draining the infarcting myocardium. Verapamil (0-2 mg/kg intravenously) produced a significant reduction (50-60%) in the epicardial ST elevation when it was given before coronary occlusion; when administered 15 minutes after coronary occlusion and infusion continued for two hours, it minimized (30-40%) ST segment elevation, and prevented the fall in cardiac index and rise in systemic resistance found in the untreated animals in which the ST segment remained persistently elevated. Changes in epicardial ST segment occurred without alterations in the QRS duration. Verapamil had no effect on either the total collateral blood flow or the relative distribution of flow to the endocardial and epicardial halves of the ischemic ventricular myocardium. No significant differences were found between the levels of lactate in blood sampled from small epicardial veins at the center of the infarct when the control animals were compared with those treated with verapamil.

Open-chest anaesthetized dogs were given verapamil after left anterior descending artery occlusion, and ST-segment alterations and haemodynamic variables were monitored. Verapamil produced a highly significant reduction in ST-segment elevation in the epicardial electrocardiogram and prevented the haemodynamic deterioration seen in the control animals in which ST-segment elevation persisted. The apparent protective effect of verapamil in myocardial ischaemia is discussed in relation to its ability to inhibit selectively the transmembrane fluxes of calcium ions in excitable tissues.

SUMMARY Myocardial creatine phosphokinase (CPK) activity and myocardial blood flow (MBF, 15 ± 5 ,u microspheres) were measured at 24 hours after ligation of the left anterior descending coronary artery in nine untreated anesthetized dogs, in eight dogs pretreated with intravenous propranolol 5 mg/kg and in eight which had both pretreatment as well as infusion of propranolol (1.25 mg/kg/hour) after occlusion. Loss of CPK activity from the border and center zones of the myocardial infarct was similar in extent in dogs which had pretreatment but no infusion of propranolol as it was in the control group. Loss of CPK from the center zone was greater REDUCTION OF MYOCARDIAL OXYGEN CON-SUMPTION with beta-adrenergic blocking drugs1 is of proven clinical value for the treatment of angina pectoris and might also be beneficial in the treatment of the acute imbalance between oxygen supply and demand which occurs during the early stages of myocardial infarction. In spite of an initially encouraging report,2 however, oral administration of propranolol in early randomized trials3 was not found to reduce mortality from myocardial infarction in patients.More recently, Maroko et al. suggested that propranolol could reduce the intensity of experimental myocardial ischemia, as judged by electrocardiographic as well as other criteria.5 The findings have been consistent with the results of histological studies of the posterior papillary muscle after circumflex coronary artery ligation in the dog6 and with the reports that propranolol used experimentally preserved high energy stores in infarcting myocardium'5 and reduced gross anatomic infarct size.t1 Moreover, a recent clinical study has shown that propranolol may improve myocardial oxygenation in patients with uncomplicated infarction.12The present study was designed to re-examine the effect of high doses of propranolol, using our previously described model for the measurement of myocardial blood flow, both at 15 min and 24 hours after coronary occlusion, and measurement of the intensity of creatine phosphokinase (CPK) depletion at 24 hours after onset of infarction.,3 The effects of propranolol on these parameters were correlated with the hemodynamic alterations produced by the drug in relation to its plasma concentrations. (P < 0.005) in dogs receiving pretreatment followed by constant infusion of the drug. Propranolol had no significant effect on collateral blood flow to the border or center zone of the infarct. In separate experiments, there was no important difference in hemodynamic measurements, except a slower heart rate (P < 0.01), when pretreated dogs were compared with control dogs up to 2 hours after coronary ligation. We conclude that propranolol given in this dose does not influence myocardial damage, on the basis of regional myocardial blood flow or tissue CPK depletion values at 24 hr after coronary occlusion. MethodsForty-eight mongrel dogs, weighing 18-32 kg (mean 24 kg) were divided into two groups.Group 1 (25 dogs), designated the survival group, was divided into ...