SUMMARY The respective contributions of 3-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective 8-adrenoceptor blockade with propranolol and ,81-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of 1,1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 + 162, 640 190 and 584 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 ± 2.1 to 97.7 2.7 mg/di) and on atenolol (from 99.7 ± 2.2 to 102.1 ± 4.8 mg/dl), but fell on propranolol (from 96.4 1.9 mg/dl to 87.2 ± 2.5 mg/dl, p < 0.01). These results indicate that blockade of vascular smooth muscle 12 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through /83-adrenoceptor mechanisms, whereas /2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metabolic responses to acute exercise 2 h after prolonged prior exercise to induce skeletal muscle glycogen depletion, enhancing the dependence on hepatic glucose output and circulating free fatty acids (FFA). Plasma catecholamines were higher during exercise after, as opposed to before, glycogen depletion and were elevated further by all three drugs. Propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. Atenolol reduced systolic blood pressure and did not change diastolic blood pressure. Both beta-blockers reduced FFA levels, but only propranolol lowered plasma glucose relative to placebo during exercise after glycogen depletion. In contrast, prazosin reduced systolic and diastolic blood pressures and resulted in elevated FFA and glucose levels. The results indicate important differences in the hemodynamic effects of beta 1-selective vs. nonselective beta-blockade during exercise after skeletal muscle glycogen depletion. Furthermore they confirm the importance of beta 2-mediated hepatic glucose production in maintaining plasma glucose levels during exercise. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamines, which in the absence of blockade of hepatic beta 2-receptors produces elevation of plasma glucose. The results suggest there is little role for alpha 1-mediated hepatic glucose production during exercise in humans.

1 The effect of oral doses of the pl-selective adrenoceptor antagonist atenolol (50 mg), the non-selective antagonist propranolol (40 mg) and placebo was investigated during exercise in a crossover comparison in six healthy but untrained subjects. Descriptors of ventilation, respiratory gas exchange, and arterialized blood lactate and glucose were obtained during steady state bicycle ergometric exercise at 20% and 60% of the subjects' previously determined maximal oxygen uptake (Vo2 max). 2 At these work intensities, the previously reported increase of respiratory exchange ratio (RER) during non-selective 3-adrenoceptor blockade was found to be trivial (placebo = 0.96 ± 0.03 s.e. mean; propranolol = 0.97 + 0.01; atenolol = 0.97 + 0.04; 60% Vo2 max, 10 min exercise) and only present during the early minutes of effort.Oxygen uptake and carbon dioxide production did not differ between treatments. 3 Both drugs produced highly significant falls in peak expiratory flow (PEF) rates and tidal volume (VT) which were compensated by an increase in respiratory rate. PEF, 60% Vo2 max: placebo = 3.8 + 0.3 l/s; propranolol 3.6 + 0.3 1/s (P < 0.03); atenolol 3.1 + 0.3 1/s (P < 0.01). VT, 60% Vo2 max: placebo 2.0 + 0.1 1; propranolol 1.8 + 0.2 1 (P < 0.05); atenolol 1.7 ± 0.1 1 (P < 0.01). 4 Arterialized lactate was significantly elevated during work at 20% and 60% Vo2 max, but rose progressively at the 60% Vo2 max load. Ventilation, oxygen uptake and ventilatory equivalent for carbon dioxide also rose progressively at this workload. Ventilatory equivalent for oxygen showed no significant rise. There were no treatment differences, either at the aerobic or anaerobic workloads. During steady state exercise, previously described determinants of anaerobic threshold (RER, 02 ventilatory equivalent) appear not to be valid. 5 We conclude that normoglycaemic aerobic or anaerobic work is associated with a I3l-adrenoceptor response which reduces airway resistance. Despite antagonism of lipolysis and hepatic glycogenolysis, ,B-adrenoceptor blockade does not appear to alter the pattern of substrate utilization.

A 34-year-old woman presented with a 6-month history of progressive dyspnoea. Past history included cerebral palsy and epilepsy. At the age of 14 years she had a ventriculoatrial (VA) shunt for hydrocephalus secondary to congenital aqueduct stenosis. There was no past history of deep vein thrombosis, liver disease, appetite suppressant use, intravenous drug abuse or other systemic disease. On examination she was unwell with central cyanosis, tachypnoea (respiratory rate 36 breaths per minute), sinus tachycardia (heart rate 120 beats per minute), and blood pressure 100/60 mmHg. There was ankle oedema, raised jugular venous pressure, accentuated pulmonary second sound and a right ventricular gallop. Chest X-ray showed cardiomegaly with prominent pulmonary arteries (Figure 1). Electrocardiogram demonstrated right axis deviation, dominant R wave in V1 and ST depression across the precordial leads (Figure 2). On room air her arterial partial pressures of oxygen and carbon dioxide were 7.1 KPa and 3.2 KPa respectively. Transthoracic echocardiography showed dilated right ventricle and right atrium with severe tricuspid regurgitation and moderate pulmonary regurgitation. Estimated pulmonary artery pressure was 100 mmHg. There was no evidence of intracardiac thrombus and left ventricular systolic function normal. A ventilation perfusion scan showed multiple sub-segmental perfusion defects. Cardiac catheterization confirmed severe pulmonary hypertension (pulmonary vascular resistance 1048 dynes/sec/cm2) with normal left heart pressures and no intracardiac shunt. Calculated cardiac index was low (1.5 litre/min/kg) with high right atrial pressure (20 mmHg) and low mixed venous oxygen saturation (50%). Pulmonary angiography and chest computed tomogram with contrast showed thrombus in the main pulmonary trunk extending into the proximal right and left pulmonary arteries. Duplex ultrasonography of both legs suggested no evidence of deep vein thrombosis. A thrombophilia, vasculitis and infection screen was negative. The patient was commenced on nasal continuous positive airways pressure, high flow oxygen, intravenous heparin and intravenous colloid with haemodynamic stability maintained for the first 4 days. After this she became more hypoxic and hypotensive so fluids were stopped and a frusemide, dopamine and prostacyclin infusion commenced to reduce right ventricular distension with some improvement. Because of her deteriorating haemodynamic state, pulmonary thromboendarterectomy was performed with removal of extensive thrombus from the proximal pulmonary tree. The patient died in the immediate postoperative period. Postmortem showed a distended and hypertrophied right heart with extensive chronic thromboembolic changes in the distal pulmonary tree. The tip of the VA catheter in the right atrium had no signs of infection and at this time was free of thrombus. The coroner concluded cause of death was pulmonary hypertension secondary to longstanding thromboembolic disease.