1. We have previously reported the relative mRNA and protein level of the long and short splice variants of G s α (G s αL and G s αS) in human atrium. We have now measured the relative proportions of the serine + and serine − variants of G s αL and G s αS in human atrium, and assessed, indirectly, whether their differential expression may (i) regulate G s α phosphorylation, and (ii) be regulated by atrial cyclic AMP levels. 2. The serine + and serine − variants of G s αL and G s αS were estimated by single nucleotide primer extension in 36 right atrial strips of which half were from β-adrenoceptor-blocked patients. The ratio of serine + to serine − variants was 0.06 ± 0.12 for G s αL, compared with 8.04 ± 12.16 for G s αS ( P < 0.001). 3. Isoelectric points of G s αL and G s αS in the atria of four β-adrenoceptor-blocked and four non-β-adrenoceptor-blocked patients were estimated by two-dimensional gel electrophoresis. Two-dimensional gel analysis gave a consistent pattern with several spots for both G s αL and G s αS; however, the isoelectric points of G s αS were more acid (5.18 ± 0.24) than those of G s αL (5.87 ± 0.17, P < 0.001). 4. No significant difference in either the serine variants or isoelectric point value was observed between β-adrenoceptor-blocked and non-β-adrenoceptor-blocked patients. 5. In conclusion, all four G s α variants were expressed in human atrium, but G s αL is almost entirely of the serine − form. G s αS has a more acidic isoelectric point than G s αL, indicating a possible post-translational modification. The lack of difference in our results between β-adrenoceptor-blocked and non-β-adrenoceptor-blocked patients suggests indirectly that cyclic AMP is an unlikely candidate for regulating splicing or post-translational modification of G s α in vivo .

1. Superior mesenteric artery blood flow was examined by Doppler ultrasound in six male subjects aged 19–23 years during the infusion of saline (control), 10 and 40 ng of adrenaline min −1 kg −1 for 30 min, or propranolol and 10 ng of adrenaline min −1 kg −1 for 30 min, on four separate occasions. 2. Adrenaline infusion resulted in significant peak mean (SEM) rises in circulating adrenaline concentrations during the infusion period only [control, 0.20 (0.05) nmol/l; 10 ng of adrenaline min −1 kg −1 , 1.37 (0.29) nmol/l; 40 ng of adrenaline min −1 kg −1 , 3.73 (0.40) nmol/l; 10 ng of adrenaline min −1 kg −1 and propranolol, 1.48 (0.16) nmol/l, P < 0.001 versus control]. These values are within the physiological range. 3. Superior mesenteric artery blood flow rose in a dose-dependent manner during the adrenaline infusions alone, but not during the infusion of adrenaline and propranolol [mean (95% confidence interval) area under the curve: control, −4.2 (−11 to +2.7)%; 10 ng of adrenaline min −1 kg −1 , +4 (−1 to 11.9)%; 40 ng of adrenaline min −1 kg −1 , +34 (+ 6.5 to + 61.5)%; 10 ng of adrenaline min −1 kg −1 and propranolol, −8.4 (−23 to +6)%]. 4. Superior mesenteric artery resistance fell during the adrenaline infusions alone and rose during the combined adrenaline and propranolol infusion [mean (SEM) area under the curve: control, 6.4 (2.7)%; 10 ng of adrenaline min −1 kg −1 , −2.9 (2.5)%; 40 ng of adrenaline min −1 kg −1 , −15 (1.4)%; 10 ng of adrenaline min −1 kg −1 and propranolol, 16.9 (10)%]. 5. These data suggest that splanchnic vasodilatation is mediated via a β-adrenergic mechanism.

1. The influence of β-adrenoceptor-blockade on skeletal muscle was studied in ten healthy males with propranolol, atenolol and pindolol randomly given for 8 days each in a cross-over double blind test. After 7 days on each drug, muscle function was tested by an isokinetic dynamometer. Thermogenesis in biopsy samples taken from vastus lateralis muscle after a low grade exercise was studied after 8 days on each drug by direct calorimetry with a perfusion microcalorimeter. 2. Before drug administration, a median heat production rate of 0.67 mW/g of muscle was measured. This value was significantly reduced by 25% during propranolol, but no significant change was found during atenolol or pindolol administration. 3. Peak torque decline during isokinetic endurance test changed significantly in knee flexor but not in extensor muscles, from 15% to 27% after propranolol and from 15% to 23% after pindolol. Maximum dynamic strength was unaltered. 4. Our data suggest that blockade of sympathetic β 2 -receptors decreases thermogenesis in human skeletal muscle and impairs isokinetic endurance.

1. Electrophoretic and enzyme techniques have been used to study the structure and function of the contractile protein system in the myocardium of dogs before and after β-adrenoceptor blockade. Animals were examined after acute β-adrenoceptor blockade by using intravenous atenolol (0.2 mg/kg) and following chronic therapy with oral atenolol (100 mg twice daily) for a mean period of 106 days. 2. Two-dimensional polyacrylamide-gel electrophoretic techniques were used to examine the myocardial contractile and regulatory proteins present in endomyocardial biopsy specimens obtained after acute and chronic β-adrenoceptor blockade. No differences in charge, molecular weight or the relative proportions of actin, myosin light chains, tropomyosin or troponin-C were seen after either acute or chronic β-adrenoceptor blockade. 3. The maximal activity and calcium sensitivity of the myofibrillar adenosine triphosphatase (ATPase) was also unchanged after acute and chronic atenolol therapy. 4. It is concluded that β-adrenoceptor blockade has no significant adaptive effect on the structural or functional properties of the myofibril.

1. Previous studies have shown that non-selective β-adrenoceptor blockade attenuates the blood glucose recovery rate after hypoglycaemia in type I diabetes. Apart from possible effects on hepatic glycogenolysis propranolol also inhibits the release of the important gluconeogenic substrates lactate and glycerol. 2. To determine whether the effect of non-selective β-adrenoceptor blockade on glucose recovery could be associated with diminished availability of gluconeogenic substrates, lactate and glycerol were infused during hypoglycaemia in four insulin-dependent diabetic patients. Comparisons were made of the blood glucose recovery on placebo, propranolol and propranolol combined with the infusion. 3. The blood glucose recovery rate after hypoglycaemia was less on propranolol than with placebo but was significantly improved and not different from placebo when propranolol treatment was combined with lactate and glycerol infusions. Thus, at least for type I diabetic patients, in whom gluconeogenesis is proportionally greater than in healthy subjects, non-selective β-adrenoceptor blockade attenuates the glucose recovery rate from hypoglycaemia mainly by reducing the availability of gluconeogenic substrates.

1. Twelve hypertensive patients with cardiomegaly were treated with equivalent antihypertensive doses of prazosin (11 weeks) and β-adrenoceptor-blocking drug (9 weeks) in random crossover fashion. 2. At the end of each treatment period haemodynamic assessment included the response to isometric handgrip exercise (4 min at 30% of maximum voluntary contraction). 3. Resting cardiac index and heart rate were higher on prasozin although the latter was only 65 beats/min. Systemic vascular resistance and left ventricular filling pressure were insignificantly higher on β-adrenoceptor-blocking drug. 4. During isometric handgrip the blood pressure rise was similar on the two regimens, but the mechanism whereby it was achieved was quite different. On prazosin an increase in cardiac output accounted for the pressor response with virtually no change in systemic vascular resistance, whereas on β blockade there was a flat cardiac output response with a marked increase in the systemic vascular resistance. 5. Ventricular function curves indicated a predominant utilization of the Frank-Starling mechanism during β blockade, whereas enhanced contractility played a major role during prazosin treatment. 6. The isometric exercise response pattern during prazosin treatment resembles that in normal subjects whereas in the β blockade phase it corresponded to that in untreated hypertensive patients with left ventricular hypertrophy or cardiomegaly or to that in congestive heart failure patients. 7. There was no evidence of harmful effects of combined pre- and after-load reduction in hypertensive patients with cardiomegaly and normal filling pressure, even under conditions of moderately severe cardiac loading with isometric exercise.

1. After 10 years of β-adrenoceptor blockade in five female patients with essential hypertension, the β-adrenoceptor-blocking agent was withdrawn, and the women were then followed up for 1 year, with measurements of cardiac output and peripheral resistance. 2. Blood pressure remained low during the first year after withdrawal in spite of the fact that the heart rate increased within the first few days. 3. Cardiac output was found to increase during the first year after withdrawal, although total peripheral resistance was essentially unchanged. 4. The maintenance of low blood pressure after withdrawal of the antihypertensive drug might indicate a regression of structural changes in the resistance vessels during successful long-term antihypertensive treatment. 5. Minimal resistance in hands and calves did not increase during the year after withdrawal.

1. BM 12.434 was compared with a known β-adrenoceptor-blocking agent, metipranolol, and a combination of metipranolol and isosorbide-5-mononitrate in healthy volunteers. BM 12.434 and metipranolol were given in equi-effective β-adrenoceptor-blocking doses (reduction of exercise-increased pulse-pressure product). 2. Responses of the cardiovascular system were determined by non-invasive methods. 3. BM 12.434 increased the peripheral resistance less than metipranolol. 4. After BM 12.434, in contrast to metipranolol, both arterial flow and the venous capacity showed significant increase. 5. The combination of isosorbide-5-mononitrate and metipranolol differed from metipranolol alone mainly by the effect on venous capacity, which showed a slight increase. 6. BM 12.434 is a β-adrenoceptor-blocking agent whose additional actions on the veins and arteries are potentially useful for the treatment of both coronary heart disease and of arterial hypertension.

1. Noise stimulation (100 dBA) for 10 min caused a significant increase in diastolic (7.0%, P < 0.001) and mean arterial blood pressure (4.3%, P < 0.01) in patients with essential hypertension. 2. The blood pressure response to noise was due to an increase in total peripheral resistance (4.8%, P < 0.02); heart rate, stroke volume and cardiac output were unchanged. 3. β 1 -selective adrenoceptor blockade (metoprolol) did not change the haemodynamic reaction pattern induced by noise. 4. Noise exposure during non-selective β-adrenoceptor blockade (propranolol) caused an accentuated blood pressure response with increments of both systolic and diastolic blood pressure as well as a more pronounced rise in total peripheral resistance. 5. The haemodynamic changes induced by noise stimulation at 100 dBA totally disappeared after 5 min of quiet rest at 40 dBA.

1. Carbohydrate and lipid metabolism and the capacity to perform prolonged submaximal physical exercise were studied in six young healthy subjects treated in a randomized double-blind fashion for 2 days with either placebo, the non-selective β-adrenoceptor antagonist propranolol (80 mg b.i.d.) or the cardioselective agent metoprolol (100 mg b.i.d.). On day 3, 1 h after the last dose, the subjects exercised for 30 min periods followed up 10 min rest up to the point of exhaustion. 2. The capacity to perform exercise was decreased with both β-adrenoceptor antagonists. However, at an equal degree of β 1 -adrenoceptor blockade, all subjects could exercise for a longer period of time on the cardioselective agent as compared with the non-selective drug. 3. Blood glucose levels decreased during exercise irrespective of the type of treatment, but the attenuation occurred most rapidly on propranolol. At exhaustion the average non-esterified fatty acid levels had increased 256% on placebo, 148% on metoprolol and 65% on propranolol. A significant positive correlation was found between changes in non-esterified fatty acid levels during exercise and total working time. It is concluded that β-adrenoceptor blockade diminishes the capacity for prolonged submaximal exercise at least in part by reducing the availability of substrates to the working muscles.

1. The immediate haemodynamic and metabolic effects of intravenous administration of dl-propranolol and d-propranolol were studied in healthy male subjects at rest and during dynamic forearm exercise. The dose of dl-propranolol and of d-propranolol was 0.1 and 1.0 mg/kg body weight respectively. 2. dl-Propranolol reduced heart rate significantly at rest, during forearm exercise and post-exercise, whereas d-propranolol had a lesser effect on heart rate which was significant only at the end of the exercise period. Arterial blood pressure and forearm blood flow were unchanged after either drug. 3. Both drugs reduced the release of lactate from the exercising forearm. Forearm exchange of oxygen, glucose, free fatty acids and triglycerides remained unchanged. 4. The arterial blood glucose concentration increased after d-propranolol, but was unchanged after dl-propranolol. The arterial serum free fatty acid concentration decreased after dl-propranolol, but was not changed after d-propranolol. Arterial concentrations of lactate and triglycerides were not influenced by the drugs. 5. The chronotropic response to β-adrenoceptor blockade appears to be stereoselective, suggesting specific blockade of β-adrenoceptors. Metabolic responses to β-adrenoceptor blockade are difficult to explain in terms of the known adrenoceptor system and may be due to nonspecific actions of β-adrenoceptor antagonists. An exception is inhibition of lipolysis, which is probably mediated via β-adrenoceptors.

1. Central and regional haemodynamics and leg metabolism at rest, during and after a prolonged exercise were studied in seven untreated hypertensive males before and after a long-term treatment (6 weeks) with an unselective β-receptor-blocking drug (alprenolol). 2. Alprenolol treatment (200–400 mg, twice daily) decreased arterial blood pressure at rest and during exercise; it reduced heart rate in relation to drug plasma concentrations during and after exercise; it left cardiac output unchanged; it reduced leg blood flow at rest, but had no effect on leg blood flow during exercise. 3. Alprenolol treatment also decreased lipolysis and lactate release in relation to drug plasma concentrations during exercise.