Gastro-oesophageal variceal haemorrhage is one of the most dreadful complications of portal hypertension and can be controlled with vasoconstrictors. Nevertheless, sympathetic tone abnormality and vascular hyporesponsiveness in portal hypertension may impede the haemostatic effects of vasoconstrictors. Propranolol, a β-blocker binding the G-protein-coupled adrenoceptor, is a portal hypotensive agent. However, whether propranolol influences the collateral vasoresponse is unknown. Portal hypertension was induced by PVL (portal vein ligation) in Sprague–Dawley rats. In an acute study with an in situ perfusion model, the collateral responsiveness to AVP (arginine vasopressin) was evaluated with vehicle, propranolol (10 μmol/l), propranolol plus suramin (100 μmol/l, a G α inhibitor) or suramin pre-incubation. G α mRNA expression in the splenorenal shunt, the most prominent intra-abdominal collateral vessel, was measured. In the chronic study, rats received DW (distilled water) or propranolol (10 mg·kg −1 of body weight·day −1 ) for 9 days. Then the concentration–response relationship of AVP and G α mRNA expression were assessed. Propranolol pre-incubation elevated the perfusion pressure changes of collaterals in response to AVP, which was inhibited by suramin. The splenorenal shunt G αq and G α11 mRNA expression were enhanced by propranolol. The group treated with propranolol plus suramin had a down-regulation of G α11 as compared with the propranolol group. Chronic propranolol treatment reduced mean arterial pressure, PP (portal pressure) and the perfusion pressure changes of collaterals to AVP. G αs expression was up-regulated. In conclusion, propranolol pre-incubation enhanced the portal-systemic collateral AVP responsiveness in portal hypertensive rats, which was related to G αq and G α11 up-regulation. In contrast, the attenuated AVP responsiveness by chronic propranolol treatment was related to G αs up-regulation. The G α signalling pathway may be a therapeutic target to control variceal bleeding and PP in portal hypertension.

1. The influence of long-acting propranolol and of atenolol on the circadian rhythm of heart rate was assessed using 24 h electrocardiographic recordings in elderly patients with essential hypertension. Eighteen elderly patients were investigated before treatment and after 12 weeks on 60 mg of long-acting propranolol once a day; 21 elderly patients were studied before treatment and after 12 weeks on 50 mg of atenolol once a day. The mean hourly heart rate in 24 h electrocardiographic recordings was used to fit cosine curves by the statistical technique of least squares, and the following parameters were estimated: mesor (rhythm-adjusted mean of the heart rate), amplitude (one-half of the total diurnal variation of the heart rate) and acrophase (the time when the heart rate was at its peak above the mean). 2. The cosine curves were fitted with a P value of 0.01 or less before and after treatment in all patients. 3. In the long-acting propranolol group, the mesor and amplitude were reduced significantly after treatment. The acrophase appeared significantly earlier after treatment than before treatment. 4. In the atenolol group, the mesor and amplitude decreased significantly after treatment. However, the acrophase did not change with treatment. 5. We conclude that both propranolol and atenolol decrease the mesor and amplitude through blocking cardiac β 1 -receptors, and that only propranolol may have some effects on the central nervous system, resulting in the circadian phase shift.

1. Disturbances of calcium metabolism, mimicking mild, compensated secondary hyperparathyroidism, accompany essential hypertension, but it is not known whether these alterations are primary or only secondary to the elevated blood pressure. 2. Indices of systemic calcium metabolism were followed prospectively during 6 months' treatment with either propranolol, bendroflumethiazide or verapamil in 35 patients with essential hypertension. Multivariate statistical methods were employed to study the effects of blood pressure reduction upon the metabolic indices with adjustment for the effects of the different antihypertensive agents. 3. Propranolol treatment increased the plasma ionized calcium and serum phosphate concentrations, and reduced the serum levels of parathyroid hormone, free fatty acids and glycerol. Neither the total nor the total albumin-modified serum calcium concentration was significantly affected. Thus, presumably the decrease in free fatty acids reduced the calcium complex and the calcium binding to albumin, and consequently increased the plasma ionized calcium, thereby suppressing the secretion of parathyroid hormone. 4. Bendroflumethiazide caused a reduction of the fasting renal calcium excretion to half the pretreatment level, but produced no other significant changes in the various indices of calcium metabolism. 5. During verapamil treatment, the fasting renal excretion of calcium and magnesium increased, whereas the free fatty acids and glycerol concentrations in serum were reduced. These two changes presumably balanced each other, as the plasma ionized calcium and serum parathyroid hormone concentrations were not significantly altered. 6. There were no consistent relationships between the decrease in blood pressure and the changes in the metabolic indices, either in the total sample or within any subgroup. These findings indicate that disturbances of calcium metabolism in essential hypertension are primary to, and not induced by, the elevated blood pressure per se.

1. The physiological changes of pregnancy have been shown to alter the disposition of some drugs. However, there are no data on the possible influence of pregnancy or its complications on drug effect. We have applied drug concentration–effect analysis to determine whether pregnancy influences the action of propranolol. 2. Twelve women with pregnancy induced hypertension were studied during the third trimester and again 2–3 months post partum. On each occasion propranolol (10 mg) was given intravenously and measurements of heart rate, blood pressure and whole blood propranolol concentration were determined over the ensuing 8 h. 3. Pregnancy did not alter propranolol disposition. Clearance was 0.63 ± 0.18 and 0.71 ± 0.24 litre h −1 kg −1 , and volume of distribution at steady state was 4.02 ± 2.98 and 3.07 ± 1.58 litres/kg during and after pregnancy respectively. 4. There was no fall in blood pressure over the period of the acute study. The reduction in heart rate (beats/min per ng of propranolol/ml) was greater during compared with after pregnancy: −0.61 ± 0.23 and −0.39 ± 0.19 respectivly ( F = 6.64; df 1,9; P <0.03). There was no relationship between blood pressure or pretreatment heart rate and the slope of the concentration–effect relationship. 5. We conclude that pregnancy can significantly alter drug effect in the absence of any pharmacokinetic changes. These findings suggest that therapeutic ranges established in non-pregnant patients may not be applicable during pregnancy.

1. Plasma ammonia and heart rate were measured in normal volunteers before, during and after an exercise test following administration of placebo, propranolol, pindolol, metoprolol and nadolol. 2. Small changes in plasma ammonia occurred during exercise after placebo. However, all four β-adrenoceptor antagonists produced considerably greater rises. This effect was most marked after propranolol with the response to pindolol, metoprolol and nadolol being similar and intermediate between placebo and propranolol. 3. Resting heart rate was reduced by all the β-adrenoceptor antagonists except pindolol. Exercise induced changes in heart rate were significantly reduced to a similar degree by all the β-adrenoceptor antagonists.

1. β-Adrenoceptor blocker therapy is known to cause disturbances of the lipoprotein profile. The long-term effects of β-adrenoceptor blockers and the influence of intrinsic sympathomimetic activity (ISA) has not been clearly defined. We measured serum lipoproteins during chronic β-adrenoceptor blockade in patients with stable angina pectoris treated with propranolol (without ISA) (n = 21) or pindolol (with ISA) ( n = 19). 2. No significant changes occurred in the lipoprotein profile of the patients taking pindolol. In those taking propranolol, very low density lipoprotein (VLDL) increased at 52 weeks ( P < 0.05) and total high density lipoprotein (HDL) decreased at 26 weeks ( P < 0.01) and at 52 weeks ( P < 0.05). However, HDL 2 rose significantly at 52 weeks ( P < 0.05). There was a corresponding increase in HDL 2/ HDL 3 ratio. 3. We conclude that pindolol is less likely to exert a harmful effect on plasma lipoproteins than β-adrenoceptor blockers without ISA.

1. The relative contribution of the efferent components of the sympathetic and parasympathetic nervous systems to the heart rate (HR) response to dynamic physical exercise was evaluated in 23 normal males. 2. The dynamic exercise was performed on a bicycle ergometer at work loads of 25, 50 and 100 W, before and after pharmacological blockade with atropine (13 individuals) or propranolol (10 individuals). 3. Parasympathetic blockade significantly depressed the rapid HR response at the beginning of the exercise period at all levels of intensity, whereas sympathetic blockade only affected the slow-response phase (1–4 min), especially at the highest level of effort. 4. The present results suggest that the tachycardia evoked by dynamic exercise is mediated by a biphasic mechanism initially depending on rapid vagal release, which increases progressively with increasing effort. An increased sympathetic activity manifests itself in a more delayed manner, especially at the higher levels of activity. 5. Continuous monitoring of HR during the entire period of activity at different levels of intensity permits the utilization of dynamic exercise as a simple and non-invasive method for the functional evaluation of the two components of the autonomic nervous system of the heart.

1. Five continuous records of arterial plasma potassium were obtained from three normal subjects during brief periods (5–7 min) of exercise (100 W). 2. In two of these subjects hepatic venous blood samples were withdrawn at 0.5–1.0 min intervals and analysed in vitro for plasma potassium. 3. Arterial plasma potassium rose rapidly at the start of exercise from 3.8 ± 0.3 mmol/l (mean ± sd) to plateau levels of 5.4 ± 0.1 mmol/l. 4. One of the above subjects and a further subject were studied after β-blockade with propranolol. This resulted in an exaggerated rise in arterial plasma potassium during exercise. 5. Hepatic venous potassium measurements indicated that the liver probably had little effect on potassium changes during exercise. 6. The changes in arterial plasma potassium during exercise are rapid and substantial. If transmitted to the extracellular fluid these changes would alter cell transmembrane potential and might as a result alter receptor sensitivity.

1. The effect of 4-6 weeks’ treatment with propranolol and nadolol on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) was studied, in 14 patients with essential hypertension, in single blind, random and cross-over design. 2. Both drugs caused comparable effective lowering of pulse and blood pressure. 3. When taken as the first drug, propranolol caused significant reduction in ERPF and GFR and a rise in filtration fraction (FF) and renal vascular resistance (RVR), whereas nadolol caused distinct rise in ERPF and a fall in FF and RVR but GFR remained unchanged. 4. These haemodynamic effects were reduced when propranolol was given immediately after the withdrawal of nadolol and were obviated when nadolol followed propranolol therapy. This suggested a carry-over effect of the first drug into the second phase of treatment. 5. We conclude that with short term therapy in essential hypertension, propranolol has a renal vasoconstrictor and nadolol a vasodilator effect.

1. Ten normal, non-asthmatic subjects performed an 18 min graduated exercise test on a static exercise bicycle on 3 separate days. They received either no medication, or propranolol 80 mg orally 2 h before, or ipratropium bromide 0.216 mg by inhalation 30 min before, the start of exercise. 2. With no medication, transpulmonary index (TPI), a measure of airway resistance, fell linearly during exercise from a resting value of 0.269 ± 0.024 to 0.170 ± 0.014 kPa·1 −1 ·s by the end of exercise. This returned to baseline between 2 and 4 min after stopping exercise. 3. Propranolol elevated baseline TPI slightly from 0.270 ± 0.024 to 0.294 ± 0.024 before exercise and during exercise this fell linearly to 0.185 ± 0.016 kPa·1 −1 ·s. The fall in TPI during exercise after propranolol was not significantly different from the fall seen with no medication. Six minutes after exercise stopped TPI rose to 0.336 ± 0.035 kPa·1 −1 ·s after propranolol. All values for TPI from 4 min to 16 min after exercise were significantly higher after propranolol than the corresponding values found after no medication ( P <0.05). 4. Ipratropium bromide decreased baseline TPI from 0.264 ± 0.024 to 0.163 ± 0.013 kPa·1 −1 ·s ( P <0.001) and this did not change significantly further either during or after exercise. 5. Normal subjects show considerable airway dilatation during exercise and this appears to result from inhibition of resting vagal tone. The sympathetic system does not appear to mediate the airway dilatation during exercise, but it may be important in protecting against post-exercise bronchoconstriction.

1. The forearm blood flow responses to hypoxia obtained from ten subjects (ages 26–37 years) before and after propranolol showed no relation with either plasma osmolality or plasma concentrations of K + , Na + , Ca 2+ , P i and Cl − . The average oral dose of 3.3 mg of propanolol/kg body weight decreased the overall mean flow response to hypoxia by 42.2% ( P < 0.025). This reflects some β-adrenoceptor involvement. The residual vasodilatation observed after β-blockade by propranolol could be attributed to activation of cholinergic vasodilator fibres by hypoxic stress. 2. The mean heart rate during acute hypoxia before and after propranolol administration was 95 and 89 beats/min respectively. The residual tachycardia could be due to reduction of vagal tone during the hypoxic stress. 3. The response of arterial blood pressure to the hypoxic stress before and after propranolol administration, on the other hand, was found to be negligible in most subjects. This lack of response during emotional stress is in agreement with previous findings. In the present circumstances the possible increase in baroreceptor activity is probably masked by the general peripheral vasodilatation.

1. Since endothelial damage due to flow disturbances is of postulated significance in the pathogenesis of atherosclerosis, this study examined the effects of antihypertensive drugs on carotid flow patterns in patients with known carotid stenosis. A Doppler Echoflow unit was used to display arterial velocities in red (normal range), yellow (increased velocity) and blue (abnormally increased velocity thought to represent turbulence and other departures from laminar flow). 2. Twenty patients were studied before drug, then during intravenous administration of hydralazine, 6–12 mg, and propranolol, 2–5 mg, over 10–15 min each, with return to baseline between drugs. 3. After hydralazine, the occurrence of abnormal high velocity flow patterns increased in 17 of 20 patients; there was no change in three patients. Propranolol reduced the occurrence of abnormal high velocity flow patterns in 19 of 20 patients ( P < 0.00001; chi-square). 4. These effects of antihypertensive drugs on arterial velocity patterns may be important in the selection of antihypertensive drugs to prevent or minimize the progression of atherosclerosis.

1. Propranolol and folic acid absorption were studied separately in healthy subjects, non-coeliac patients and patients with treated and untreated coeliac disease. 2. The surface pH of jejunal biopsy samples was measured with a pH electrode. 3. When compared with values found in healthy subjects, plasma propranolol levels were elevated in coeliac disease and, in contrast, serum folic acid levels were depressed after oral administration of the drug. Jejunal surface pH was more alkaline in the coeliac groups than in the healthy and non-coeliac subjects. 4. Pharmacokinetic analysis of the plasma drug levels allowed evaluation of the rate constants associated with absorption and elimination. The absorption rate constant was decreased for folic acid in the coeliac group, but increased for propranolol. These changes correlated with variation in surface pH. 5. Although the changes in drug disposition in treated and untreated coeliac disease are the result of several factors, it is suggested that jejunal surface pH may affect the rate of absorption and therefore the plasma concentration-time profile of drugs which undergo dissociation.

1. Pharmacokinetics of metoprolol, propranolol and atenolol were investigated in six healthy volunteers after 7 days of oral monotherapy with these drugs and after 7 days concurrent administration, with each of these β-adrenoceptor antagonists with cimetidine. 2. Cimetidine did not interact with atenolol, whereas mean peak plasma concentrations of metoprolol were increased by 70%, and those of propranolol by 95% with concurrent administration of cimetidine ( P < 0.05). 3. The area under the plasma concentration-time curve for propranolol and metoprolol was similarly increased ( P < 0.05).

1. Twenty-four-hour intra-arterial blood pressure recordings were made before and after chronic β-receptor blockade in 34 patients with essential hypertension. 2. Subjects were randomized in double blind fashion to either atenolol, metoprolol, pindolol or slow-release propranolol. 3. Drugs were administered in a once-daily variable dose regimen for a period of 3–8 months (mean 5.0 ± sd 1.4). 4. All four drugs reduced blood pressure significantly 24 h after the last dose but there were considerable differences in control when each intervening hour was assessed separately. 5. Not all β-receptor blockers in conventional formulations are equally effective as antihypertensive agents over 24 h when taken once daily.

1. The effects of metoprolol and propranolol on heat production and body temperature have been studied in six male subjects during insulin-induced hypoglycaemia in a thermoneutral environment. Hypoglycaemia was induced by insulin infusion on three occasions in each subject, accompanied by the infusion of sodium chloride solution (154 mmol/l) (control), metoprolol (β 1 -selective antagonist) or propranolol (non-selective antagonist). 2. During the period of hypoglycaemia in the control experiments mean heat production (calculated from respiratory gas exchange) increased by 1·07 ± sem 0·13 kJ/min and remained elevated for 30−40 min. This heat production response was reduced by metoprolol and abolished by propranolol. During the recovery period, heat production was significantly reduced in the presence of propranolol. 3. Skin and core temperatures fell during the period of hypoglycaemia in all three experiments. The fall in skin temperature was significantly greater in the presence of propranolol (−2·51 ± 0·47°C). The reductions in core temperature recorded during the three experiments were similar (control −0·73 ± 0·17, metoprolol −0·99 ± 0·21, propranolol −0·88 ± 0·22°C), but core temperature was still falling at the end of the propranolol experiment. 4. The cardiovascular responses to hypoglycaemia were similar in the control and metoprolol experiments but were substantially modified by propranolol. During the period of hypoglycaemia in the control experiments, plasma adrenaline levels rose to 7·78 ± 1·79 nmol/l; significantly higher levels were measured in the metoprolol (10·11 ± 1·64) and propranolol (22·76 ± 7·02) experiments. The very high adrenaline levels may have been responsible for the modified cardiovascular responses to hypoglycaemia observed in the propranolol experiment.

1. The effects of propranolol on heart rate, arterial pressure, portal venous pressure and fractional hepatic blood flow were studied in rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats. The effect of propranolol on cardiac output was also studied in normal rats. 2. In rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats, propranolol decreased heart rate and portal venous pressure significantly and did not alter arterial pressure. Propranolol decreased fractional hepatic blood flow significantly in rats with hepatic artery ligature, but did not change hepatic blood flow in rats with portal vein stenosis or in sham-operated rats. 3. We conclude therefore that: (a) propranolol decreases portal venous pressure in rats; (b) this decrease in portal venous pressure results in a reduction in portal blood flow which is related, in part, to a reduction in cardiac output; (c) propranolol does not alter hepatic blood flow in normal rats or in rats with portal hypertension.

1. To compare the bioavailability and the elimination of propranolol in seven untreated coeliac patients and six normal subjects, plasma concentrations were measured after oral and intravenous propranolol. The bioavailability and clearance of propranolol were similar in both groups. 2. With the use of a perfusion technique, propranolol absorption in the proximal jejunum was found to be decreased by 71% in five untreated coeliac patients, compared with the absorption in four normal subjects. 3. These results indicate that propranolol absorption is decreased in the proximal jejunum in untreated coeliac disease but overall absorption in the small bowel is not impaired.

1. The effects of intravenous administration of neostigmine and propranolol, individually or in combination, on baroreflex responsiveness have been evaluated in 18 borderline hypertensive subjects and in 14 age-matched control subjects. 2. Baroreceptor sensitivity was tested by evaluating both heart rate response to phenylephrine-induced increase in arterial pressure, and heart rate and blood pressure changes induced by increasing neck-tissue pressure by means of a neck-chamber. 3. In borderline hypertensive subjects a reduced baroreflex responsiveness was demonstrated with both stimuli as compared with normal subjects. Neostigmine administration improved consistently both reflex responses. Similarly, after propranolol treatment, borderline hypertensive subjects showed a significant enhancement of the baroreflex sensitivity. Finally, the combined administration of neostigmine and propranolol restored the baroreflex responses. In fact, both the mean slopes of the regression lines between blood pressure and R-R interval after phenylephrine and the increase in mean arterial pressure and heart rate induced by the reduction in carotid transmural pressure in borderline hypertensive subjects were similar to those observed in normals. 4. These findings indicate that in borderline hypertensive subjects the impairment of baroreflex responsiveness is mainly due to abnormalities of autonomic regulation.

1. The plasma aldosterone responses to exogenous angiotensin II and adrenocorticotropic hormone (ACTH) were studied before and after 1 month of propranolol therapy (120–240 mg/day) in eight patients with essential hypertension. 2. Basal supine plasma renin activity was decreased ( P < 0.001) after propranolol, whereas plasma aldosterone was unchanged. After 3 h of upright posture the increases in both plasma renin activity and aldosterone were decreased ( P < 0.05) after propranolol. 3. Plasma aldosterone responses to exogenous angiotensin II and ACTH were not significantly different after propranolol. Serum and urinary electrolytes and plasma cortisol were also unaffected by propranolol therapy. 4. It is concluded that changes in adrenal sensitivity are not responsible for maintaining unchanged supine plasma aldosterone concentrations after β-adrenoceptor antagonism in essential hypertension.

1. The effect of treatment with a thiazide-like diuretic alone or combined with a β-adrenoceptor blocker on serum lipoproteins was investigated in 35 patients with essential hypertension. 2. In group I (18 patients), serum low-density lipoprotein cholesterol was increased ( P < 0.001) during monotherapy with chlorthalidone (100 mg/day) but not during combined chlorthalidone-β-blocker therapy. 3. This tendency was similar in subgroups studied with an inverse sequence of drug administration. In subgroup I A (11 men), a 22% increase ( P < 0.01) in low-density lipoprotein cholesterol after 6 weeks of chlorthalidone was reversed after use of a β-blocker as well as chlorthalidone; in subgroup I B (five men, two post-menopausal women), low-density lipoprotein cholesterol was increased by 41% ( P < 0.05) above placebo values 6 weeks after withdrawal of the β-blocker from combination therapy. 4. In group II (18 men), low-density lipoprotein cholesterol was increased by 13% ( P < 0.025) after 4 weeks of monotherapy with clopamide (5 mg/day) but restored to control levels 4 weeks after addition of pindolol (10 mg/day). 5. No significant changes occurred during any treatment phase in high-density lipoprotein cholesterol. 6. Certain β-receptor blocking agents may prevent or reverse diuretic-induced increases in serum low-density lipoprotein cholesterol.

1. With a double-blind cross-over protocol, 20 hypertensive captopril-treated patients were studied by adding in a variable sequence a placebo and propranolol (80 mg three times a day) to their captopril regimen (200 mg three times a day), during periods each lasting 1 month. During captopril—placebo treatment their diastolic blood pressure remained elevated between 90 and 114 mmHg. 2. The additional administration of propranolol produced a significant hypotensive effect, but no alterations of the plasma angiotensin II and aldosterone concentrations and of the urinary aldosterone excretion occurred. The present data indicate that in captopril-treated patients the hypotensive effect of propranolol is achieved independently of changes in the plasma angiotensin II and aldosterone concentration. 3. The additional administration of propranolol also produced an increase in the serum potassium levels in the absence of any change in the plasma aldosterone concentration or in the urinary aldosterone excretion.

1. α 1 -Adrenoceptor-mediated vasoconstriction was studied before and during propranolol therapy in eight normal renin essential hypertensive patients; four were known ‘responders’ and four, age-matched ‘non-responders’ to previous β-receptor blocker monotherapy. Plasma renin activity, plasma adrenaline and noradrenaline concentrations as well as forearm blood flow were measured before and during regional postjunctional α 1 -adrenoceptor blockade with prazosin. All measurements were done on placebo and again after 6 weeks’ propranolol monotherapy (320 mg/day). 2. Propranolol reduced heart rate and plasma renin activity to the same extent in ‘responders’ and ‘non-responders’. Resting plasma adrenaline concentrations tended to be higher in ‘responders’ before propranolol; they remained unchanged in both groups on propranolol. Plasma noradrenaline concentrations were similar in both groups before and on propranolol. 3. Before propranolol forearm flow was not different in ‘responders’ and ‘non-responders’. Non-specific vasodilatation with sodium nitroprusside produced a similar increase in forearm flow before and after propranolol in both groups. 4. Prazosin-induced increments in forearm flow tended to be higher in ‘responders’ before propranolol. After propranolol the vasodilator effect of prazosin was attenuated in ‘responders’ but it remained unchanged in ‘non-responders’ ( P < 0.01). 5. In patients with normal renin essential hypertension the antihypertensive response to propranolol monotherapy is paralleled by a decrease in postjunctional α 1 -adrenoceptor-mediated vasoconstriction.

1. The basic mechanism underlying the structural vascular changes occurring in hypertension was studied in cultured aortic smooth muscle cells (SMC) obtained by an explant method from spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared with that in normotensive Wistar—Kyoto (WKY) rats. 2. The growth rate of SMC from SHR and SHRSP at the age of 2.5–11 months was greater than that of SMC from WKY rats even after repeated passages. 3. [ 3 H]Thymidine and [ 14 C]leucine incorporation, and ornithine decarboxylase (ODC) activity of SMC were increased in SHR and SHRSP in comparison with WKY rats. 4. The application of isoprenaline but not noradrenaline to the culture media increased ODC activity acutely in SMC from WKY rats and this increase was blocked by propranolol. 5. These results indicate that SMC from SHR and SHRSP are more prone to proliferate than those from WKY rats and that a β-adrenergic neurohumoral mechanism accelerates SMC growth independently of blood pressure.

1. The effect of prolonged administration of β-adrenoreceptor-blocking agents was studied in growing rabbits. Equivalent doses of propranolol and timolol were given parenterally for 8 weeks. 2. Animals given propranolol had a significantly lower heart rate than that in the controls. After subcutaneous injection, plasma propranolol levels were twice those obtained after intraperitoneal injection. 3. Growth rate of animals given propranolol intraperitoneally was significantly less than controls, whereas animals given propranolol subcutaneously or timolol intraperitoneally grew normally. Reduced growth rate was associated with reduced food intake and was not related to the β-adrenoreceptor-blocking activity of the drugs. 4. At the end of the experiment the heart and other organs were examined. β-Adrenoreceptor blockade produced no significant changes in ventricular size or water content, and no significant changes in ultrastructure were found.

1. The role of the sympathetic nervous system in the release of renin during head-up tilt has been studied in five normal subjects and in four tetraplegic patients with cervical spinal-cord transection above the sympathetic outflow. Blood pressure, heart rate and concentrations of plasma noradrenaline, plasma adrenaline and plasma renin activity were measured during head-up tilt to 45° before and after acute β-adrenoreceptor blockade with intravenous propranolol. 2. In the normal subjects there were minimal changes in blood pressure during head-up tilt and there was a rise in both plasma noradrenaline concentration and plasma renin activity. After propranolol values of plasma renin activity at rest fell with little change occurring during head-up tilt. 3. In the tetraplegic patients there was a substantial fall in blood pressure during head-up tilt. Concentrations of plasma noradrenaline and adrenaline did not change but there was a marked increase in plasma renin activity. Values of plasma renin activity both at rest and during head-up tilt were unaffected by propranolol. 4. We conclude that in tetraplegic patients renin release during head-up tilt may occur independently of sympathetic nervous activity and is probably largely dependent on activation of renal vascular receptors.

1. The effects of coitus on heart rate, blood pressure and plasma concentration of noradrenaline were studied in six male rabbits. 2. During coitus, heart rate rose from 228 ± 6 to 324 ± 8 beats/min (mean ± sem; n = 24). Mean blood pressure rose from 87 ± 3 to 165 ± 4 mmHg, and plasma concentration of noradrenaline from 2.07 ± 0.21 to 5.02 ± 0.26 nmol/l. The maximum heart rate did not occur until after the peak in blood pressure. 3. Propranolol had no effect on the power expended during coitus, but there was a dose dependent fall in the changes in heart rate, blood pressure and plasma concentration of noradrenaline.

1. We have studied whether the progressive rise in peripheral resistance observed in response to chronic intracoronary administration of dobutamine in conscious dogs could have resulted from extracardiac or non-β-adrenergic cardiac effects of the drug. 2. Six conscious dogs received dobutamine, 1.56 × 10 −8 mol min −1 kg −1 , intravenously for a 7 day period and seven conscious dogs were given dobutamine, 1.51 × 10 −8 mol min −1 kg −1 , into the left coronary artery under oral propranolol treatment for the same period while arterial pressure, cardiac output (electromagnetic flowmeter) and heart rate were measured. 3. Intravenous dobutamine produced no increase in arterial pressure, but a decrease in peripheral resistance and an increase in cardiac output which persisted until the end of the infusion. 4. With propranolol treatment intracoronary dobutamine induced no significant haemodynamic changes but a short-lasting increase in mean arterial pressure and peripheral resistance. 5. It is concluded that β-adrenergic cardiac effects of dobutamine are essential to the development of hypertension and increased peripheral resistance after prolonged intracoronary infusion of this drug.

1. Sixteen neurosurgical patients received (oral) β-adrenoreceptor-blocking agents (β-receptor blockers) for 3–22 days. 2. Lipophilic β-receptor blockers (propranolol) and metoprolol appeared in cerebrospinal fluid at concentrations similar to the free drug plasma concentration. 3. Cerebrospinal fluid concentrations of β-receptor blockers were poor predictors of brain concentrations 4. Both lipophilic β-receptor blockers appeared in high concentrations in the brain: the brain/plasma ratio was approximately 15:1. 5. Hydrophilic atenolol appeared at low concentrations in brain tissue (about 20 times lower than the lipophilic β-receptor blockers): the brain/plasma ratio was approximately 0.1:1. 6. Central nervous system-related side effects associated mainly with lipophilic β-receptor blockers possibly result from high brain tissue concentrations.

1. Fifty-five patients with uncomplicated essential hypertension were admitted to hospital, where 25 of them were treated with propranolol (average daily dose 240 mg) and 30 were left untreated. 2. In all of them renal arteriography was carried out, after which procedure renal plasma flow ([ 123 I]hippuran clearance), cortical blood flow (xenon washout) and renal noradrenaline release were measured. 3. Compared with the untreated hypertensive patients, responders to propranolol (mean blood pressure ≤ 110 mmHg) during treatment showed enhanced cortical blood flow and reduced noradrenaline secretion. Non-responders had reduced cortical flow rates, but increased noradrenaline secretion. 4. Both in the untreated group and in the propranolol-treated group an inverse relationship between arterial noradrenaline concentration and cortical blood flow was found. 5. The results indicate that sympathetic activity may be an important determinant of renal blood flow in hypertension. The effectiveness of propranolol seems to depend upon a reduction in α-adrenergic tone.

1. The effect of a single oral dose of propranolol on the ventilatory response to hypercapnia has been studied in five healthy subjects. 2. Propranolol produced a small but significant reduction in the slope of the ventilation/end-tidal P co 2 regression line. 3. Propranolol did not significantly change vital capacity or forced expiratory volume in 1 s.

1. The role of baroreceptors in the cardiovascular mechanism of action of dl-propranolol has been studied by comparing the acute effects of subcutaneous injection of 1 and 5 mg/kg (3·3 × 10 −6 and 16·5 × 10 −6 mol/kg) of this drug in conscious baroreceptor-denervated spontaneously hypertensive (SH) rats with those in sham-operated control SH rats. 2. At 5 mg/kg (16·5 × 10 −6 mol/kg) propranolol caused a small, but significant, increase in blood pressure in sham-operated SH rats, whereas both after 1 and 5 mg/kg (3·3 × 10 −6 and 16·5 × 10 −6 mol/kg) immediate hypotension was observed in baroreceptor-denervated animals. 3. Heart rate dropped rapidly after injection of 1 or 5 mg/kg (3·3 × 10 −6 and 16·5 × 10 −6 mol/kg) propranolol both in the baroreceptor-denervated and sham-operated SH rats. Bradycardia was significantly larger in the baroreceptor-denervated animals after an injection of 5 mg/kg (16·5 × 10 −6 mol/kg). 4. It is concluded that the lack of an early hypotensive effect of propranolol in intact animals is caused by an increased baroreceptor reflex activity as a consequence of the fall in cardiac output.

1. In eight patients with essential hypertension (EHT) and six patients with renovascular hypertension (RVHT) peripheral venous enzymatically active and inactive renin values were followed after acute stimulation of renin release by the vasodilating agent diazoxide (300 mg intravenously). Active renin rose during the first hour after diazoxide and remained high during the following 15 h, but inactive renin fell during the first hour and rose thereafter. Peripheral venous active and inactive renin were not different from arterial values both before and after diazoxide. 2. Sixteen patients with EHT received propranolol, 80 mg, four times a day. Six of them had a first injection of diazoxide the day before propranolol was started and a second one after 10–14 days of propranolol treatment. Peripheral vein active renin was lowered by propranolol, but inactive renin was raised. Both the diazoxide-induced rapid rise of active renin and the fall of inactive renin observed in untreated patients were absent during treatment with propranolol. 3. In four patients with EHT and seven patients with RVHT renal vein sampling was performed before and 30 min after diazoxide. Increased release of active renin from kidneys that were not markedly contracted was associated with a fall of the renal vein to peripheral vein ratio of inactive renin to a value less than one. 4. It is concluded that under certain circumstances stimulated release of active renin is associated with removal of inactive renin from the circulation by the kidney. This may in fact be due to intrarenal transformation of circulating inactive renin into its active counterpart. The findings suggest that a β-adrenoreceptor might be involved in this activation process.

1. Propranolol, saralasin and captopril changed blood pressure in normotensive as well as hypertensive subjects. 2. The percentage change in blood pressure with these three drugs for a given plasma renin activity was similar in normotensive and hypertensive subjects. 3. This suggests that when the renin-angiotensin system is maintaining blood pressure, it maintains the blood pressure to the same extent in percentage terms in normotensive and hypertensive subjects for a given plasma renin activity. 4. Saralasin has marked agonist activity, and probably underestimates the participation of the renin—angiotensin—aldosterone system in the maintenance of blood pressure. The fall in blood pressure that occurred with captopril in normal subjects on their normal sodium intake suggests that the renin—angiotensin—aldosterone system may have an important role in the control of blood pressure in normal subjects on their normal sodium intake. If it does, our results suggest that the renin—angiotensin—aldosterone system plays no greater role in maintaining blood pressure in patients with essential hypertension than normotensive subjects for a given plasma renin activity.

1. Propranolol and metoprolol were given in the diet of spontaneously hypertensive (SH) rats during the development of hypertension. 2. At the early established phase of hypertension, protein synthesis and protein composition of the left ventricle, aorta, mesenteric artery and vena cava were measured. 3. The left ventricle, aorta and mesenteric artery from the SH rats were hypertrophied compared with control Wistar—Kyoto rats, and protein composition was not dramatically changed. The increased protein content could only in a few cases be assigned to an increased protein synthesis at this age. 4. Both β-adrenergic antagonists prevented the hypertrophy of aorta and mesenteric artery but not in heart.

1. The β-adrenoreceptor-blocking effects of pindolol were compared with those of propranolol and a placebo in a double-blind cross-over trial involving nine hypertensive African patients. 2. Heart rate, systolic blood pressure and diastolic blood pressure were measured at rest and immediately after exercise before and at intervals up to 6 h after oral administration of the drugs. In addition, plasma pindolol and propranolol concentrations were determined at the same intervals. 3. Pindolol diminished systolic blood pressure at rest and after exercise and antagonized exercise-induced tachycardia, but had no effect on resting heart rate. Propranolol diminished systolic blood pressure predominantly after exercise and reduced both resting and exercise heart rate. Both drugs had no effect on diastolic pressure. 4. The mean plasma concentration reached a peak at 2 h for each drug and this coincided with the interval at which maximal β-adrenoreceptor-blocking effect was observed.

1. Haemodynamic effects of adrenaline were studied in 27 hypertensive patients, successively during treatment with propranolol and metoprolol. In 12 patients β-adrenoreceptor blockade was combined with diuretics and in 15 patients the blockade was combined with vasodilators. 2. During propranolol adrenaline caused a marked pressor effect: there was a considerable rise in systolic as well as in diastolic blood pressure and a marked fall in heart rate. During metoprolol there was only a slight rise in blood pressure and an increase in heart rate. 3. Forearm blood flow was decreased by adrenaline during propranolol and was increased during metoprolol. Calculated vascular resistance showed opposite changes. 4. Results were essentially the same when β-adrenoreceptor blockade was combined with diuretics or with vasodilators and did not differ from previous results obtained in patients treated by blockade alone. 5. If adrenaline infusion can be considered as a model for acute stress, our results seem to favour a selective β-adrenoreceptor blocking agent over a non-selective one, even when the blocker is combined with a diuretic or a vasodilator.

1. The effects of 160 mg of propranolol and 160 mg of a long-acting (LA) formulation of propranolol were studied in healthy subjects. 2. Both drugs reduced an exercise tachycardia but the peak was less and the 24 h effect greater after long-acting propranolol than after propranolol. 3. These differences were maintained on repeated dosing for 8 days. 4. In contrast to single doses of 400 mg of sotalol, 160 mg of oxprenolol and 160 mg of slow-release oxprenolol, the peak effect of long-acting propranolol was less and that at 24 h was greater.

1. A standardized method of objectively measuring performance during simulated car driving is described. 2. The effect of a single dose of propranolol and metoprolol were compared with placebo in two groups of patients with untreated essential hypertension. 3. Performance was similar after β-adrenoreceptor-blocking agents or placebo. 4. Blood pressure response to stress persisted after administration of the blocking agents.

1. In hypertension, the β-adrenoreceptor-blocker-withdrawal syndrome comprises tachycardia, sweating, tremor and general malaise, symptoms resembling thyrotoxicosis. 2. The effect of abrupt cessation of propranolol on serum concentrations of thyroxine (T 4 ) and tri-iodothyronine (T 3 ) was therefore investigated in five patients with uncomplicated essential hypertension, treated with propranolol in doses from 160 to 480 mg/day. 3. Four of the five patients developed one or more of the above-mentioned symptoms within 2–6 days after withdrawal of propranolol. 4. A mean relative increase in serum free T 3 of 51% (range 22–74%) was found in these four patients on the day of onset of symptoms. 5. The increase in free T 3 in the five patients correlated positively with total serum propranolol on the last day the drug was given ( r = 0·91, 2 P = 0·03). 6. As an increase in T 3 was found only in patients suffering the withdrawal syndrome, and was maximal the day the symptoms appeared, despite a variation in time of onset from 2 to 6 days, it is suggested that the β-adrenoreceptor-blocker-withdrawal syndrome, at least partially, is caused by a rebound increased production of T 3 , induced by the well-known inhibition of the monodeiodination of T 4 to T 3 during β-adrenoreceptor blockade. 7. This assumption may explain the clinical symptoms and the reported transient increased β-adrenoreceptor sensitivity with unchanged serum concentrations of catecholamines.

1. The effect on respiration of a single dose of propranolol has been studied in normal subjects. 2. The degree of β-adrenoreceptor blockade was assessed in terms of the impaired heart-rate response to progressive exercise and the plasma propranolol concentration. 3. No effect of propranolol was demonstrated on either the ventilatory response to rebreathing CO 2 in hyperoxia, or the response to progressive isocapnic hypoxia. Simple indices of maximal expiratory flow (FEV 1.0 % and PEFR) were also unchanged. 4. The absence of any effect of propranolol on the chemical control of breathing in man is discussed in relation to the conflicting literature.

1. Chronic ligation of the bile duct in dogs is associated with salt retention and a blunted natriuretic response to extracellular volume expansion. The mechanism of this phenomenon has not been clarified. 2. We have examined the influence of chronic β-adrenergic blockade on sodium excretion in dogs with bile-duct ligation during extracellular hypotonic volume expansion. 3. Urinary excretion of sodium and fractional excretion of sodium rose significantly after 5 days of oral dl-propranolol administration to dogs with bile-duct ligation. 4. The antinatriuresis after bile-duct ligation was not followed by a significant alteration in the mean peripheral plasma renin activity as compared with control values. 5. It is suggested that propranolol can partially reverse the antinatriuresis of chronic bile-duct ligation, and that this is mediated by an extrarenal effect of the β-adrenergic blockade.

1. The bronchial response to α-adrenoreceptor stimulation has been investigated in normal and asthmatic subjects with a specific α-receptor agonist, methoxamine hydrochloride, after atropine and β-adrenergic blockade. 2. No significant changes in forced expiratory volume in 1 s (FEV 1·0 ) were seen in normal subjects. 3. Methoxamine inhalation caused mild symptomatic wheezing and significant falls in FEV 1·0 in asthmatic subjects. No change in FEV 1·0 occurred after inhalation of distilled water as control. 4. It therefore appears that methoxamine causes bronchoconstriction in asthmatic subjects through its α-adrenergic-stimulating properties, since we were not able to detect any β-receptor-blocking activity of methoxamine on the airways.

1. Six essential hypertensive patients (five with low renin) were treated in successive weeks with placebo; hydrochlorothiazide 100 mg (382 μmol)/day; hydrochlorothiazide and 50 mmol of sodium/day diet; hydrochlorothiazide, 50 mmol of sodium diet and propranolol 160 mg (544 μmol)/day; and hydrochlorothiazide, 50 mmol of sodium and indomethacin 100 mg (287 μmol)/day. 2. Although blood pressure remained unchanged and serum potassium fell on diuretic with or without low salt, there was a marked increase of active renin and a lesser increase of inactive renin, resulting in an increased proportion of active to total renin. 3. Propranolol decreased both active and inactive renin, but not significantly. 4. Indomethacin produced a marked suppression of active renin, a smaller reduction in inactive renin, and a reduction of the ratio of active to total renin almost to placebo values. 5. Blood pressure rose to control values on indomethacin despite the fall in renin whereas it fell with propranolol with little change in renin. 6. Serum aldosterone rose with stimulation but remained elevated despite effective renin suppression with indomethacin and continuing reduced serum potassium concentration.

1. Dose—response curves of isoprenaline were constructed in nine hypertensive patients before and after either propranolol or metoprolol. 2. The decrease of diastolic blood pressure and increase of heart rate with isoprenaline were significantly more inhibited by propranolol than by metoprolol. 3. The increase in calf blood flow with isoprenaline was significantly more depressed after propranolol than after metoprolol. 4. The results suggest that the response of the vessels in the limbs to sympathetic stimulation is much less affected after metoprolol than after propranolol.

1. The cardiovascular effects of enkephalins have been tested in normotensive Wistar—Kyoto rats. Methionine—enkephalin and leucine—enkephalin increased blood pressure and heart rate after infusion into the brain ventricles. 2. After intravenous injection, blood pressure was increased by methionine—enkephalin and leucine—enkephalin, but heart rate was increased by methionine—enkephalin only. 3. Propranolol treatment reduced the increases in blood pressure following intraventricular methionine—enkephalin and leucine—enkephalin, while only the methionine—enkephalin-induced increases in heart rate were reduced by propranolol. 4. Heart rate and blood pressure responses after intravenous administration of methionine— enkephalins and leucine—enkephalin were not affected by propranolol. 5. Since opioid peptides occur in the blood and in regions of the brain involved in blood pressure regulation, the demonstrated cardiovascular effects to intraventricular and intravenous enkephalins support a role of these peptides in central and peripheral mechanisms of blood pressure control.

1. Chlorothiazide twice a day plus atenolol, metoprolol, pindolol and propranolol in single daily doses administered to patients with essential hypertension achieved effective control of blood pressure. 2. Each β-adrenoreceptor-blocking drug was associated with small, but significant, increases in plasma triglyceride concentrations and suppression of fasting immuno-reactive glucagon concentrations.

1. Plasma adrenaline and noradrenaline were measured in supine and upright positions in 27 essential hypertensive patients and in 12 age-matched control subjects. 2. Plasma adrenaline was markedly increased in a large proportion of patients, compared with control subjects, either in supine or in upright positions, whereas no significant differences were found in plasma noradrenaline. 3. Six hypertensive patients were chronically treated with β-adrenoreceptor-blocking agents (five with propranolol and one with pindolol). Plasma noradrenaline was not significantly changed in the supine position but was markedly increased on standing in four out of six patients. Plasma adrenaline was decreased in five out of six patients either in supine or upright positions. 4. These findings support the view that the adrenergic system participates in the mechanism of essential hypertension.

1. The effects of two groups of diuretics on renin secretion have been compared in dogs anaesthetized with pentobarbital. 2. Frusemide, ethacrynic acid and bumetanide cause an immediate rise in renin secretion which is not inhibited either by dl-propranolol or by a bilateral ureterovenous anastomosis which prevents salt and water loss. 3. Clopamide, metolazone and indapamide do not cause an immediate rise in renin secretion. Renin hypersecretion is induced only 1 h after intravenous injection of these diuretics. 4. Renin secretion was studied for 6 h after frusemide injection: the immediate rise was followed by a later increase in renin secretion. This later rise was inhibited by propranolol and by ureterovenous anastomosis. 5. These results allow us to distinguish between a direct renal mechanism responsible for early renin hypersecretion, which appears to be connected with the action of the diuretic on the ascending limb of Henle's loop, and an indirect mechanism responsible for late renin hypersecretion, which appears to be connected with salt and water loss.

1. Propranolol was administered to groups of mature rats before and during the development of renal hypertension induced by ligation of the aorta between the renal arteries. 2. At a dose 10 μmol (3 mg) of propranolol/kg, administered by intraperitoneal injection, the onset and severity of hypertension were not affected, although plasma renin concentration was significantly lower than in the untreated hypertensive rats in the first 5 days after the operation. 3. With 200 μmol (60 mg) of propranolol/kg, administered in the drinking water, peak blood pressure 5 days after aortic ligation was lower than in the untreated control rats, but plasma renin concentration was no lower than with the smaller dose. 4. The development of severe hypertension despite reduction in plasma renin concentration on the low dose of propranolol suggests the participation of renal vasopressor factors other than renin in this model. 5. A higher dose of propranolol reduced the rise in plasma concentration to an equal extent but the rise of blood pressure at 5 days was also reduced, which supports this concept.