Beta-adrenoceptor Blocking Effect Research Articles

A Randomized, Controlled, Double-Blind Trial of s-Pindolol in Irritable Bowel Syndrome (IBS)

Purpose: Pindolol is a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity which exists as a racemic mixture of the R and S enantiomers. The R and S enantiomers of pindolol differ in both their pharmacokinetics and pharmacodynamics. The beta-adrenoceptor blocking effects of pindolol are largely confined to the S enantiomer, while the intrinsic sympathomimetic activity is shared equally by the R and S enantiomers. In addition, 5HT1a antagonism is a property of s-pindolol. Given these properties and our current understanding of IBS, our aim was to evaluate the efficacy of s-pindolol in IBS. Methods: Following a 8–14 day run-in period, eligible patients were randomly allocated to s-pindolol 2.5 mg t.i.d or placebo t.i.d. for four weeks. Patients receiving s-pindolol then had dose adjusted to 5 mg t.i.d for a further four weeks and to 7.5 mg t.i.d for the final four weeks, if tolerated. Three primary endpoints: Difference in the percentage of responders between AGI-001 and placebo based on 1. patient's global impression and 2. relief of abdominal pain/discomfort; 3. use of rescue medication (paracetamol). Numerous secondary endpoints were also assessed. The pre-defined statistical analysis was a one-sided analysis based on the hypothesis that s-pindolol is better than placebo. Results: There was no difference between treatments in terms of the number of patients who felt better on at least 50% of study days (one-sided P= 0.30). Logistic regression analysis yielded an odds ratio for AGI-001 relative to placebo: 0.73 (95% C.I. 0.24–2.20). The proportion of days of adequate relief of abdominal discomfort/pain did not differ between treatments (one-sided P= 0.34); odds ratio for AGI-001 relative to placebo: 0.77 (95% C.I. 0.25–2.42). Use of paracetamol was sparse and similar in both groups (one-sided P= 0.11). There were significant s-pindolol related improvements compared to baseline in the secondary endpoints of global severity of illness, abdominal pain, bloating/distention and straining at the highest dose visit (week 12). The incidence of adverse events was similar in s-pindolol- and placebo-treated groups. Conclusion: In this IBS study we have failed to reveal a significant benefit for s-pindolol at the doses administered in terms of global relief of IBS symptoms, relief of abdominal pain, or use of rescue medication.

40 Jahre Beta-Blocker in der Psychiatrie

Beta-adrenoceptor blockers belong to the most successful drug classes of medicine. Mainly they are used in internal medicine. 40 years ago beta-adrenoceptor blockers have occasionally been used in psychiatry for the treatment of anxiety disorders. Over the past four decades, the effects of beta-adrenoceptor blockers in the treatment of schizophrenic and manic psychoses, withdrawal syndromes and aggressive behaviour with temper outbursts has been investigated. Beta-adrenoceptor blockers are also used in the treatment of side-effects of psychopharmacological agents like neuroleptic or antidepressant-induced tachycardias, lithium-induced tremor, antipsychotic-induced akathisia or tardive dyskinesia as well. Since the mid-nineties it has been attempted to improve the efficacy of antidepressant agents by means of the 5-HT-(1a)-receptorantagonist pindolol. Presumedly memory consolidation of traumatic events can be enhanced by adrenergic activation. Therefore some open clinical trials investigated the effects of propranolol, a lipid soluble drug, which crosses the blood-brain barrier easily, to reduce the manifestation of PTSD. The present review presents the results of the literature with respect to the indications for beta-blockers in psychiatry. Considering evidence-based-medicine criteria beta-blockers are indicated to treat lithium-induced tremor, antipsychotic-induced akathisia and to reduce aggressive behavior of patients with brain-injuries.

Carvedilol in the Treatment of Hypertension - A Review of the Clinical Data Base

Carvedilol is a novel antihypertensive agent. It is a multiple-action neurohormonal antagonist with a beta-adrenoceptor blocking effect combined with a vasodilating action based on alpha 1 -adrenoceptor blockade. In addition, carvedilol exerts a number of well documented ancillary effects such as being a scavenger of free radicals. It also has an antiproliferative action on smooth muscle cells. This combination of effects opens up a number of interesting clinical perspectives. It is the purpose of this brief review to summarize some of the clinical studies that have been performed with carvedilol. Investigations in hypertensive patients will form the basis of this review, but special interest will also be devoted to other patient groups. In particular the therapeutic value of carvedilol will be discussed in patients with concomitant disorders such as atheromatosis, left ventricular hypertrophy, angina pectoris, myocardial infarction, congestive heart failure, arrhythmias, stroke, renal failure or diabetes. Finally, the usefulness of carvedilol in the treatment of elderly hypertensive patients will be reviewed. It is evident from the available scientific literature that carvedilol is an antihypertensive agent with a novel mode of action. It is effective in many of the subpopulations of patients alluded to above. It appears reasonable to assume that some of these therapeutic effects can be attributed to its ancillary properties.

The differentiation of propafenone from other class Ic agents, focusing on the effect on ventricular response rate attributable to its beta-blocking action.

Propafenone, encainide and flecainide have been categorized as class Ic antiarrhythmic drugs, since they produce similar clinical electrophysiological effects. However, propafenone has also modes of action that differ substantially from pure class Ic activity. The most distinctive electrophysiological difference from other class Ic antiarrhythmic drugs stems from its structural similarity with other beta-adrenoceptor antagonists. The potency of the beta-adrenoceptor blocking property of propafenone has been estimated to range from 1/20 to 1/50 that of propranolol on a molar basis. Because the plasma concentrations of propafenone during long-term treatment may be up to 50 or more times that of propranolol, the beta-adrenoceptor blocking effect may be clinically relevant. However, although the beta-adrenoceptor blocking effects are readily demonstrable in vitro, clinical data are more inconsistent, because the beta-adrenoceptor blocking action has been reported as being undetectable to significant. During atrial fibrillation, with or without accessory pathways, propafenone exerts effective and prompt control of the ventricular rate in patients who fail to convert to sinus rhythm. However, compared with other class Ic antiarrhythmic drugs, propafenone has not been proved generally better in controlling the ventricular rate.

Stereoselective Vascular Effects of the (R)- and (S)-Enantiomers of Propranolol and Atenolol

All beta-adrenergic antagonists have an asymmetric carbon atom, and most commercially available beta-blockers consist of (R)- and (S)-enantiomers in a fixed 1:1-ratio. The drugs are believed to be contraindicated when peripheral vascular disease exists, presumably due to unopposed alpha-adrenergic vasoconstriction. However, little is known about direct vascular effects of beta-blockers or of stereoselective effects on peripheral arteries. Therefore, we investigated the effects on forearm blood flow (FBF) of brachial artery infusions of the (R)- and (S)- enantiomers of propranolol and atenolol (2, 10, and 50 micrograms/min each) and their inhibitory effects on isoprenaline (Iso)-induced vasodilatation by forearm venous occlusion plethysmography in 12 healthy subjects. Only (R)-propranolol caused an increase in FBF (+21%, p < 0.05), whereas (S)-propranolol and (R)- and (S)-atenolol had no direct effect on peripheral arteries. Vasodilatation induced by Iso was abolished by (S)-propranolol and reduced by (R)-propranolol (-56%, p < 0.05) and (S)-atenolol (-68%, p < 0.05), whereas (R)-atenolol had no effect. Our results indicate that the optically pure (R)- and (S)-enantiomers of propranolol and atenolol do not exert direct vasoconstrictive effects. Furthermore, our results confirm that predominantly (S)-enantiomers have beta-adrenoceptor blocking effects, but they also show that neither the non-beta-blocking (R)-enantiomer of propranolol nor the (S)-enantiomer of the beta 1-selective agent atenolol is completely devoid of blocking effects on vascular beta 2-adrenoceptors.

Endothelial prostacyclin production, synergistic effect between adrenergic stimulating and blocking drugs

Endothelial cells (EC) produce prostacyclin (PGI 2) in high quantities which at the luminal surface decreases platelet aggregation and adhesion and basal to the cell relaxes smooth muscle cells (SMC). Connections have been reported between prostacyclin production, hypertension and the degree of adrenergic activation. The present study tested the hypothesis that prostacyclin production by EC could be regulated by adrenergic mechanisms. EC were isolated from human umbilical cord veins. Washed cells were seeded and grown to confluency on tissue culture dishes. The test drugs were simultaneously added to parallel dishes. Samples were collected from the conditioned medium and analyzed for 6-keto-PGF 1a with RIA technique. Endothelial cells pretreated with the betaadrenoeceptor blocking drugs metoprolol or propranolol synergistically increased basal prostacyclin production when exposed to betaadrenergic stimulation. However, using isomers with high or low betaadrenoblocking effect, this synergism was demonstrated not to be associated to the betaadrenoceptor blocking effect of the drugs per se. These findings may have implications on the arterial hypertensive state characterized by high sympathetic tonus and low PGI 2 production. The data may offer an explaination why hypertensive individuals react with increased PGI 2 production, upon betaadrenoceptor blocking therapy.

COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (1.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit. 2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19 +/- 4% (mean +/- s.e.m.; P < 0.01), flecainide by 27 +/- 9% (P < 0.001), amiodarone by 11 +/- 2% (P < 0.01) and sotalol by 13 +/- 3% (P < 0.01). 3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 +/- 4% (P < 0.03) and 16 +/- 6% (P < 0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 +/- 7% [P < 0.05] and 20 +/- 5% [P < 0.01], respectively). Flecainide caused only a small (6 +/- 1%; P < 0.01) increase in CO and sotalol had no effect on either CO or TPR. 4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 +/- 2% (P < 0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade. 5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its beta-adrenoceptor blocking effect.

Cerebral Blood Flow Measurements During Blood Pressure Control with Intravenous Labetalol Following Craniotomy

Cerebral blood flow measurements using a thermal diffusion technique were made in conjunction with an extensive cardiovascular evaluation, during and after administration of intravenous labetalol given for blood pressure control in craniotomy patients. Eighteen patients, ages 30-65 years, ASAII and III, scheduled for elective craniotomy, became hypertensive during emergence and recovery from a pentothal/fentanyl/vecuronium/N2O/isoflurane general anesthesia. Labetalol was administered in a stepwise manner every 10 minutes during an average period of 1 h. After this titration period, an 8-h maintenance period followed. During titration and maintenance periods, comprehensive systemic hemodynamic parameters were collected through intra-arterial and flow-directed pulmonary artery catheters. Cerebral cortical blood flow (CBF) was continuously recorded using a thermal diffusion cortical blood flow probe (Saber System). Data were analyzed using variance F tests to evaluate changes from baseline over time. Labetalol controlled postoperative hypertension in all cases with a total dose range of 0.4-6.8 mg/kg. During titration, statistically significant decreases in blood pressure were obtained, accompanied by a small decrease in systemic vascular resistance (SVR) and slight increase in cardiac index (CI). Heart rate decreased in a manner directly proportional to the dose of labetalol administered. In the maintenance period, further decreases in blood pressure and heart rate were observed, with significant decreases in central venous pressure, pulmonary capillary wedge pressure, and SVR and an increase in CI. All values remained within normal ranges and no adverse effects were observed. CBF decreased slightly during the study period, although not significantly (from 67 +/- 8 to 57 +/- 7 ml 100 g min). Blood pressure control achieved with labetalol in postoperative neurosurgical patients seems to be the result of mild alpha-adrenoceptor blocking effects (i.e., reduced SVR) and beta-adrenoceptor blocking effects (i.e., reduced heart rate) at higher doses. The 6-8 h duration of effect of labetalol was enough to control postoperative hypertension in all patients with no additional therapy. Compared with alternative drugs available for blood pressure control in similar clinical conditions, labetalol appears to be reliable, safe, and effective, by providing a lasting effect with no evidence of rebound hypertension, increased CBF, or cardiac dysfunction.

Pharmacokinetics and pharmacodynamics of conventional and controlled-release formulations of metipranolol in man

The pharmacokinetics and beta-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.

Participation of the Vasodilating Property of Nipradilol in Improving Ischemic Derangement of Myocardial Energy Metabolism

The effects of equipotent doses in negative inotropic and chronotropic properties of nipradilol [10 micrograms/kg/min intravenously (i.v.)] and propranolol (20 micrograms/kg/min i.v.) on hemodynamics and transmural energy metabolites in ischemic hearts were examined in anesthetized dogs. After 5-min infusion of these agents, coronary perfusion pressure of 30 mm Hg was induced by acute coronary stenosis for 10 min. Coronary blood inflow and myocardial contractile force (MCF) in the control ischemic area decreased to about one-third and two-thirds of the respective starting levels. In the nipradilol group, similar changes were observed, but in the propranolol group the MCF tended to decrease further. Cardiac effort index decreased to about two-thirds in both groups. The left ventricular end-diastolic pressure (LVEDP) increased by 4.3 mm Hg with saline, by 8.8 mm Hg with propranolol, and by 1.3 mm Hg with nipradilol. ATP depletion in the ischemic myocardium (by 29 and 22% in inner and outer layers, respectively) was restored to normal level by either agent. A decrease in creatine phosphate and an accumulation of lactate were significantly alleviated by nipradilol (by 74 and 59----by 39 and 21%, and by 4.9 and 2.3----by 0.7 and 0.2 times, respectively), but not by propranolol. The results indicate that in addition to a decrease in myocardial oxygen consumption caused by the beta-adrenoceptor blocking effects of nipradilol, reductions in preload and afterload caused by the vasodilating property significantly contribute to nipradilol-induced improvement in the ischemic derangement of transmural energy metabolism.

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats.

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats was studied. Pentobarbital sleep time was not affected whereas zoxazolamine paralysis time was shortened 72% in rats, 24 h after the cigarette smoke exposure. The beta-adrenoceptor blocking effect of propranolol observed at 10 and 20 min time intervals was abolished in rats exposed to cigarette smoke 24 h after the exposure. The blood propranolol concentrations were decreased in rats pretreated with phenobarbital, 3,4-benzpyrene and ethanol as well as in cigarette smoke exposed rats. Among several factors that could influence propranolol metabolism, in this study, enzyme induction is suggested to be dominant.

Pharmacological studies of indole alkaloids obtained from domestic plants, Uncaria rhynchophylla Miq. and Amsonia elliptica Roem. et Schult

Pharmacological studies on hirsutine (HS), hirsuteine (HST), rhynchophylline (RP), isorhynchophylline (IRP) and dihydrocorynantheine (DCT) which were isolated from the domestic plant Uncaria rhynchophylla Miq. and beta-yohimbine (beta-Y) which was isolated from the domestic plant Amsonia elliptica Roem. et Schult. were carried out. These alkaloids showed a mild central depressive effect in mice, a week non-competitive anti-spasmodic action in the mouse intestine, and a hypotensive effect in rats. Since beta-Y showed alpha-adrenoceptor blocking action, the hypotensive effect of beta-Y may be partly due to the vasodilative effect induced by its alpha-adrenoceptor blocking action. HS and beta-Y showed a preventive effect on the development of gastric erosions in mice. HS had antiarrhythmic effects on both aconitine-induced arrhythmias in mice and ouabain-induced arrhythmias in guinea pigs. The potency of the antiarrhythmic effects induced by HS was approximately the same as that of ajmaline, an indole alkaloid. Since HS did not show beta-adrenoceptor blocking action, the antiarrhythmic effects of HS would not be due to its beta-adrenoceptor blocking effect.

The effect of beta-adrenoceptor blockers on the absorption and excretion of chlorothiazide in man.

The effect of beta-adrenoceptor blockers on the absorption and elimination of the diuretic chlorothiazide was studied in healthy subjects. A week of pretreatment with either pindolol (10 mg twice daily) or propranolol (80 mg twice daily) resulted in significant reduction in 36 h mean cumulative urinary recovery of chlorothiazide in two groups of six subjects compared with a control (untreated) group. A week of pretreatment with atenolol (100 mg daily) did not significantly alter 36 h cumulative urinary excretion in another group of six subjects. None of the beta-blockers significantly changed chlorothiazide half-life. It is suggested that the non-selective (as opposed to the cardioselective) beta-blockers reduce chlorothiazide absorption by the mechanism(s) discussed.

Resting and Postexercise Hemodynamic Effects of Carvedilol, a β-Adrenergic Blocker and Precapillary Vasodilator in Hypertensive Patients

Carvedilol is a recently developed antihypertensive drug that combines in the same molecule a nonselective beta-adrenoceptor blocking effect and a vasodilating precapillary activity. In our study, we have investigated the effects of carvedilol 25 mg b.i.d. on blood pressure, heart rate, and plasma noradrenaline in hypertensive patients at rest and during exercise after acute and repeated oral administration for 7 days. The daily average supine blood pressure of the 12 patients with essential hypertension was 178 +/- 10/107 +/- 3 mm Hg (means +/- SD of 8 measurements in each patient) after placebo and was significantly (p less than 0.01) reduced to 162 +/- 17/99 +/- 8 mm Hg on the first day and to 158 +/- 15/96 +/- 8 mm Hg on the seventh day of carvedilol treatment. Similar values were found in the upright posture. Heart rate was slightly but significantly lowered during acute and repeated administration. The exercise-induced increase in systolic blood pressure was significantly reduced by carvedilol 25 mg b.i.d., while there was a nonsignificant reduction in the tachycardic response. There was a significantly greater rise in plasma noradrenaline during exercise on the seventh day of carvedilol treatment. Carvedilol significantly lowered blood pressure and heart rate at rest and the exercise-induced rise in systolic blood pressure.

The influence of bordetella pertussis and its constituents on the beta-adrenergic receptor in the guinea pig respiratory system

In the present study, the effect of vaccination of guinea pigs with Bordetella pertussis was investigated, 4 days after treatment, on the cholinergic and beta-adrenergic receptor function in isolated tracheal spirals and the number of beta-adrenoceptor binding sites in guinea pig lung. It was found that B. pertussis caused an impairment in the beta-adrenoceptor function and a decrease in its number. Similar results were obtained with endotoxin. Leucocytosis promoting factor, however, was ineffective. These results indicate that endotoxin is the constituent responsible for the beta-adrenoceptor blocking effects of the bacterium. Also the combined whole cell diphteria, B. pertussis and tetanus toxoid vaccine induced a beta-adrenoceptor blockade; the acellular vaccine was less effective. The results obtained with the B. pertussis vaccines are discussed in relation to the possible side-effects that sometimes occur after immunization of infants.

Comparison of two slow‐release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.

We have compared the beta-adrenoceptor blocking and antihypertensive effects of chronic once daily treatment with conventional metoprolol 200 mg, two 'long-acting' formulations of metoprolol 200 mg and atenolol 100 mg in a cross-over study in 12 hypertensive patients concurrently receiving diuretic therapy. The peak effects of all compounds were similar, with significant reductions in exercise heart rate and blood pressure. Twenty-four hours after dosing only atenolol treatment was consistently associated with a reduction in both exercise heart rate (P less than 0.001) and blood pressure (P less than 0.02) when compared with placebo. Once daily treatment of hypertension with metoprolol, even in 'long-acting' formulations, cannot be recommended because of waning antihypertensive effect which would be missed at routine clinic attendance. Metoprolol should be prescribed twice daily in hypertension. So-called long-acting formulations do not always confer benefits over conventional dose forms.

Oros controlled-release formulations of metoprolol: an approach to the development of a system for once daily administration.

A combined biopharmaceutical and haemodynamic approach to the development of a metoprolol Oros controlled-release delivery system for once daily administration is reported. Two studies, each involving 18 healthy volunteers, were performed in which twice daily administration of 100 mg conventional metoprolol tartrate tablets was compared with once daily administration of Oros systems containing 190 mg metoprolol fumarate but with different drug release rates. Plasma drug concentrations and beta-adrenoceptor blocking effects were measured over 24 h on days 1 and 5 of each treatment, and pre-dose in the interval between the main study days. The results of the first study with a 19 mg/h Oros system indicated that this rate was too rapid to provide the required response under steady-state dosing conditions. Theoretical calculations based on a one-compartment pharmacokinetic model and input functions for hypothetical Oros systems were then performed to define the optimal release rate for a once daily preparation. The results of the second study confirmed that a 14 mg/h system possessed the required characteristics in that it maintained more uniform beta-adrenoceptor blockade throughout 24 h, and produced pre-dosing plasma concentrations and haemodynamic effects which were identical to those for the conventional tablet twice daily regimen.

Iloprost (ZK 36374) modulates the responses to beta-adrenoceptor agonists in guinea-pig airways and pulmonary vasculature

The effect of iloprost on airway smooth muscles and its influence on the actions of beta-agonists and histamine were studied in the isolated perfused lung and isolated tracheal strips from guinea-pigs. Bolus injection of iloprost into the pulmonary artery elicited a concentration-dependent decrease in pulmonary perfusion pressure and an increase in airway resistance. These effects are not mediated through cholinergic, serotoninergic and histaminergic receptors. A rapid tachyphylaxis affected the effect of iloprost in airway resistance but not in pulmonary perfusion pressure. Iloprost did not induce a response in the isolated tracheal strips and did not alter the effect of histamine in both tracheal strips and airway resistance. This compound, however, caused an inhibition in the airway resistance-reducing effect of adrenaline and isoprenaline in the isolated perfused lung and a potentiation in the perfusion pressure-increasing effect of adrenaline. Iloprost also inhibited the relaxing effect of adrenaline and isoprenaline in the isolated tracheal strips precontracted with histamine and potentiated the inhibitory effect of propranolol against adrenaline and isoprenaline. From these results it was concluded that: Iloprost, a stable analogue of prostacyclin, modulates the beta-adrenoceptor blocking effect of propranolol in both airway smooth muscles and pulmonary vasculature.

Inhibition of synaptosomal [3H]noradrenaline uptake by beta-adrenoceptor blocking drugs: influence of lipophilicity.

Ten beta-adrenoceptor blocking drugs varying in lipophilicity and beta-adrenoceptor blocking potency were examined for inhibitory effects on synaptosomal [3H]noradrenaline uptake. All compounds produced a concentration-dependent inhibition of noradrenaline uptake, but were at least one order of magnitude less potent than desmethylimipramine and cocaine. The order of potency was pronethalol greater than propranolol greater than betaxolol greater than alprenolol greater than oxprenolol greater than practolol greater than metoprolol greater than acebutolol greater than sotalol greater than atenolol, with IC50 values ranging from 4.0 X 10(-6) to 2.2 X 10(-3) M. Uptake inhibition was unrelated to beta-adrenoceptor blocking potency, but was highly correlated with drug lipophilicity. (+)-Propranolol was an effective uptake inhibitor, as was the local anaesthetic procaine. Kinetic analysis of uptake inhibition by propranolol, oxprenolol, metoprolol and procaine revealed a mixed inhibition for all four agents examined. It is suggested that this effect of beta-adrenoceptor blockers may be mediated, at least in part, by an action on membrane phospholipids associated with the noradrenaline carrier protein, and that noradrenaline uptake inhibition may underlie certain central side-effects observed with some drugs in this group.

Metabolic side effects of diuretics and beta-adrenoceptorblockers.

A review is made of the metabolic side effects of diuretics and beta-adrenoceptorblockers. The review is based on results from a population study, performed by the author, of women and on a survey of the literature. While diuretics give rise to hypokalemia, which may be of clinical importance, beta-adrenoceptorblockers tend to increase the serum potassium levels. This does not, however, seem to be of clinical significance. Both diuretics and beta-adrenoceptorblockers increase serum uric acid levels. Beta-adrenoceptorblockers increase serum triglycerides, which is not observed when diuretics are used. Total cholesterol in serum is usually not changed either by diuretics or by beta-adrenoceptorblockers. These drugs seem to have no influence on body weight when studied during long-term treatment. A further deterioration of glucose tolerance may be expected in subjects with an initially impaired glucose tolerance when diuretics are administered, while results from studies on glucose tolerance in subjects taking beta-adrenoceptorblockers have been controversial. Diabetes mellitus seems to be more common among subjects on diuretics as well as among subjects on beta-adrenoceptorblockers, but as yet it cannot be stated whether this is an effect of the antihypertensive drugs or of the hypertension per se or of some other factor or factors.