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1. 1. The adrenergic agonists, noradrenalin (mainly an α-agonist) and isoprenalin (isoproterenol, mainly a β-agonist) produced a marked increase of 32 P-incorporation into phosphatidylinositol of rat vas deferens slices. Other tissue phospholipids did not show the same effect. 2. 2. 32 P-incorporation into phospholipids of the vas deferens increased with time and in the presence of noradrenalin or isoprenalin. The extent of labelling of phosphatidylinositol was related to the concentration of these adrenergic agonists. 3. 3. Adrenergic blocking agents were used to prevent the action of noradrenalin or isoprenalin on 32 P-incorporation into phosphatidylinositol. Phenoxybenzamine (α-blocker) and sotalol (β-blocker) did not appreciably change the basal 32 P-incorporation into phosphatidylinositol. Phentolamine (α-blocker) was found to stimulate the phosphatidylinositol labelling. 4. 4. Preincubation with phenoxybenzamine resulted in a marked decrease of the noradrenalin and isoprenalin stimulation of phosphatidylinositol labelling but preincubation with sotalol had no effect. 5. 5. It appears that the adrenergic stimulation of phosphatidylinositol metabolism in vas deferens is mediated through α-adrenergic receptors.

SummarySotalol (MJ-1999) appears to act as a weak agonist in releasing catecholamines from isolated perfused bovine adrenals. Low concentrations of sotalol enhance and high concentrations inhibit acetylcholine-induced adrenal catecholamine release. Adrenal catecholamine release by high potassium media is decreased by sotalol only at high concentrations. Thus ganglionic actions of sotalol are seen at lower concentrations than are the local anesthetic actions. This study supports the suggestion that the effect of sotalol on blood sugar is due to enhanced adrenal catecholamine release and suggests that ganglionic blockade can be produced by sotalol in concentrations below those required for local anesthetic action.

A heart-rate inappropriately rapid and likely to affect adversely the magnitude of the infarct occurred during movement of one-third of patients with acute myocardial infarction. Pain relief prior to transport did not reduce significantly the incidence of a rapid heart-rate. The prophylactic administration of practolol was of limited value, but the more potent negative chronotropic beta-blocking agent sotalol ('MJ 1999') usually prevented tachycardia. Neither beta-blocking agent gave rise to significant bradycardia when administered concomitantly with atropine.

In pentobarbitone anaesthetized rats (±)-propranolol reduced the stimulatory effect of glucose, sulphonylureas, isoprenaline or phentolamine on insulin secretion. (+)-Propranolol produced similar effects to those produced by the racemate. Sotalol reduced only the insulin secretion stimulated by isoprenaline or phentolamine but not that stimulated by glucose or sulphonylureas. Complete inhibition of isoprenaline-induced hyperinsulinaemia was obtained with practolol, in a dose which was without effect on the plasma insulin elevations produced by glucose or glibenclamide. (±)-Propranolol inhibited glucose or tolbutamide-stimulated insulin secretion from chopped pancreas in vitro indicating a direct action of the drug on the pancreas. It is suggested that propranolol-induced inhibition of insulin secretion may not be entirely due to the β-adrenoceptor blocking activity of the drug.

SummaryPropranolol at doses of 5 and 30 mg/kg and sotalol in a dose of 100 mg/kg only partially inhibited the hyperglycemic response to epinephrine in the rat. These β-adrenergic antagonists completely antagonized the glycogenolytic effect of epinephrine on skeletal muscle, but they did not modify the marked effect of epinephrine on liver glycogen.

Rabbits, irradiated with moderate doses of X-rays on their trunk exhibit a hyperthermic response. Evidence is presented that this temperature response is mediated by leucocytic pyrogen.

Increased sympathetic activity involves increased oxygen consumption by the heart. β-Adrenergic receptor blocking (β-blocking) drugs generally reduce myocardial oxygen consumption. These drugs, regardless of their associated properties such as membrane stabilising action and intrinsic sympathomimetic effect, have all been found to increase exercise tolerance in angina pectoris. The membrane stabilising action has no relevance in the effect of these drugs in angina. The (+)-isomer of propranolol in clinical doses is devoid of haemodynamic action and is ineffective in angina, and the non-membrane-active β-adrenoceptor blocking drugs are effective antianginal agents. Acute exercise tests have failed to reveal any differences between the various β-blocking drugs, except Inpea which was found ineffective at maximum tolerated doses. However, short-term administration is different from long-term clinical use; certain side-effects are not apparent from single-dose administration. Therapeutic trials of β-blocking drugs have shown them to be effective prophylactics when administered over a long period. Trials that have not given clear results have been defective in design; inadequate ‘run-in’ period, sub-optimum fixed dosage and too short a period of assessment are common sources of error. Aspects of trial design are discussed as the response to β-blocking agents is assessed. Far the greatest experience has been with propranolol and best results have been obtained in trials that have used larger and individualised dosages. A clear dose response relationship has been established. Comparative trials of any two drugs in any condition requires that each should be given in optimum dosage if the assessment is to be meaningful. Studies with propranolol and practolol indicated that the former is more effective, and likewise, propranolol is superior to sotalol. Sotalol, which has minimum membrane stabilising activity, unlike practolol, was superior to a low dose (one eighth) of propranolol. Important contra-indications to β-blocking drugs are asthma (except the cardioselective practolol) and heart failure. If these contra-indications are observed β-blocking drugs are relatively safe. Dosage should be commenced at a low level and then gradually increased (say 25 % increments) until optimum effect is obtained. The greatest change in sympathetic environment of the heart occurs at the commencement of treatment (e.g. propranolol 10 mg 3 times daily) and it is then that heart failure may suddenly occur if patient selection has not been adequate. Subsequently, any small increase in dosage does not produce any sudden change in sympathetic environment and thus is relatively safe. An increase in dosage from say 500 mg three times daily of propranolol to 550 mg three times daily is negligible in pharmacological terms, and by such small percentage changes the dosage can be safely and gradually increased to the desired level.

The propellants used in aerosols were investigated in anesthetized mice. The 15 propellants studies can be placed into the following three groups: 6 propellants that induce arrhythmia and sensitize the heart to epinephrine; 6 propellants that sensitize the heart to epinephrine-induced arrhythmia; and 3 propellants that neither induce arrhythmia nor sensitize the heart. The most toxic with respect to the induction of cardiac arrhythmia is trichlorofluoromethane (FC 11) which is, coincidentally, the most widely used low pressure propellant in aerosols.

d1-Isoproterenol, a β agonist, injected into the cerebroventricles of satiated sheep and cattle resulted in increased feed intake; however, higher doses caused hypophagia in sheep. The d-stereoisomer was not effective. The responses to isoproterenol could be blocked by β antagonists. 1-Norepinephrine, an α agonist, induced feeding in sheep, but anorexia in cattle. These responses were blocked by α antagonists. 1-Norepinephrine and d1-isoproterenol injected into the hypothalamus during separate tests but in the same loci induced feeding in sheep; however, much less isoproterenol than 1-norepinephrine was required to induce feeding.

—Norepinephrine and epinephrine, in combination with either adenosine or histamine, enhanced the accumulation of cyclic AMP in guinea pig cerebral cortical slices. Isoproterenol had only marginal effects under the same conditions. Studies with d- and l-norepinephrine and with the α- and β-adrenergic blocking agents, phenoxybenzamine, phentolamine, dihydroergokryptamine, propranolol and sotalol, indicated that the effect of catecholamines on cyclic AMP levels in this tissue was stereo-specific and was mediated primarily via interaction with a classical α-adrenergic receptor. Studies with the antihistaminics, diphenhydramine and pheniramine, and the antiserotonin agent, methysergide, indicated that guinea pig cerebral cortical slices contain receptors for histamine and serotonin, whose activation also stimulates an enhanced accumulation of cyclic AMP in the presence of adenosine.

1. The effect of several beta-adrenoceptor blocking drugs on the pregnant ewe and foetus were studied. Bunolol, butidrine, oxprenolol, propranolol and USVP65-24 all crossed the ovine placenta and produced a beta-adrenoceptor blockade in the ovine foetus. AH3474, AY21011 and sotalol did not cross the ovine placenta as assessed by the absence of a beta-blockade in the foetus when these compounds were administered to the pregnant ewe.2. Of the beta-blocking compounds tested, only propranolol and oxprenolol produced a prolonged blockade in the foetus. The beta-blockade with propranolol was of 3 h duration in the ewe and 10 h duration in the foetus. Oxprenolol produced a beta-blockade of 3 h duration in the ewe and 8 h in the foetus.3. The beta-blocking drugs which did cross the ovine placenta were more soluble in organic solvents (ether, chloroform, corn oil and olive oil) than those which did not cross the ovine placenta.

Low concentrations of secondary and tertiary amine local anesthetics were found to increase the strength of contraction of the electrically driven frog ventricle. The positive inotropic effect occurred at concentrations of the local anesthetic that did not elevate the threshold for electrical stimulation. The enhanced contraction is shown to be due to a block of muscarinic receptors in the ventricle and a consequent reduction of the negative inotropic modulation of the myocardial contraction due to acetylcholine release during electrical stimulation. Acetylcholine in low concentrations depresses contraction; in intermediate concentrationss acetylcholine has a stimulatory action which is blocked by the beta adrenergic blocking agent, sotalol. Catecholamines Sotalol (M.J. 1999) Adrenergic nerves Inotropic Acetylcholine

The effects of d,l-propranolol, d-propranolol, l-propranolol, and sotalol on myocardial contractility and vascular coronary resistance (V.C.R.) were studied on isolated perfused rat and guinea pig hearts, using a modified Langendorff technique. Left ventricular intracavitary pressure (L.V.P.) and maximum dp/dt were depressed by d,l-propranolol and d-propranolol but not by sotalol and l-propranolol. At constant coronary flow, perfusion pressure was decreased to 40% of control values by d,l-propranolol and d-propranolol but perfusion pressure remained unchanged with l-propranolol and increased with sotalol. The drop in V.C.R. following d,l-propranolol and d-propranolol preceded the fall of L.V.P. and occurred in fibrillating hearts as well. The same effect was obtained in noradrenaline-depleted hearts following pretreatment with 6-OH-dopamine. These observations suggest that d,l-propranolol has a coronary vasodilator action unrelated to its adrenergic-receptor blocking properties, and which appears specifically to be an effect of its dextro-isomer.

In rabbit colon muscle there was a quantitative correlation and a co-ordination in time between relaxation and an increase in cyclic AMP on stimulation of adrenergic β-receptors. The cyclic AMP content had increased before the muscle had started to relax. There was an increase in the phosphorylase a activity and reduction of the ATP content. The adrenergic β-receptor blocking agent sotalol inhibited the relaxation and the increase in cyclic AMP content. Reduction of the Ca++ content of the muscle decreased the cyclic AMP content and the phosphorylase a activity. These effects were restored on addition of Ca++ ions. In a Ca-poor muscle adrenergic β-receptor stimulation still produced an increase in cyclic AMP content and phosphorylase a activity but there was an increase in the ATP content instead. The reduction of cyclic AMP which followed an adrenergic a-receptor stimulation was eliminated in the Ca-poor muscle. The existence of a Ca++-accumulating ATP-utilizing mechanism, stimulated by cyclic AMP, might explain the relation between relaxation, cyclic AMP and Ca++ and adrenergic β-receptor stimulation.

Several studies comparing β receptor blocking agents have raised the possibility that practolol or sotalol may act more selectively on β receptors affecting heart rate than on β receptors influencing contractility. To further evaluate this potentially important hypothesis, the relative effects of practolol, sotalol and propranolol on heart rate and contractile force were measured in thoracotomized dogs. Animals receiving substantial β receptor stimulation manifested a dose-related reduction in both heart rate and contractile force after treatment with all three drugs. Furthermore, dosages of each drug matched to produce equal decreases in heart rate also caused equal decrements in contractile force. In contrast, dogs devoid of β receptor stimulation due to prior administration of reserpine and adrenalectomy responded to practolol with a dose-related increase in contractile force (maximum 22 percent) and in heart rate. Effective β-blocking doses of propranolol (up to 0.64 mg/kg) caused neither stimulatory nor depressant effects in reserpinized-adrenalectomized preparations. Thus, practolol differs from propranolol in that it exerts a positive inotropic influence, detectable when β stimulation is absent. Nevertheless, such an effect is inapparent if β stimulation is substantial, which is often true when β blockade is used clinically. Neither practolol nor sotalol, as used therapeutically, appear to act on heart rate more selectively than propranolol.

1. Carrageenin or 5-hydroxytryptamine-induced oedema of the mouse hind paw was antagonized by catecholamines acting on both alpha- and beta-adrenoceptors.2. Increased permeability of the mouse peritoneum induced by the local injection of acetic acid or pro-inflammatory mediators was antagonized by catecholamines acting predominantly on beta-adrenoceptors.3. The anti-inflammatory effect of catecholamines was due neither to hyperglycaemia nor to the release of adrenal cortical hormones.

Propranolol (10 to 30 μg/kg), oxprenolol (trasicor) (5 to 10 μg/kg), and sotalol (10 to 50 μg/kg) evoke an acute and prolonged increase of arterial pressure in normal and nephrectomized rats, while after adrenalectomy the arterial pressure remains unchanged or is reduced. The pressor effect is accompanied by a reduction of heart rate. The dose of the three beta blockers evoking an arterial pressure increase does not antagonize the effect of isopropylnoradrenaline. To block the beta receptors, doses 10 to 100 times higher than those effective on arterial pressure have to be used. The block of the beta receptors is accompanied by an initial fall of the blood pressure and by a significant decrease of the heart rate. The pressor effect of beta blockers is not antagonized but rather is potentiated by phenoxybenzamine and phentolamine. Moreover, in the presence of an alpha receptor blockade, the administration of beta blockers partially restores the response to catecholamines. These results support the hypothesis that the pressor effect evoked by beta receptor blocking agents may be due: (a) to the release of endogenous catecholamines and (b) to the interference by beta blockers with phenoxybenzamine and phentolamine on the alpha receptors.

α- and β-adrenergic blockers have been examined on the bradykinin- and adrenaline-induced relaxation of the acetylcholamine contracted guinea-pig ileum. The α-adrenergic blocker piperoxan potentiated, while phentolamine reduced the bradykinin relaxation. Both reduced the acetylcholamine contraction, but had no effect on the adrenaline relaxation. The bradykinin relaxation of the guinea-pig ileum was about 10 times more sensitive to phentolamine than the rat duodenum. The β-adrenergic blocker propranolol potentiated the bradykinin relaxation and reduced the acetylcholine contraction. Sotalol was in these respects less potent than propranolol. The adrenaline relaxation was partially blocked by propranolol, but almost completely by satalol. A combination of phentolamine and propranolol slightly potentiated the bradykinin relaxation, and partially blocked the adrenaline relaxation. The bradykinin relaxation is not due to a direct action on either the α- and β-adrenergic receptors of the guinea-pig ileum. The potentiation of the 0radykinin relaxation is probably indirect via the reduction of the acetylcholine contraction. The action of phentolamine cannot be explained by this mechanism. Seemingly only β-adrenergic receptor activity mediates relaxation with adrenaline.

A comparative study has been carried out on sotalol and propranolol with regard to their ability to block adrenergic β-receptors, their toxicity and their circulatory effects. Both agents blocked the hypotensive effects of isoprenaline in cats. The relationship between intravenously infused doses of propranolol and sotalol which were equally potent in their adrenergic β-receptor blocking properties was 1:3. In toxicity tests, propranolol was 6–20 times more toxic than sotalol under different experimental conditions and in different species of animals. Propranolol, infused intravenously into cats in a dose of 0.25 mg/kg/min, reduced the cardiac output, heart rate, blood pressure, and cardiac work. Sotalol in the same dosage reduced only the blood pressure and heart rate, while the cardiac output and cardiac work remained unchanged because of a compensatory increase in stroke volume. Propranolol, but not sotalol, reduced the contractile strength and increased the refractory period of electrically stimulated papillary muscle from the cat. Sotalol failed to inhibit ouabain-induced cardiac arrhythmias in dogs, an effect exerted by propranolol. These effects of propranolol, and also its local anesthetic properties, are probably not related to its adrenergic β-receptor blocking properties. As sotalol lacks direct effects it has an advantage over propranolol when specific adrenergic β-receptor blockades are required.

Spontaneous activity was recorded from postganglionic cardioaccelerator fibers in cats anesthetized with α-chloralose. The effects of sotalol and the d(+)− and 1(−)− isomers of practolol were examined in these experiments. The 1(−)− isomer of practolol caused a dose- related depression of adrenergic nervous activity while d(+)− practolol had no effect. Sotalol had no influence on nervous discharge. The results suggest that 1(−)− practolol depresses adrenergic nervous activity and that this effect may be important in the antiarrhythmic action of this agent.

1. The influence of feeding 2 levels of sotalol on the incidence of beta-aminopropionitrile (BAPN)-induced aortic ruptures of immature turkeys was determined.2. Four of 22 turkeys fed 0.12% sotalol and 0.07% BAPN died of aortic ruptures, but 6 of 21 turkeys fed only BAPN died of the syndrome.3. Blood pressure, heart rate, aortic tensile strength, and aortic structure as seen by light- and electron-microscope were similar in turkeys fed BAPN alone or both BAPN and 0.12% sotalol concurrently.4. In a second experiment, 13 of 24 turkeys fed 0.7% BAPN alone died of aortic ruptures, but only 2 of 24 turkeys fed BAPN and 0.2% sotalol concurrently died of the disease.5. Aortic tensile strength was lower, heart rate was faster, alterations of aortic elastic fibres as seen by light- and electron-microscope were more severe, and aortic salt soluble collagen with a higher amino acid content was increased in turkeys fed only BAPN, as compared to turkeys fed both BAPN and 0.2% sotalol.

Beta-adrenergic blocking agents inhibit serotonin uptake by human blood platelets; in addition they induce release of the previously accumulated amine in vitro. Propranolol was the most active drug, followed by alprenolol, Kl 255, Ko 592, INPEA, oxprenolol, pindolol, Ko 1366, practolol, and sotalol. Kinetic analysis revealed a mixed type of inhibition of serotonin uptake. A significant correlation between these parameters and the lipid solubilities of the respective drugs was found. In contrast to the active serotonin uptake labelled β-sympatholytics were accumulated by the platelets passively, i. e. independently of temperature and of time of incubation. The degree of accumulation by human blood platelets and human erythrocyte ghosts was again correlated with the hydrophobicity of the compounds. Therefore, it is concluded that these effects of β-adrenergic blocking agents are mainly unspecific in nature, depending on the lipid solubility of the drugs, and leading to conformational changes within the membranes. This assumption is supported by the electron microscopical findings in human platelets, indicating ultrastructural changes and cell lysis.

This work describes the mass fragmentation patterns of trifluoroacetylated derivatives of five aryloxy β-blocking drugs as well as five metabolites of this chemical and therapeutic class. This chemical class is characterized by intense ions at m/e 308, 266, and 43 and by a strong metastable ion at m/e 229.2. The mechanism of fragmentation was confirmed with the hexadeuterated (d6) analogs of these compounds. In addition, mass spectral features are described for three arylalkyl β-blocking drugs. These mass spectral data should facilitate the rapid and accurate determination of the metabolic fate of these and other β-blocking drugs of this chemical class.

Sotalol (MJ 1999), a beta-adrenergic blocking agent found to have no significant intrinsic myocardial depressant effects, was administered intravenously to 20 patients with heart disease. Eight of the patients had clinical and hemodynamic evidence of chronic heart failure. Doses ranged from 0.2 to 0.6 mg/kg. In all studies, heart rate decreased significantly, accompanied by comparable decreases in cardiac index and tension-time index. There were, however, no significant changes in stroke index, mean blood pressure, or left ventricular end-diastolic pressure—even in those patients with advanced heart failure, indicating that the changes noted were primarily rate-related and could not be ascribed to myocardial depression. To confirm this, further studies were performed in which heart rate was held constant by atrial pacing in normal and catecholamine-depleted dogs. Sotalol, at doses much higher than the minimal beta-blocking dose, did not change stroke index, blood pressure, left ventricular end-diastolic pressure, or estimated maximal velocity of isotonic shortening (V max ), confirming that myocardial contractility was unaffected. It is concluded that sotalol-induced beta blockade had no observable myocardial depressant action in dogs or adverse hemodynamic effects in cardiac patients, even when advanced chronic heart failure was present.

The effects of cumulative i.v. doses of the β-blocking drrugs practonol, oxprenolol, sotalol, (±)-propanolol and dexpropranolol upon d P d t , left ventricular strain gauge measurements and atrioventricular conduction times have been determined at fixed rates in open-chested vagotomized normal and catecholamine-depleted dogs. Practolol, oxprenolol, sotalol and (±)-propranolol, in doses between 0.1 and 2.56 mg/kg, caused dose-dependent reductions in d P d t and strain gauge measurements and an increase in conduction time. When these drugs were administered in the same dose range to catecholamine-depleted dogs, (±)-propranolol and sotalol did not alter these parameters from control values, whilst oxprenolol and practolol decreased conduction time and increased d P d t and strain gauge measurements. Dexpropranolol, 0.01–2.56 mg/kg, had no effect on d P d t , strain gauge measurements or conduction time in normal or catecholamine-depleted dogs. In doses greater than 2.56 mg/kg, oxprenolol, sotalol and (±)-propranolol caused further increases in conduction time and decrease in d P d t and strain gauge measurements in both normal and catecholamine-depleted dogs. Dexpropanolol in doses greater than 2.56 mg/kg also caused similar changes. In contrast, practolol, in doses up to 82 mg/kg, caused no changes in these parameters additional to those observed at lower doses in either normal or catecholamine-depleted dogs. It is concluded that the initial decreases in d P d t and strain gauge measurements and increase in conduction time caused by low doses of practolol, oxprenolol, sotalol and (±)-propranolol aree due to adrenergic β-receptor blockade. The increase in d P d t , strain gauge measurements and decrease in conduction time in catecholamine-depleted dogs caused by practolol and oxprenolol are due to the intrinsic sympathomimetic activity of these drugs. Further decreases in d P d t and strain gauge measurements, and increase in conduction time after high doses of oxprenolol, sotalol (±)-propranolol and dexopropranolol in both normal catecholamine-depleted dogs indicate that these drugs also have membrane-stabilizing properties. Practolol was shown not to have membrane-stabilizing properties in doses up to 82 mg/kg. The technique described may be useful in relating the additional properties of β-blocking agents to their adrenoceptive blocking actions.

The administration of perhexiline was followed by slowing of heart rate in the anesthetized dog, the isolated rat heart and the isolated rabbit heart. This effect was not altered by previous vagotomy or the prior injection of either atropine or sotalol in the dog. A local effect on the rat atrial muscle and on the rabbit sino-atrial node was confirmed by microelectrode technique. There was prolongation of depolarization time and of repolarization time, suggesting that this drug may be useful in situations in which coronary insufficiency is complicated by increase in excitability of atrial muscle and of the sino-atrial node.

Alpha and beta adrenergic receptor blocking agents were injected into the cerebral ventricles of unanesthetized cats and their effects on subsequent responses to intraventricular norepinephrine were determined. The alpha receptor blocking agent phentolamine (100 μg) antagonized the hypothermie and emetic responses to 100 μg norepinephrine. The beta receptor blocking agents practolol (100 and 200 μg), propranolol (100 μg), and sotalol (100 and 200 μg) did not inhibit hypothermie or emetic responses to norepinephrine. In some cats, 400 μg sotalol interfered with the norepinephrine hypothermia but the effect was inconsistent and may not have been related to beta blockade. The three beta receptor blocking agents produced hyperthermia when administered alone. None of the antagonists prevented the behavioral sedation induced by norepinephrine. Norepinephrine hypothermia in the cat appears to result from activation of alpha adrenergic receptors in the hypothalamus.

In a dose of 40 mg, sotalol (MJ 1999) was more potent than 10 mg propranolol in blocking the cardiovascular effects of isoproterenol (5 healthy males, age 22–28 years). In a dose of 10 mg sotalol had weaker blocking properties. In a dose of 10 mg, propranolol under true basal conditions significantly decreased cardiac output (1.7 ± 0.34 1), stroke volume (31 ± 11 ml) and “heart work” (− 20 ± 7%), and increased the peripheral resistance (+35 ± 6%). Sotalol (10–40 mg i.v.) had no significant actions on cardiac output or any other cardiac function. There were statistically significant differences in the haemodynamic effects of sotalol and propranolol at doses producing a similar adrenergic β-receptor blocking effect.

Isolated canine papillary muscle-false tendon preparations stimulated at 95/min were perfused with Tyrode's solution containing ouabain, 2.1 x 10 -7 M. Action potentials of Purkinje fibers were recorded. Initially ouabain increased the slope of phase-4 depolarization. Subsequently it decreased the maximum diastolic potential and the rising velocity of phase 0, the amplitude, and the duration of the action potential. The slope of phase-4 depolarization increased progressively, and eventually the configuration of the action potential changed to resemble that of sinoatrial node fibers. Onset of enhanced phase-4 depolarization was delayed significantly by treatment before exposure to ouabain with lidocaine, 3.7 x 10 -5 M, or propranolol, 2.1 x 10 -5 M, but not with sotalol, 3.2 x 10 -4 M. Enhanced phase-4 depolarization produced by exposure to ouabain was reduced in slope by subsequent treatment with lidocaine or propranolol but not sotalol. Application of lidocaine or propranolol to fibers with action potentials in the configuration characteristic of sinoatrial node fibers returned the contour of the action potentials toward normal; sotalol was not effective in this regard. These results, coupled with the relative effectiveness of these drugs in intact animals with digitalis arrhythmias, support the hypothesis that enhanced phase-4 depolarization of Purkinje fibers is a factor in the production of digitalis-induced ventricular arrhythmias.

The hemodynamic effects of sotalol (MJ 1999) were studied during diagnostic catheterization in 24 adult male patients, at rest, during exercise, and during constantrate right ventricular pacing. The depression in cardiac index at rest and during exercise appears to be secondary to the negative chronotropic effect of the drug, since there was no change in stroke volume. The change in dP/dt and left ventricular end-diastolic pressure may also be a function of slowing of the heart rate. However, with heart rate maintained constant by right ventricular pacing, there was significant depression of cardiac function, as indicated by a decrease in cardiac index, stroke index, and dP/dt, and increase in arteriovenous oxygen difference. Sotalol appears to have both a significant negative chronotropic and negative inotropic effect in man.

Sotalol, at a fixed dose of 20 mg was given intravenously to 34 patients with cardiac arrhythmias of varying aetiology. It was effective in the treatment of supraventricular tachycardias, acute onset atrial and ventricular ectopics and acute onset atrial fibrillation. In chronic arrhythmias sinus rhythm was not restored, but in 77% there was slowing of the cardiac rate. Side effects were seen in only one patient who developed moderate bronchospasm.

No unequivocal central effects were found with either ±-propranolol (120 mg) or ±-sotalol (240 mg) in acute dosage in normal subjects. Subjective feelings of drowsiness and muzziness were found with sotalol and both sotalol and propranolol caused subjects to feel more troubled. These changes were not accompanied by physiological or behavioural evidence of sedation. Adequate β-adrenoceptor blockade was achieved as measured by a significant fall in pulse-rate on both active drugs but no other significant peripheral physiological changes occurred.

SummarySotalol and propranolol enhanced insulin-induced hypoglycemia in the rat. Neither agent displayed any significant hypoglycemic activity per se.

Sotalol, an adrenergic-blocking and antiarrhythmic agent, increases markedly and simultaneously the duration of both action potentials and contractions in papillary muscles. The active tension is manifested as a main twitch contraction followed by a maintained low level of residual tension (aftercontraction) which persists until the terminal phase of rapid repolarization. The Strength of the aftercontraction is augmented when the extracellular concentration of calcium is increased.

Effects of 3,5-diethyl hydantoin on cardiac phosphorylase were investigated in open-chest rat preparations. It was found that 3,5-diethyl hydantoin caused an increase in cardiac phosphorylase a, bradycardia and hypotension. The elevation in enzyme activity was blocked by propranolol or sotalol, but not the decrease in heart rate or blood pressure.

Antagonism of β-adrenergic receptors by (−)-sotalol has been examined in isolated guinea-pig trachea by the use of pA 2 plots. When (−)-isoproterenol was used as agonist, the slope value of the pA 2 plot was 0.82 and was increased to 0.98 when experiments were performed in the presence of tropolone, 10 −4 M, to inhibit COMT. When a COMT resistant compound, (−)-soterenol, was used as agonist, the slope value was 0.95. To test the hypothesis that high concentrations of agonists which are substrates for COMT saturate the enzymatic sites or access to these sites and thereby potentiate their own effects during competitive receptor antagonism, the ability of sotalol to block effects of (+)-isoproterenol was examined. Since a low slope value (0.80) of the pA 2 plot was still obtained under these experimental conditions, agonist saturation of either process does not appear to be operative in this tissue. This suggest that the β-receptor antagonist may impede the O-methylation process in concentration-dependent fashion. The apparent nonclassical antagonism of β-receptors produced by sotalol in guinea-pig trachea can be attributed to changes in agonist disposition in the tissue than deviations from currently accepted receptor theory.