Estimation of the nonspecific cardiovascular toxicity of beta-adrenoceptor blocking drugs with different hydrophobic properties in the cat

The structure-activity relationship between the acute nonspecific cardiovascular depressant effects of the beta-adrenoceptor blocking drugs and their hydrophobic properties was evaluated experimentally for propranolol, pindolol, practolol, and atenolol, in the anaesthetized cat after preceding beta-adrenoceptor blockade. The LD50 values (geometric mean and range in mumol/kg i.v., each drug n = 5) for the nonspecific depression of max dp/dt were: 7.5 (5.6-9.1) for propranolol, 21 (15.5-28) for pindolol, 190 (115-290) for practolol, and 230 (170-400) for atenolol. The respective partition coefficients in octanol buffer (pH 7.0) as a measure of hydrophobicity were: propranolol 5.4, pindolol 0.20, practolol 0.025, and atenolol 0.0032. These experimental data showed a good fit into the regression equation obtained previously [18]. Practolol, in contrast, had a lower toxicity than calculated because of a pronounced intrinsic sympathomimetic activity (ISA), even after catecholamine depletion. The nonspecific cardiovascular toxicity of 15 other clinically used beta-adrenoceptor blocking drugs were estimated from their respective octanol buffer partition coefficients. The fall of the diastolic blood pressure was representative of the toxicity of the compounds. It is concluded that the cardiovascular toxicity is lowest in compounds with low hydrophobicity and with distinct ISA.     

CARDIAC AND BRONCHIAL β-ADRENOCEPTOR ANTAGONISTIC POTENCIES OF ATENOLOL, METOPROLOL, ACEBUTOLOL, PRACTOLOL, PROPRANOLOL AND PINDOLOL IN THE ANAESTHETIZED DOG

1. The β-adrenoceptor antagonists atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol have been tested for their ability to reduce isoprenaline-induced bronchodilation and tachycardia in the anaesthetized dog. 2. Atenolol, metoprolol, acebutolol and practolol all possessed a similar degree of cardioselectivity in this animal model.     

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol

1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects.

2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol.

3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents.

4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β₁-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β₂-adrenoceptors might also be involved.

5 The results are compatible with the hypothesis that both β₁- and β₂-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

     

Immediate haemodynamic effects of propranolol,practolol, pindolol,atenolol and ICI 89,406 in healthy volunteers

Summary Changes in cardiac output, heart rate and arterial blood pressure were determined in 31 healthy volunteers after i. v. administration of equipotent doses of five different adrenergic betareceptor blocking drugs. Propranolol was given to seven subjects, atenolol to five, practolol to seven, pindolol to five, and (a new drug) ICI 89,406 to seven. Each drug was given in six logarithmically spaced doses. Propranolol is non-cardioselective and lacks intrinsic sympathomimetic activity. Atenolol, practolol, and ICI 89,406 are cardioselective. Practolol, pindolol, and ICI 89,406 have intrinsic sympathomimetic activity. Cardiac output was determined by impedance cardiography at supine rest. The dose-response curves for cardiac output and heart rate were of three different types: one obtained after administration of drugs without intrinsic activity, represented by propranolol and atenolol, both of which caused a maximal decrease in cardiac output of about 27%, and in heart rate of about 21%. A second type, obtained after drugs with moderate intrinsic sympathomimetic activity, represented by practolol, showed small but significant decreases in cardiac output of 12%, and in heart rate of 11 per cent. A third type, after drugs with marked intrinsic sympathomimetic activity, was represented by pindolol and ICI 89,406, which did not significantly reduce cardiac output or heart rate. The blood pressure was essentially unchanged in all subjects, even after the largest dose of any of the drugs. It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.     

PROFILE OF A NEW PRAZOSIN CONGENER, BL-5111A. STUDIES IN THE RAT

1. The intrinsic sympathomimetic acitivity of a range of β-adrenoceptor antagonists and its relationship to β-adrenoceptor blockade was studied in pentobarbitone-anaesthetized, vagotomized rats which had been depleted of catecholamines by pretreatment with syrosingopine. Dichlorisoprenaline, practolol, oxprenolol, pindolol and acebutolol, produced dose-dependent positive chronotropic responses in this preparation. 2. The relationship between the dose requirements for this intrinsic sympathomimetic activity and β-adrenoceptor-blocking activity was not the same for all drugs: (i) dichlorisoprenaline and practolol had intrinsic activity at all β-adrenoceptor-blocking doses; and (ii) oxprenolol, pindolol and acebutolol had predominantly β-adrenoceptor blockade at the lower dose levels and agonist activity only became significant at high doses relative to those producing β-adrenoceptor blockade. 3. The positive chronotropic response to both practolol and pindolol was observed in rats which had been pithed and was antagonized by propranolol (0.1-3.0 mg/kg, i.v.), indicating that β-adrenoceptors were involved. 4. It was concluded that the intrinsic sympathomimetic activity of β-adrenoceptor antagonists was not a simple property as it was described by the relationship between the dose requirements for intrinsic sympathomimetic activity and for β-adrenoceptor blockade as well as the degree of partial agonist activity.     

Comparative haemodynamic dose-response effects of intravenous propranolol and pindolol in patients with coronary heart disease

Summary To determine whether the depression of left ventricular pumping activity associated with beta-blockade alone could be offset by a substantial degree of partial agonist activity, the haemodynamic dose-response effects of intravenous propranolol and pindolol were compared in a randomised between-group saline controlled study in twenty patients with angiographically proven coronary artery disease. The intravenous doses of propranolol (2–16 mg) and pindolol (0.2–1.6 mg) used were selected on the basis of published reports of equivalence in terms of exercise blockade of chronotropic beta-adrenoceptors. Following four intravenous boluses of each drug, administered according to a cumulative log-dosage schedule, there was a log-linear increase in the plasma concentrations of each drug. The range of plasma concentrations achieved were those which have been shown to be associated with substantial attenuation of sympathetic stimulation of cardiac beta-adrenoceptors. At rest propranolol resulted in dose-related linear reductions in heart rate and cardiac output and linear increases in left heart filling pressure and systemic vascular resistance compared with saline-controlled measurements. The only statistically significant change at rest after pindolol was a small increase in the left heart filling pressure. The calculated systemic vascular resistance was increased after propranolol but unchanged after pindolol. During supine bicycle exercise the systolic blood pressure increased less after propranolol than after saline or pindolol. The increments in all other measured haemodynamic variables during exercise were equally influenced by the two drugs. Propranolol resulted in a significantly greater depression of the relationship between left heart filling pressure and cardiac output at rest and during exercise than an equivalent beta-blocking dose of pindolol. The contrasting haemodynamic profile of the two drugs is explicable by the partial agonist stimulation of the heart by pindolol directly maintaining left ventricular pumping activity and simultaneously lowering afterload by stimulating vasodilator beta₂-adrenoceptors in peripheral arteriolar resistance vessels. In patients with impairment of left ventricular function due to coronary heart disease who require intravenous beta-blocking therapy, partial agonist activity in a beta-blocking drug may be haemodynamically advantageous.     

A comparison of the haemodynamic effects of propranolol, 4-hydroxypropranolol and practolol in anaesthetized dogs

1. The haemodynamic effects of propranolol, practolol and 4-hydroxypropranolol have been compared in anaesthetized dogs both at free heart rates and at heart rates fixed by electrical pacing. All three drugs produced a fall in heart rate at the lowest dose of 0.09 mg/kg.2. Practolol caused less change in dP/dt, cardiac output and blood pressure than did propranolol. 4-Hydroxypropranolol had intermediate effects. Since the changes in dP/dt caused by these three drugs were still present when the heart rate was fixed by pacing, it is concluded that these were independent of changes in heart rate.3. The fact that practolol and 4-hydroxypropranolol cause less change in haemodynamic function than propranolol may be associated with the intrinsic sympathomimetic activity possessed by the first two of these drugs.     

The assessment of β-adrenoceptor blocking potency and cardioselectivity in vitro and in vivo

The β-adrenoceptor blocking potencies and cardioselectivities (versus tracheal smooth muscle) of propranolol, practolol and M & B 17803A have been assessed on in vitro and in vivo guinea-pig preparations. Propranolol was found to be potent but non-selective, practolol to be less potent but cardioselective. M & B 17803A resembled practolol in potency but had a more modest degree of cardioselectivity in vivo. These observations suggest that the procedures used form a simple scheme which permits a probably relevant assessment of β-adrenoceptor blocking potency and cardioselectivity.     

The effect of atenolol on contractility and hemodynamics of the infarcted heart in comparison to propranolol and practolol (author's transl)]

In animals without myocardial infarction the new beta-sympathicolytic agent atenolol (4-[2'-hydroxy-3'-iso-propylaminopropoxy]-phenyl acetamide, ICI 66 082) dose-dependently decreased heart rate, systolic aortic pressure and cardiac output. Coronary mean flow, coronary resistance, stroke volume, left ventricular enddiastolic pressure and total peripheral vascular resistance did not change significantly. Atenolol significantly reduced myocardial contractility, expressed by (dp/dtmax), Vpm, t-(dp/dtmax) and pre-ejection period. Furthermore, the comparative studies in animals with myocardial infarction and concomitant reduced cardial efficiency revealed, that atenolol has neither a positive intrinsic activity as has practolol nor a negative intrinsic activity as has propranolol. The dose-contractility relation of atenolol resembles that of practolol: in low dosages a strong decrease is achieved, in higher dosages no further reduction of the contractility parameters is observed. Because of the strong negative inotropic and blood pressure lowering effect it is suggested to use atenolol only with great caution in patients with reduced cardiac efficiency.     

Selective regulation of beta 1- and beta 2-adrenoceptors in the human heart by chronic beta-adrenoceptor antagonist treatment.

1. In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the beta-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on beta-adrenoceptor density in right atria (containing 70% beta 1- and 30% beta 2-adrenoceptors) and in lymphocytes (having only beta 2-adrenoceptors) was studied. 2. beta-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)-[125I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial beta 1- and beta 2-adrenoceptors was determined by inhibition of ICYP binding by the selective beta 2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3. With the exception of pindolol, all beta-adrenoceptor antagonists increased right atrial beta-adrenoceptor density compared to that observed in atria from patients not treated with beta-adrenoceptor antagonists. 4. All beta-adrenoceptor antagonists increased right atrial beta 1-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial beta 2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5. Similarly, in corresponding lymphocytes, only sotalol or propranolol increased beta 2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it. 6. It is concluded that beta-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte beta-adrenoceptor subtypes. The selective increase in cardiac beta 1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective beta 1-adrenoceptor antagonists.     

Analysis of cardiac chronotropic responses to some autonomic blocking agents in conscious trained dogs

The changes of heart rate in response to i.v. administration of methylatropine (0.5 mg/kg) and/or propranolol (2 mg/kg) or practolol (2.5 mg/kg) were studied in conscious trained dogs. Cholinergic blockade alone or combined blockade of sympathetic and parasympathetic effector systems resulted in cardiac acceleration. Conversely, β-adrenoceptor antagonism with either propranolol or practolol reduced heart rate. The data were analysed by means of a new method, whereby the heart rate (HR_N) of the dog is considered to be the product of the intrinsic heart rate (HR₀) and 3 further factors: HR_N = HR₀ · S · V · W (multiplicative model). 2 of these factors represent the tonic sympathetic (S) and parasympathetic (V) influences, whereas the third (W) represents the sympathetic—parasympathetic interaction. This type of analysis reveals that W was approximately 1, i.e., the sympathetic—parasympathetic interaction did not play any significant role in determining the heart rate of conscious resting dogs (HR_N = HR₀ · S · V · W = HR₀ · S · V). The change of heart rate due to the action of parasympathetic system (?53% of the intrinsic heart rate) was more important than the change caused by the action of the sympathetic system (26% of the intrinsic heart rate).     

Differences in haemodynamic response to beta-blocking drugs between stable coronary artery disease and acute myocardial infarction

Summary Theoretically the increased sympathoadrenal activity following acute myocardial infarction might augment the haemodynamic impact of beta-adrenoceptor blockade. To evaluate this question 32 haemodynamic studies were performed to compare the effects of equivalent beta-blocking doses of propranolol (8 mg i.v.) and pindolol (0.8 mg i.v.) in patients with a recent acute myocardial infarction (A.M.I.) or stable coronary artery disease (and a presumptive low sympathetic state). In stable coronary artery disease there were clear differences between the haemodynamic impact of propranolol and pindolol. Propranolol decreased both heart rate (HR –7 beat/min) and cardiac index (CI –0.4l/min/m²), with an increased pulmonary artery occluded pressure (PAOP +4 mmHg) and systemic vascular resistance index (SVRI +358 dyn · s · cm^–5 m²). However an equivalent beta-blocking dose of pindolol increased PAOP (PAOP +3 mmHg) leaving other variables unchanged. These differential actions of propranolol and pindolol have previously been ascribed to the intrinsic synpathomimetic activity (I.S.A.) of pindolol maintaining cardiac pumping function in a low sympathetic state. In contrast following myocardial infarction, both drugs reduced cardiac index to a significantly greater extent compared with stable coronary artery disease (CI propranolol –0.8l/min/m²; pindolol –0.4l/min/m²;p<0.05); propranolol also reduced the systemic arterial blood pressure (systolic –10 mmHg; mean –5 mmHg;p<0.05). The haemodynamic relevance of the I.S.A. of pindolol appeared attenuated following A.M.I. These data are compatible with experimental evidence of sympathetic nervous activation following coronary occlusion; the resulting hyperadrenergic state appears to condition an augmented haemodynamic response to beta-blocking drugs irrespective of their ancillary pharmacological properties. The implications of these findings for clinical therapy warrant further examination.     

The pharmacology of epanolol (ICI 141292)--a new beta 1-selective adrenoceptor partial agonist

The clinical benefit of beta-adrenoceptor partial agonists is still debated. To clarify the situation, epanolol, ICI 141,292 [N-[-2-(3-o-cyanophenoxy-2-hydroxypropylamino)ethyl]-4- hydroxyphenylactamide], has been developed to assess the role of modest beta-adrenoceptor partial agonist activity in humans. Animal studies have shown that epanolol is a potent beta-adrenoceptor partial agonist with a greater affinity for beta 1- than beta 2-adrenoceptors. In vitro, the PA2 values obtained for espanolol at atrial and tracheal beta-adrenoceptors were 8.42 and 6.33, respectively (isoproterenol as agonist), giving a selectivity ratio of 123. The potency was studied in vivo in the dog, where it was also shown that as an antagonist at the cardiac beta 1-adrenoceptor, it was 18 and 40 times more potent than atenolol and practolol, respectively. Espanolol has less partial agonist activity in the rat than pindolol, but more than practolol. In this species, it is also a classical partial agonist, exhibiting agonist activity at all beta-adrenoceptor blocking doses. This is in contrast to pindolol, which caused predominantly beta-adrenoceptor blockade at low doses and partial agonist activity at higher doses. These differences were confirmed in haemodynamic studies in the dog. In contrast to many other partial agonists, the partition coefficient, log P, of epanolol in octanol and water is low (0.92).     

Intrinsic heart rate on exercise and the measurement of beta-adrenoceptor blockade

1 Methods of expressing the effects of β-adrenoceptor blocking drugs on exercise heart rate have been evaluated using a standardised exercise test.

2 In six normal subjects given atropine (0.04 mg/kg) on two separate occasions, the mean ± s.e. mean exercise heart rate rose by 10.3± 1.8 beats/min and by 11.0± 1.6 beats/min respectively. This increase was designated the `vagal effect and was not significantly different in the two studies.

3 After atropinsation, propranolol (0.2 mg/kg) reduced mean ± s.e. mean exercise heart rate by 45.3 ± 2.6 beats/min and 0.4 mg/kg by 50.8 ±4.5 beats/min. This mean sympathetic blockade was not altered significantly by increasing the dose of propranolol but, in four of the six subjects, the larger dose produced an increased effect of 4, 6, 12 and 16 beats/min, suggesting that maximum sympathetic blockade may not have been produced by 0.2 mg/kg.

4 Knowledge of the vagal effect in each subject with standardised exercise enabled prediction to be made of the exercise heart rate after propranolol (0.4 mg/kg) without previous atropinisation. Propranolol (0.4 mg/kg) was then given intravenously to each subject and the actual exercise heart rate measured. There was no significant difference between the predicted and observed exercise heart rates.

5 Propranolol (0.6 mg/kg) without atropine was then given to the four subjects who had shown increased effect with (0.4 mg/kg) and the sympathetic blockade was measured. In one subject, a further increase in sympathetic blockade of 10 beats/min was found.

6 The intrinsic heart rate at rest and on exercise was measured for propranolol (0.2 and 0.4 mg/kg) and, for propranolol (0.6 mg/kg), the intrinsic heart rate on exercise was calculated. At rest, although no significant difference was found between the two dose levels, three subjects did not appear to have maximum autonomic blockade at 0.2 mg/kg. Similarly, several subjects had lower intrinsic heart rates on exercise after 0.4 or 0.6 mg/kg than after 0.2 mg/kg. The intrinsic heart rate on exercise was significantly greater than that obtained at rest.

7 Using the maximum sympathetic blockade obtained in each subject as the sympathetic component of exercise, the effects of increasing oral doses of practolol on exercise heart were measured as percentage blockade of sympathetic effect and this was compared with other conventional methods of measuring β-adrenoceptor blockade. It was found that percentage blockade of sympathetic effect correlated most closely with both percentage and absolute reduction of exercise heart rate. Correlations with exercise heart rate after drug and percentage inhibition of tachycardia, whilst also significant, did not appear as good.

8 When the effects of practolol were expressed in terms of the potential blockade, a plateau occurred between 70 and 80% of `maximum' sympathetic blockade. The failure to achieve higher levels with practolol may be the result of its partial agonist or intrinsic sympathomimetic activity.

     

The effect of atenolol on the cardiovascular system (author's transl)

Effects of atenolol on the cardiovascular system were studied in rats and dogs. Atenolol (10 microgram/kg - 3 mg/kg) did not increase heart rate significantly in rats pretreated with reserpine (5 mg/kg), while a significant increase occurred with practolol (30 microgram/kg - 3 mg/kg). Atenolol (100 microgram/kg) inhibited the response of canine heart (heart rate and myocardial contractile force) to isoproterenol to a similar degree as seen with propranolol (100 microgram/kg) did. The ability of atenolol to inhibit vasodilating action of isoproterenol, however, was about 1/12 of that of propranolol. Atenolol (0.5 mg/kg) did not inhibit hemodynamic responses to ouabain and CaCl2 in dogs, while this drug inhibited these responses to isoproterenol. Atenolol decreased heart rate, myocardial contractile force, left ventricular pressure, and rate of rise of the left ventricular pressure (dp/dt LV max) dose-dependently. Atenolol (1 mg/kg) decreased coronary venous outflow and myocardial oxygen consumption in dogs, but did not alter the myocardium to a more reduced state, as determined by coronary arterial and venous lactate and pyruvate levels. These results confirmed that atenolol is a potent cardioselective beta-blocker devoid of intrinsic sympathomimetic action. The results also suggest that atenolol inhibits cardiac function without disturbing the intracellular redox state of the myocardium.     

Differential effect of selective beta 1 and nonselective beta-adrenoceptor blockade on epinephrine and atropine response in normal humans.

Sympathetic stimulation with epinephrine (EPI) combined with parasympathetic blockade with atropine was studied in 10 healthy volunteers premedicated with placebo or three different beta-adrenoceptor blockers: atenolol (62.5 micrograms/kg, beta 1-selective), propranolol (62.5 micrograms/kg, nonselective), and pindolol (7.5 micrograms/kg, nonselective with intrinsic sympathomimetic activity, ISA). EPI infusion (0.06 microgram/kg/min) after placebo increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP). Pretreatment with atenolol reduced the HR increase, and caused similar changes in BP. In contrast, pretreatment with propranolol and pindolol decreased HR and increased BP. Combined EPI and atropine (15 micrograms/kg) after placebo increased HR by 40% without causing BP changes. Similar HR changes were observed after administration of all beta-adrenoceptor blockers, but whereas a marked pressor response was observed after propranolol and pindolol a blunted response was observed after atenolol. Propranolol and pindolol reduced myocardial oxygen demand estimated by the HR x BP product after EPI, but this response was abolished by atropine. Serum potassium decreased from 3.9 +/- 0.2 to 3.2 +/- 0.3 mM after EPi and atropine. This effect was less after atenolol, and potassium increased after premedication with propranolol and pindolol. Our results show that nonselective beta-adrenoceptor blockade has a favorable effect on potassium homeostasis and oxygen demand parameters during EPI infusion but causes a marked pressor response, contrary to a beta 1-selective agent, during combined sympathetic stimulation and parasympathetic blockade. They also highlight the importance of the vasodilator cholinergic system as a defense mechanism in such situations.     

The effect of “selective” β-adrenoceptor blocking drugs on the myocardial circulation

1. A comparison has been made of the effects of a relatively specific beta(1)-adrenoceptor blocking drug (practolol) and a relatively specific beta(2)-adrenoceptor blocking drug (butoxamine) on myocardial and general haemodynamics in anaesthetized cats.2. Practolol, in a dose (10 mg/kg, intravenously) which had little effect on arterial pressure, heart rate, myocardial blood flow or myocardial vascular resistance, markedly reduced the effects of isoprenaline infusions on heart rate, aortic dp/dt, myocardial blood flow, vascular resistance and metabolic heat production, and the cardiac effort index. Isoprenaline induced vasodepression was unaffected.3. Butoxamine (5 mg/kg, intravenously) decreased heart rate, aortic dp/dt, the cardiac effort index and myocardial blood flow and increased myocardial vascular resistance. This is taken as further evidence for the existence of beta(2)-adrenoceptors in the myocardial microcirculation.4. After butoxamine, the effects of isoprenaline on myocardial blood flow, myocardial vascular resistance and heart rate were unaffected but the peripheral vasodilator effect was abolished. The effects on aortic dp/dt and the cardiac effort index were potentiated.5. It is concluded that the effect of isoprenaline in increasing myocardial blood flow is due predominantly to increased cardiac work and oxygen consumption and that practolol, since it has little direct effect on myocardial blood flow yet abolishes the cardiac stimulant and oxygen wasting effects of released catecholamines, has properties which indicate that it should be an effective and safe anti-anginal drug.     

Differential cardiovascular effects of propranolol,atenolol, and pindolol measured by impedance cardiography

Summary We have evaluated Sramek's method of impedance cardiography as a non-invasive way of detecting the cardiovascular effects of drugs. We made cardiovascular measurements using the method during passive tilting and exercise 2 h after the oral administration of atenolol (50 and 100 mg), propranolol (40 and 80 mg), pindolol (5 and 10 mg), and placebo in seven separate studies involving eight healthy male volunteers.Equivalent doses of the pure antagonists atenolol (₁) and propranolol (₁, ₂) produced similar reductions in heart rate, systolic blood pressure, and cardiac index, and increases in stroke volume and total peripheral resistance, particularly during exercise. In contrast the partial agonist pindolol produced increases in heart rate and cardiac index, and reductions in peripheral resistance at rest. During passive tilting and exercise pindolol reduced heart rate, but cardiac output and total peripheral resistance were unchanged except at the highest levels of exercise.The similar cardiovascular effects of atenolol and propranolol, but differing effects of pindolol, are consistent with reports using other methods of measurement. This suggests that impedance cardiography may have a place in the non-invasive assessment of the cardiovascular effects of drugs.     

Influence of propranolol and pindolol on the haemodynamic effects of papaverine,isoprenaline and noradrenaline in hypertensive patients

Summary The influence of two -adrenoceptor antagonists, propranolol and pindolol, on the haemodynamic effects of papaverine, isoprenaline and noradrenaline was investigated in 9 male patients with first degree essential hypertension. Propranolol and pindolol were given according to a doubleblind, crossover scheme. Heart rate and blood pressure were measured before and after each treatment. Propranolol 670 µg/kg i. v. reduced the supine and standing systolic blood pressures by 2.3% and 1.6%, respectively. Similarly, the intravenous administration of pindolol 35 µg/kg reduced supine and standing systolic blood pressure by 5.5% and 8.3% respectively (clinically insignificant). Neither drug affected diastolic blood pressure. Following propranolol, there were moderate reductions in supine and standing heart rates, respectively by 24% and 20% (p<0.001). Similarly, but to a lesser extent, pindolol reduced supine and standing heart rate by 12% and 17% (p<0.001). The effects of papaverine, which, at 1.5 mg/kg i. v. reduced systolic blood pressure by 5–10% and increased heart rate by 8–15%, were not significantly influenced by the -blockers. The blood pressure and heart rate responses to isoprenaline, on the other hand, were attenuated or inhibited by both -blockers. While the -blockers inhibited the -adrenoceptor component of noradrenaline, the pressor component of noradrenaline, which is mediated through the -adrenoceptors, was not influenced by propranolol, but was inhibited after pindolol. It is concluded that pindolol differs qualitatively from propranolol in that it inhibited both the -and -adrenoceptor effects of noradrenaline.Abbreviations BP blood pressure - ECG electrocardiogram - HR heart rate - ISA intrinsic sympathomimetic activity     

Evidence that reversal of mouse aggression is not related to beta blockade

The ED₅₀s for reversal of mouse aggression were determined for nine beta adrenergic receptor blockers: metoprolol, nadolol, pindolol, propranolol, acebutolol, penbutolol, labetalol, timolol, and atenolol. Propranolol and penbutolol generated linear doseresponse curves, suggesting easy access to brain. To determine if beta blockade was actually occurring at the receptor level, upregulation of beta receptors after 10 days of chronic treatment with the ED₅₀s was determined in the limbic system as well as other areas of brain. These areas included: olfactory bulbs, hypothalamus, septum, amygdala, cortex, midbrain, cerebellum, pons, and medulla. Upregulation occurred in all areas of the brain in animals treated with propranolol and penbutolol, suggesting that at the dose required to block aggressing in fighting mice, beta receptors were also effectively blocked. With other drugs (timolol, atenolol, pindolol, metoprolol, nadolol, and acebutolol) the ED₅₀s produced localized upregulation of beta receptors, but nothing consistent in the limbic areas. The beta blocker labetalol at the ED₅₀ for reversal of mouse aggression produced virtually no upregulation of brain receptors, suggesting no correlation between antiaggression and beta blockade.