Summary
The chronotropic and inotropic effects of fourteen β-adrenoceptor blocking agents were studied in vitro on preparations of isolated heart muscle from kittens and guinea pigs. Most of the agents exert negative inotropic and chronotropic effects that increase rapidly with concentration above 10−6 M. Exceptions are the closely related compounds practolol and atenolol, which have minimal depressant effects in concentrations as high as 2×10−3 M. Dose-response relations for the depressant effects are similar for pacemaker frequency and for tension development in atrial and papillary muscle. The cardiodepressant effects of β-blockers are non-stereospecific and are apparently unrelated to the actions of the drugs at β-adrenoceptors. Many β-blockers exert positive inotropic and chronotropic effects at concentrations lower than those that depress. The stimulant effects are slow in onset and do not fade. In most instances these effects are blocked by propranolol and may therefore be considered to be mediated through β-adrenoceptors; (−)-enantiomers are more potent than (+)-enantiomers as adrenoceptor stimulants. Adrenoceptor-mediated inotropic effects are usually more pronounced in atrial than in ventricular muscle. Certain β-blockers, notably INPEA and sotalol, exert positive inotropic effects that are not blocked by propranolol or phenoxybenzamine. The effects are very slow in onset and offset, and are accompanied by the development of contractions with a late tonic component which coincides with a greatly prolonged action potential. Unlike the adrenoceptor-mediated effect, the non-sympathomimetic inotropic effect is more pronounced in ventricular than in atrial muscle, and is not stereospecific. Pindolol also causes the development of a late tonic component, but the accompanying positive inotropic effect is overcome by the simultaneous development of the depressant action of the drug.
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References
Åblad, B., Brogard, M., Ek, L.: Pharmacological properties of H56/28—A β-adrenergic receptor antagonist. Acta Pharmacol. Toxicol.25, (Suppl. 2), 9–40 (1967)
Barrett, A. M., Carter, J.: Comparative chronotropic activity ofβ-adrenoceptive antagonists. Br. J. Pharmacol.40, 373–381 (1970)
Blinks, J. R.: Positive chronotropic effect of increasing right atrial pressure in the isolated mammalian heart. Am. J. Physiol.186, 299–303 (1956)
Blinks, J. R.: Convenient apparatus for recording contractions of isolated muscle. J. Appl. Physiol.20, 755–757 (1965)
Blinks, J. R.: Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J. Pharmacol. Exp. Ther.151, 221–235 (1966)
Blinks, J. R.: Evaluation of the cardiac effects of severalbeta adrenergic blocking agents. Ann. N. Y. Acad. Sci.139, 673–685 (1967)
Blinks, J. R., Koch-Weser, J.: Physical factors in the analysis of the actions of drugs on myocardial contractility. Pharmacol. Rev.15, 531–599 (1963)
Blinks, J. R., Olson, C. B., Jewell, B. R., Bravený, P.: Influence of caffeine and other methylxanthines on the mechanical properties of isolated mammalian heart muscle. Evidence for a dual mechanism of action. Circ. Res.30, 367–392 (1972)
Brandt, W., Reiter, M., Seibel, K.: A postsynaptic effect of tyramine in ventricular muscle. Naunyn-Schmiedeberg's Arch. Pharmacol.273, 283–293 (1972)
Dhalla, N. S.: Mechanisms of sympathomimetic effects of dichloroisoproterenol: Comparison with tyramine, nicotine and norepinephrine. J. Pharmacol. Exp. Ther.157, 135–142 (1967)
Dhalla, N. L., Lee, S. L.: Comparison of the actions of acebutolol, practolol and propranolol on calcium transport by heart microsomes and mitochondria. Br. J. Pharmacol.57, 215–221 (1976)
Ebner, R., Reiter, M.: The influence of (+)-propranolol on the inotropic effect of dihydro-ouabain in relation to stimulation frequency. Naunyn-Schmiedeberg's Arch. Pharmacol.307, 105–113 (1979)
Fleming, W. W., Hawkins, D. F.: The actions of dichloroisoproterenol in the dog heart-lung preparation and the isolated guinea-pig atrium. J. Pharmacol. Exp. Ther.129, 1–10 (1960)
Hellenbrecht, D., Lemmer, B., Wiethold, G., Grobecker, H.: Measurements of hydrophobicity, surface activity, local anaesthesia, and myocardial conduction velocity as quantitative parameters of non-specific membrane affinity of nine β-adrenergic blocking agents. Naunyn-Schmiedeberg's Arch. Pharmacol.277, 211–226 (1973)
Honerjäger, P., Reiter, M.: The relation between the effect of veratridine on action potential and contraction in mammalian ventricular myocardium. Naunyn-Schmiedeberg's Arch. Pharmacol.289, 1–28 (1975)
Kaumann, A. J.: Potentiation of the effects of isoprenaline and noradrenaline by hydrocortisone in cat heart muscle. Naunyn-Schmiedeberg's Arch. Pharmacol.273, 134–153 (1972)
Kaumann, A. J.: Relaxation of heart muscle by catecholamines and by dibutyryl cyclic adenosine 3′, 5′-monophosphate. Similarity of β-Adrenoceptors mediating contractile and relaxant effects of catecholamines in cat papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol.296, 205–215 (1977)
Kaumann, A. J., Blinks, J. R.: Comparative potencies ofbeta adrenergic blocking agents on isolated heart muscle. Fed. Proc.26, 401 (1967a)
Kaumann, A. J., Blinks, J. R.: Sympathomimetic and non-sympathomimetic stimulant effects ofbeta adrenergic blocking agents on isolated heart muscle. Pharmacologist9, 248 (1967a)
Kaumann, A. J., Blinks, J. R.: β-Adrenoceptor blocking agents as partial agonists in isolated heart muscle: Dissociation of stimulation and blockade. Naunyn-Schmiedeberg's Arch. Pharmacol.311, 237–248 (1980)
Kaumann, A. J., McInerny, T. K., Gilmour, D. P., Blinks, J. R.: Comparative assessment of β-adrenoceptor blocking agents as simple competitive antagonists in isolated heart muscle: Similarity of inotropic and chronotropic blocking potencies against isoproterenol. Naunyn-Schmiedeberg's Arch. Pharmacol.311, 219–236 (1980)
Kaumann, A. J., Olson, C. B.: Temporal relationship between longlasting aftercontractions and action potentials in cat papillary muscles. Science161, 293–295 (1968)
Kaumann, A. J., Olson, C. B.: Prolongación marcada del potencial de acción por tres antiarrítmicos en músculo papilar de gato. Medicina (B. Aires)30, 593–594 (1970)
Koch-Weser, J.: Direct and beta adrenergic receptor blocking actions of nethalide on isolated heart muscle. J. Pharmacol. Exp. Ther.146, 318–326 (1964)
Morad, M., Goldman, Y.: Excitation-contraction coupling in heart muscle: Membrane control of development of tension. Prog. Biophys. Mol. Biol.27, 257–313 (1973)
Noack, E., Greeff, K.: Inhibition of calcium transport in mitochondria by β-receptor blocking substances and its reactivation by phospholipids. Experientia27, 810–811 (1971)
Noack, E., Kurzmack, M., Verjovski-Almeida, S., Inesi, G.: The effect of propranolol and its analogs on Ca2+ transport by sarcoplasmic reticulum vesicles. J. Pharmacol. Exp. Ther.206, 218–288 (1978)
Rahn, K. H., Reuter, H.: Über den Zusammenhang der Wirkungen von Adrenalin, einem β-Adrenolyticum und Chinidin auf Kontraktionskraft und Calcium-Umsatz des Meerschweinchenvorhofs. Naunyn-Schmiedeberg's Arch. Pharmacol.252, 444–451 (1966)
Rieter, M.: Die Entstehung von »Nachkontraktionen« im Herzmuskel unter Einwirkung von Calcium und von Digitalisglykosiden in Abhängigkeit von der Reizfrequenz. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak.242, 497–507 (1962)
Reiter, M., Schöber, H. G.: Oscillatorische Kontraktionsphänomene des Herzmuskels unter Einwirkung von Adrenalin. Naunyn-Schmiedeberg's Arch. Pharmacol.250, 21–34 (1965)
Scalcs, B., McIntosh, D. A. D.: Effects of propranolol and its optical isomers on the radiocalcium uptake and the adenosine triphosphatases of skeletal and cardiac sarcoplasmic reticulum fractions (SRF). J. Pharmacol. Exp. Ther.160, 261–267 (1968)
Singh, B. N., Vaughan Williams, E. M.: A third class of antiarrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle of MJ 1999 and AH 3474. Br. J. Pharmacol.39, 675–687 (1970)
Singh, B. N., Vaughan Williams, E. M.: The effect on cardiac muscle of the β-adrenoceptor blocking drugs INPEA and LB 46 in relation to their local anaesthetic action on nerve. Br. J. Pharmacol.43, 10–22 (1971)
Strauss, J. C., Bigger, J. T., Hoffman, B. F.: Electrophysiological and β-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ. Res.26, 661–678 (1970)
Tarr, M., Luckstead, E. F., Jurewicz, P. A., Haas, H. G.: Effect of propranolol on the fast inward sodium current in frog atrial muscle. J. Pharmacol. Exp. Ther.184, 599–610 (1973)
Vogin, E. E., Dhalla, N. S.: Inotropic and chronotropic effects of dichloroisoproterenol on rat atria. J. Pharmacol. Exp. Ther.147, 65–69 (1965)
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Kaumann, A.J., Blinks, J.R. Stimulant and depressant effects ofβ-adrenoceptor blocking agents on isolated heart muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 311, 205–218 (1980). https://doi.org/10.1007/BF00569401
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DOI: https://doi.org/10.1007/BF00569401