Influence of glyceryl trinitrate on force of contraction and action potential of guinea-pig myocardium
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The inotropic effect of glyceryl trinitrate (GTN) was studied in guinea-pig papillary muscles and atrial strips by analysing the isometric contraction curve and the monophasic action potential (AP).
GTN, 7\sx10\t-5 M, reduced the force of contraction by 10%; increases in contractile force appeared at 2\sx10\t-4 M in papillary muscles and at 1.4\sx10\t-4 M in atrial strips. The maximum of the contractile force was reached in both preparations at 5\sx10\t-4 M GTN. Positive inotropic effects were transitory (3\2-5 min) and were followed by marked negative inotropic effects.
In the presence of GTN, only 15 of 26 papillary muscles showed a positive inotropic response and there was a great variance in its intensity. Prior exposure of papillary muscles to a low GTN concentration, which by itself reduced force of contraction (like every single GTN application), was the prerequisite for the positive inotropic effect of a subsequent higher GTN concentration.
In atrial strips the positive inotropic action was consistent and uniform. The maximum force of contraction in response to single applications of GTN was only about 50% of that in response to cumulatively increased GTN concentrations.
In the presence of 5\sx10\t-4 M GTN, the tyramine concentration-effect curve was shifted to the left (by one log unit at the ED50 level).
-Adrenoceptor blockade by (\+-)-propranolol (5\sx10\t-6 M) or noradrenaline depletion by pretreatment of the animals with reserpine (5 mg/kg, 18\2-22 hrs prior to the experiment) prevented the positive inotropic effects of GTN in both preparations. Hence, the GTN-induced increase in contractile force is induced by the liberation of noradrenaline and an inhibitory effect on the monoamine oxidase (MAO) of sympathetic nerve endings might be involved.
In atrial preparations exposed to 5\sx10\t-4 M GTN, time to peak force (t1) and relaxation time (t2) were shortened by 12% and 33%, respectively. Pretreatment of the animals with reserpine prevented the shortening of t1 and changed the shortening of t2 from 33% to 19%.
In papillary muscles, 5\sx10\t-4 M GTN shortened t1 by 10%, while t2 was prolonged by 17% in noradrenaline-depleted, and by 36% in control muscles. Prolongation of t2 at 5\sx10\t-4 M GTN was accompanied by an increase in the duration of the monophasic action potential (AP) in reserpine-pretreated as well as in control muscles by 12% and 26%, respectively (measured at 90% repolarization). The same GTN concentration slowed the maximum rate of depolarisation by 32%. After 35 min the AP returned to approximately the control value. In the presence of 5\sx10\t-4 M GTN, noradrenaline (1\sx10\t-5 M) lengthened the AP by 38% in both, control muscles and noradrenaline-depleted preparations.
Key wordsGlyceryl Trinitrate Negative Inotropic Effect Indirect Sympathomimetic Effect Relaxation Time Cardiac Muscle
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- Angelakos, E. T., Fuxe, K., Torchiana, M. L.: Chemical and histochemical evaluation of the distribution of catecholamines in the rabbit and guinea-pig hearts. Acta physiol. scand. 59, 184–192 (1963)Google Scholar
- Blaschko, H., Richter, D., Schlossmann, H.: The oxidation of adrenaline and other amines. Biochem. J. 31, 2187–2196 (1937)Google Scholar
- Blum, S. W., Quinn, J. B., Howe, B. B., Hefner, M. A., Winbury, m. M.: Pharmacologic and biochemical evaluation of organic nitrates: Attempted correlation of activities. J. Pharmacol. exp. Ther. 176, 684–691 (1971)Google Scholar
- Brandt, W., Reiter, M., Seibel, K.: A postsynaptic effect of tyramine in ventricular muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 273, 283–293 (1972)Google Scholar
- Cervoni, P., Kirpekar, S. M., Schwab, A.: The effect of drugs on uptake and release of catecholamines in the isolated left atrium of the guinea pig. J. Pharmacol. exp. Ther. 151, 196–206 (1966)Google Scholar
- Charlier, R.: Antianginal drugs. Pathophysiological, haemodynamic, methodological, pharmacological, biochemical and clinical basis for their use in human therapeutics. In: Handbook of Experimental Pharmacology, vol. XXXI, pp. 120–128 (1971)Google Scholar
- Furchgott, R. F., de Gubareff, T., Grossman, A.: Release of autonomic mediators in cardiac tissue by suprathreshold stimulation. Science 129, 328–329 (1959)Google Scholar
- Hashimoto, K., Taira, N., Chiba, S., Hashimoto jr., K., Endoh, M., Kokubun, M., Kokubun, H., Iijima, T., Kimura, T., Kubota, K., Oguro, K.: Cardiohemodynamic effects of BAY a 1040 in dog. Arzneimittel-Forsch. (Drug Res.) 22, 15–21 (1972)Google Scholar
- Kalin, M., Kylin, B.: Organic nitrate explosives as monoamine oxidase inhibitors. Arch. environm. Hlth. 18, 311–314 (1969)Google Scholar
- Koch-Weser, J.: Effect of rate changes on strength and time course of contraction of papillary muscle. Amer. J. Physiol. 204, 451–457 (1963)Google Scholar
- Korth, M.: Inotropic effects of glyceryl trinitrate on the isolated guinea-pig myocardium. Naunyn-Schmiedeberg's Arch. Pharmacol. 282, R50 (1974)Google Scholar
- Lesch, M., Gorlin, R.: Pharmacological therapy of angina pectoris. Mod. Conc. cardiov. Dis. 42, 5–10 (1973)Google Scholar
- Muscholl, E.: Die Konzentration von Noradrenalin und Adrenalin in den einzelnen Abschnitten des Herzens. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 237, 350–364 (1959)Google Scholar
- Ogawa, K., Gudbjarnason, S., Bing, R. J.: Nitroglycerin (Glyceryl Trinitrate) as a monoamine oxidase inhibitor. J. Pharmacol. exp. Ther. 155, 449–455 (1967)Google Scholar
- Ogawa, K., Gudbjarnason, S.: A correlation between the inhibition of monoamine oxidase activity and the relief of angina pain by organic nitrates. Arch. int. Pharmacodyn. 1, 172–182 (1968)Google Scholar
- Quadbeck, J., Reiter, M.: Cardiac action potential and inotropic effect of noradrenaline and calcium. Naunyn-Schmiedeberg's Arch. Pharmacol. 286, 337–351 (1975)Google Scholar
- Raff, W. K., Drechsel, U., Scholtholt, J., Lochner, W.: Herzwirkung des Nitroglycerins. Pflügers Arch. 317, 336–343 (1970)Google Scholar
- Reiter, M.: Die Wertbestimmung inotrop wirkender Arzneimittel am isolierten Papillarmuskel. Arzneimittel-Forsch. (Drug Res.) 17, 1249–1253 (1967)Google Scholar
- Reiter, M.: Drugs and heart muscle. Ann. Rev. Pharmacol. 12, 111–124 (1972)Google Scholar
- Robin, E., Cowan, C., Puri, P., Ganguly, S., Deboyrie, E., Martinez, M., Stock, T., Bing, R. J.: A comparative study of nitroglycerin and propranolol. Circulation 36, 175–186 (1967)Google Scholar
- Shore, P. A., Cohn jr., V. H., Highman, B., Maling, H. M.: Distribution of norepinephrine in the heart. Nature (Lond.) 181, 848 (1958)Google Scholar
- Smith, C. B.: The role of monoamine oxidase in the intraneuronal metabolism of norepinephrine released by indirectly acting sympathomimetic amines or by adrenergic nerve stimulation. J. Pharmacol. exp. Ther. 151, 207–220 (1966)Google Scholar
- Strauer, B. E., Westberg, C., Tauchert, M.: Untersuchungen über inotrope Nitroglycerinwirkungen am isolierten Ventrikelmyokard. Pflügers Arch. 324, 124–133 (1971)Google Scholar
- Trendelenburg, U.: Modification of the effect of tyramine by various agents and procedures. J. Pharmacol. exp. Ther. 134, 8–17 (1961)Google Scholar
- Vassort, G., Rougier, O., Garnier, D., Sauviat, M. P., Coraboeuf, E., Gargouil, Y. M.: Effects of adrenaline on membrane inward currents during the cardiac action potential. Pflügers Arch. 307, 70–81 (1969)Google Scholar
- Vater, W., Kroneberg, G., Hoffmeister, F., Kaller, H., Meng, K., Oberdorf, A., Puls, W., Schlossmann, K., Stoepel, K.: Zur Pharmakologie von 4-(2-Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarbonsäuredimethylester (Nifedipine) BAY a 1040. Arzneimittel-Forsch. (Drug Res.) 22, 1–14 (1972)Google Scholar
- Waldeck, B.: Failure to demonstrate monoamine oxidase inhibition by glyceryl trinitrate in vivo. Acta pharmacol. (Kbh.) 28, 406–412 (1970)Google Scholar
- Weidmann, S.: The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J. Physiol. (Lond.) 127, 213–224 (1955)Google Scholar
- Wiener, L., Dwyer jr. E. M., Cox, J. W.: Hemodynamic effects of nitroglycerin, propranolol, and their combination in coronary heart disease. Circulation 39, 623–632 (1969)Google Scholar
- Wurtman, R. J., Axelrod, J.: A sensitive assay for the estimation of monoamine oxidase. Biochem. Pharmacol. 12, 1439–1441 (1963)Google Scholar