Summary
In the isolated rabbit papillary muscle the effects of dopamine on the contractile force and on the level of 3′,5′-cyclic adenosine monophosphate (cAMP) at different frequencies of stimulation were studied and compared with those of isoprenaline and adrenaline.
-
1.
When the frequency of stimulation was increased from 0.5–2.5 Hz the dose-response curves for the positive inotropic effect of dopamine as well as of isoprenaline were shifted to the left, whereas the maximum of the developed tension reached for both drugs remained unchanged.
-
2.
At a frequency of stimulation of 0.5 Hz pindolol (3×10−8 M) and phentolamine (10−6 M), respectively, did not affect the dose-response curve for dopamine; only the simultaneous administration of pindolol plus phentolamine shifted the dose-response curve to the right. In the presence of cocaine (3×10−5 M) as well as in that of cocaine plus corticosterone (4×10−5 M) the dose-response curve for dopamine was shifted to the right. On the other hand, the upper part of the dose-response curve for adrenaline was shifted to the right by pindolol (3×10−8 M), the lower part by phentolamine (10−6 M) and the whole curve by the application of both antagonists.
-
3.
At a frequency of stimulation of 2.5 Hz neither pindolol (3×10−8 M) nor phetolamine (10−6 M) influenced the dose-response curve for dopamine, whereas the simultaneous administration of both drugs shifted the whole curve to the right.
-
4.
Dopamine (10−4 M) increased significantly the content of the cAMP after 60 s by about 40% (at 0.5 Hz) and 50% (at 1.0 Hz), respectively, but this increase was by far less compared with that obtained by isoprenaline (3×10−7 M).
-
5.
Pindolol (3×10−8 M) completely abolished the increase of the cAMP-content evoked by dopamine (10−4 M), while phentolamine (10−6 M) enhanced the elevation of the cAMP-level to nearly the same extent as isoprenaline (3×10−7 M) did.
-
6.
The increase of the cAMP level induced by adrenaline (10−5 M) was comparable with that caused by isoprenaline (3×10−7 M). While phentolamine (10−6 M) did not influence the adrenaline induced increase of the cAMP content, pindolol completely abolished it.
-
7.
The present results are compatible with the view, that the positive inotropic effect via stimulation of β-adrenoceptors is mediated by cAMP, while that of α-adrenoceptors is not. Furthermore it is concluded, that dopamine produces its positive inotropic effect by a cAMP-dependent direct and/or indirect β-adrenoceptor stimulation as well as by a cAMP-independent direct α-adrenoceptor stimulation to about the same degree.
Similar content being viewed by others
References
Benfey, B. G.: Lack of relationship between myocardial cyclic AMP concentrations and inotropic effect of sympathomimetic amines. Brit. J. Pharmacol. 43, 757–763 (1971)
Brodde, O.-E., Motomura, S., Endoh, M. Schümann, H. J.: Effect of dopamine on contractile force and on the cyclic 3′,5′-AMP-level in the isolated rabbit papillary muscle at different frequencies of stimulation. Naunyn-Schmiedeberg's Arch. Pharmacol. 293, R94 (1976)
Cheung, W. Y., Williamson, J. R.: Kinetics of cyclic adenosine monophosphate changes in rat heart following epinephrine administration. Nature (Lond.) 207, 979–981 (1965)
Cotten, M. de V., Pincus, S.: Comparative effects of a wide range of doses of l-epinephrine and of l-norepinephrine on the contractile force of the heart in situ. J. Pharmacol. exp. Ther. 114, 110–118 (1955)
Endoh, M., Schümann, H. J.: Frequency-dependence of the positive inotropic effect of methoxamine and naphazoline mediated by α-adrenoceptors in the isolated rabbit papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, 377–389 (1975)
Endoh, M., Wagner, J., Schümann, H. J.: Influence of temperature on the positive inotropic effect mediated by α- and β-adrenoceptors in the isolated rabbit papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, 61–72 (1975a)
Endoh, M., Brodde, O.-E., Schümann, H. J.: Accumulation of cAMP and positive inotropic effect evoked by isoprenaline under the graded inhibition of phosphodiesterase by papaverine in the isolated rabbit papillary muscle. J. Mol. Cell. Cardiol. 7, 703–711 (1975b)
Endoh, M., Schümann, H. J., Krappitz, N., Hillen, B.: α-Adrenoceptors mediating positive inotropic effects on the ventricular myocardium: some aspects of structure-activity relationship of sympathomimetic amines. Jap. J. Pharmacol. 26, 179–190 (1976)
Farmer, J. B.: Indirect sympathomimetic action of dopamine. J. Pharm. Pharmacol. 18, 261–262 (1966)
Gilman, A. G.: A protein binding assay for adenosine 3′,5′-cyclic monophosphate. Proc. nat. Acad. Sci. (Wash.) 67, 305–312 (1970)
Goldberg, L. I.: Dopamine—Clinical uses of an endogenous catecholamine. New Engl. J. Med. 291, 707–710 (1974)
Goldberg, L. I.: Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacol. Rev. 24, 1–29 (1972)
Govier, W. C.: Myocardial alpha adrenergic receptors and their role in the production of a positive inotropic effect by sympathomimetic agents. J. Pharmacol. exp. Ther. 159, 82–90 (1968)
Koch-Weser, J., Blinks, J. R.: The influence of the interval between beats on myocardial contractility. Pharmacol. Rev. 15, 601–652 (1963)
Kukovetz, W. R., Pöch, G.: The positive inotropic effect of cyclic AMP. Adv. in Cyclic Nucleotide Res. Vol. I (P. Greengard, R. Paoletti, and G. A. Robison, eds.), pp. 261–290. New York: Raven Press 1972
Kukovetz, W. R., Pöch, G., Wurm, A.: Effect of catecholamine, histamine and oxyfedrine on isotonic contraction and cyclic AMP in the guinea-pig heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 278, 403–424 (1973)
Ledda, F., Marchetti, P., Mugelli, A.: Studies on the positive inotropic effect of phenylephrine: A comparison with isoprenaline. Brit. J. Pharmacol. 54, 83–90 (1975)
McDonald, R. H., Goldberg, L. I.: Analysis of the cardiovascular effects of dopamine in the dog. J. Pharmacol. exp. Ther. 140, 60–66 (1963)
Osnes, J.-B., Øye, I.: Relationship between cyclic AMP metabolism and inotropic response of perfused rat hearts to phenylephrine and other adrenergic amines. Adv. in Cyclic Nucleotide Res. Vol. 5 (G. I. Drummond, P. Greengard and G. A. Robison, eds.), pp. 415–433. New York Raven Press 1975
Osnes, J.-B., Øye, I.: Adenosine 3′,5′-cyclic monophosphate in perfused rat heart exposed to isoprenaline and dopamine. Acta physiol. scand. 96, 100–113 (1976)
Robison, G. A., Butcher, R. W., Øye, I., Morgan, H. E., Sutherland, E. W.: The effect of epinephrine on adenosine 3′,5′-phosphate levels in the isolated perfused rat heart. Molec. Pharmacol. 1, 168–177 (1965)
Schümann, H. J., Endoh, M., Wagner, J.: Positive inotropic effects of phenylephrine in the isolated rabbit papillary muscle mediated both by α-and β-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 284, 133–148 (1974)
Schümann, H. J., Endoh, M., Brodde, O.-E.: The time course of the effects of β- and α-adrenoceptor stimulation by isoprenaline and methoxamine on the contractile force and cAMP level of the isolated rabbit papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 289, 291–302 (1975)
Schwabe, U., Ebert, R.: Different effects of lipolytic hormones and phosphodiesterase inhibitors on cyclic 3′,5′-AMP levels in isolated fat cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 287–298 (1972)
Starke, K.: Alpha sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 18–45 (1972)
Starke, K., Montel, H., Gayk, W., Merker, R.: Comparison of the effects of clonidine on pre- and postsynaptic adrenoceptors in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 133–150 (1974)
Sutherland, E. W., Robinson, G. A., Butcher, R. W.: Some aspects of the biological role of adenosine 3′,5′-monophosphate (cyclic AMP). Circulation 37, 279–306 (1968)
Tsai, T. H., Langer, S. Z., Trendelenburg, U.: Effects of dopamine and α-methyl-dopamine on smooth muscle and on the cardiac pacemaker. J. Pharmacol. exp. Ther. 156, 310–324 (1967)
van Rossum, J. M.: Cumulative dose-response curve II: Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch. int. Pharmacodyn. 143, 299–330 (1963)
Wagner, J., Endoh, M., Reinhardt, D.: Stimulation by phenylephrine of adrenergic alpha- and beta-receptors in the isolated perfused rabbit heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 282, 307–310 (1974)
Watanabe, A. M., Besch, H. R., Jr.: Cyclic adenosine monophosphate modulation of slow calcium influx channels in guineapig hearts. Circulat. Res. 35, 316–324 (1974)
Wenzel, D. G., Su, J. L.: Interactions between sympathomimetic amines and blocking agents on the rat ventricle strips. Arch. int. Pharmacodyn. 160, 379–389 (1966)
Author information
Authors and Affiliations
Additional information
This work was supported by the Deutsche Forschungsgemeinschaft
Rights and permissions
About this article
Cite this article
Schümann, H.J., Motomura, S., Endoh, M. et al. Comparison of the mechanisms underlying the positive inotropic actions of dopamine, adrenaline and isoprenaline on the isolated rabbit papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 297, 257–267 (1977). https://doi.org/10.1007/BF00509270
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00509270