Summary
The effect of 3′,4′-dihydroxy-α-methylpropiophenone (U-0521) on the rate of spontaneously contracting cultured rat heart cells and right atria of rats and kittens was investigated. The action of U-0521 on the cellular content of cyclic AMP and on the adenylyl cyclase of heart membrane particles was also studied.
-
1.
U-0521 caused positive chronotropic effects on single cultured heart cells and right atria of the rat. U-0521 was about 105 times less potent than (-)-isoprenaline. The maximum effect of U-0521 was smaller than the maximum effect of (-)-isoprenaline. A small positive chronotropic effect of U-0521 was also observed on kitten atria.
-
2.
The β-adrenoceptor blocker (-)-bupranolol antagonized the positive chronotropic effects of U-0521 to the same extent as the effects of (-)-isoprenaline on single cells and atria of the rat. The effects of both U-0521 and (-)-isoprenaline appear therefore mediated through the same β-adrenoceptors. The positive chronotropic effects of U-0521 on kitten atria were also blocked by (-)-bupranolol.
-
3.
Up to 0.1 mM U-0521 did not block the effects of (-)-isoprenaline on rat atria, not even in the presence of corticosterone or hydrocortisone.
-
4.
1 min incubations with equieffective (increase in cellular beating rate) concentrations of U-0521 (0.1 mM) and (-)-isoprenaline (1 nM) caused a significant increase in the cellular content of cAMP; this effect of both drugs was antagonized by 10 nM (-)-bupranolol.
-
5.
0.1–3.3 mM U-0521 did not stimulate the adenylyl cyclase of cell-free membrane particles of kitten ventricles. The cyclase was depressed by 10 mM U-0521. 3.3 mM U-0521 caused a 20% decrease of the maximum cyclase-stimulating effect of (-)-isoprenaline and a 1.6-fold increase of its apparent K m.
-
6.
The results with U-0521 suggest that β-adrenoceptors can be activated by agonists devoid of nitrogen. However, the affinity of U-0521 for the β-adrenoceptor is very low (KU-0521 ≈ 5.5 mM). The concentration of U-0521 (0.1 mM) causing maximal increases in beating rate of cultured cells probably occupies less than 7% of the available β-adrenoceptors.
Similar content being viewed by others
References
Ariëns, E. J.: Molecular pharmacology, Vol. 1. New York: Academic Press 1964
Arunlakshana, O., Schild, H. O.: Some quantitative uses of drug antagonists. Brit. J. Pharmacol. 14, 48–58 (1959)
Blinks, J. R.: Positive chronotropic effect of increasing right atrial pressure in the isolated mammalian heart. Amer. J. Physiol. 186, 299–303 (1956)
Blinks, J. R.: Influence of β-hydroxyl group on the inotropic and chronotropic activities of catecholamines. Pharmacologist 6, 176 (1964)
Blinks, J. R.: Convenient apparatus for recording of isolated heart muscle. J. appl. Physiol. 20, 755–757 (1965)
Boder, G. B., Johnson, I. S.: Comparative effects of some cardioactive agents on automaticity of cultured heart cells. J. Mol. Cell. Cardiol. 4, 453–463 (1972)
Bönisch, H., Uhlig, W., Trendelenburg, U.: Analysis of the compartment involved in the extraneuronal storage and metabolism of isoprenaline in the perfused heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 283, 223–244 (1974)
Brown, B. L., Albano, J. D. M., Ekins, R. P., Scherzi, A. M.: A simple and sensitive saturation assay method for the measurement of adenosine 3′,5′-cyclic monophosphate. Biochem. J. 121, 561–562 (1971)
Giles, R. E., Miller, J. W.: A comparison of certain properties of catechol-O-methyltransferase to those of adrenergic beta receptors. J. Pharmacol. exp. Ther. 156, 201–206 (1967a)
Giles, R. E., Miller, J. W.: Studies on the potentiation of the inotropic actions of certain catecholamines by U-0521 (3′,4′-dihydroxy-α-methyl-propiophenone). J. Pharmacol. exp. Ther. 157, 55–61 (1967b)
Gilman, A. G.: A protein binding assay for adenosine 3′,5′-cyclic monophosphate. Proc. nat. Acad. Sci. (Wash.) 67, 305–312 (1970)
Iversen, L. L., Salt, P. J.: Inhibition of catecholamine uptake by steroids in the isolated rat heart. Brit. J. Pharmacol. 40, 528–530 (1970)
Kaumann, A. J.: Adrenergic receptors in heart muscle: Relations among factors influencing the sensitivity of the cat papillary muscle to catecholamines. J. Pharmacol. exp. Ther. 173, 383–398 (1970)
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.: Adrenergic receptors of cardiac muscle. Two different mechanisms of β-blockers as partial agonists. Internat. Union of Biochemistry, Symposium No. 52, Acta physiol. lat.-amer. 23, 235–236 (1973)
Kaumann, A. J., Birnbaumer, L.: Adrenergic receptors in heart muscle; similarity of apparent affinities of β-blockers for receptors mediating adenyl cyclase activity, inotropic and chronotropic effects of catecholamines. Acta physiol. lat.-amer. 23, 619–620 (1973)
Kaumann, A. J., Birnbaumer, L.: Prostaglandin E1 action on sinus pacemaker and adenylyl cyclase in kitten myocardium. Nature (Lond.) 251, 515–517 (1974a)
Kaumann, A. J., Birnbaumer, L.: Characteristics of the adrenergic receptor coupled to myocardial adenylyl cyclase. Stereospecificity and determination of apparent affinity constants for β-blockers. J. biol. Chem. 249, 7874–7885 (1974b)
Kaumann, A. J., Wittmann, R.: Apparent equilibrium constant between β-adrenoceptors and a competitive antagonist on a cultured pacemaker cell of mammalian heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, 23–32 (1975)
Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J.: Protein measurements with the Folin phenol reagent. J. biol. Chem. 193, 265–275 (1951)
Salomon, Y., Londons, C., Rodbell, M.: A highly sensitive adenylate cyclase assay. Analyt. Biochem. 58, 541–548 (1974)
Trendelenburg, U., Höhn, D., Graefe, K. H., Pluchino, S.: The influence of block of catechol-O-methyl transferase on the sensitivity of isolated organs to catecholamines. Naunyn-Schmiedebergs Arch. Pharmak. 271, 59–92 (1971)
Wollenberger, A.: Rhythmic and arrhythmic contractile activity of single myocardial cells cultured in vitro. Circulat. Res. (Suppl. 2) 15, 184–201 (1964)
Wöppel, W., Trendelenburg, U.: Temperature-dependent supersensitivity of isolated atria to catecholamines. Europ. J. Pharmacol. 23, 302–305 (1973)
Author information
Authors and Affiliations
Additional information
This work was supported by grants of the Deutsche Forschungsgemeinschaft “SFB 30 Cardiologie” and “Biochemie der Morphogenese”, and by grant HD-06513 from the National Institutes of Health
Part of this work was done while L.B. and A.J.K. were visiting scientists at the Mayo Clinic
Rights and permissions
About this article
Cite this article
Kaumann, A.J., Wittmann, R., Birnbaumer, L. et al. Activation of myocardial β-adrenoceptors by the nitrogen-free low affinity ligand 3′,4′-dihydroxy-α-methylpropiophenone (U-0521). Naunyn-Schmiedeberg's Arch. Pharmacol. 296, 217–228 (1977). https://doi.org/10.1007/BF00498688
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00498688