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Characterization of the adrenergic activity of arbutamine, a novel agent for pharmacological stress testing

  • Experimental Pharmacology
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Summary

In this study, we characterized the interactions of arbutamine, a novel catecholamine developed for use as a cardiac stress testing agent, with different adrenergic receptor subtypes in vitro. These effects were compared with those of isoproterenol. In the electrically stimulated left atria of rats, arbutamine increased contractile force. The pD2 values (-log of the dose that produces 50% of the maximal responses) for arbutamine and isoproterenol were 8.45±0.15 and 8.55±0.02, respectively. Metoprolol shifted the concentration-effect curves for both isoproterenol and arbutamine to the right with a pA2 value (-log of the dose of the antagonist that reduces the maximal responses of an agonist to 50%) of 7.22–7.5. Both arbutamine and isoproterenol increased the rate of spontaneously beating rat right atria with pD2 values of 9.0±0.19 and 8.82±0.18, respectively. The affinity constants (KA) of arbutamine and isoproterenol for cardiac beta1-adrenergic receptors, as determined by competition binding assays, were found to be 7.32 and 6.04, respectively. In guinea pig trachea, arbutamine and isoproterenol produced a concentration-dependent relaxation that was blocked by propranolol. Their pD2 values were 7.9±0.1 and 8.2±0.1, respectively. Arbutamine contracted isolated rat aortic rings with a maximal increase of 38.1±6.7% that of 10 μM of norepinephrine. In rat white adipocytes, arbutamine, isoproterenol, and BRL-37344 stimulated glycerol release, with the order of potency being BRL-37344 > arbutamine > isoproterenol. In hamster brown adipocytes, the order was arbutamine > isoproterenol > BRL-37344. Moreover, arbutamine stimulated beta3-adrenergic receptors in guinea pig ileum. In conclusion, arbutamine is a novel catecholamine with similar potency and efficacy to that of isoproterenol. It stimulates cardiac beta1-, tracheal beta2-, and adiopocyte beta3-adrenergic receptors. Arbutamine does not stimulate alpha-adrenergic receptors at concentrations that wer high enough to maximally activate the beta-adrenergic receptors.

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References

  1. McLaughlin PR, Martin RP, Doherty P, et al. Reproducibility of thallium-201 in myocardial imaging. Circulation 1977; 55:497–503.

    PubMed  CAS  Google Scholar 

  2. Fung AY, Gallagher KP, Buda AJ. The physiologic basis of dobutamine as compared with dipyridamole stress interventions in the assessment of critical coronary stenosis. Circulation 1987;76:943–951.

    PubMed  CAS  Google Scholar 

  3. Nagarajan R, Parthasrathy V, Makilzhan S, Balasubramanian V. Isoproterenol infusion—An alternative to exercise testing. Indian Heart J 1989;41;99–104.

    PubMed  CAS  Google Scholar 

  4. Lockett M. Dangerous effects of isoprenaline in myocardial failure. Lancet 1965;2:104–106.

    Article  Google Scholar 

  5. Johnson GL, Ehrrich SJ, El-Hage AN, Balazs T. Effects of antiarrhythmic agents on isoproterenol induced ventricular fibrillation in heavy rats: A possible model of sudden cardiac death. Res Commun Chem Pathol Pharmacol 1986;51: 351–364.

    PubMed  CAS  Google Scholar 

  6. Tuttle RR, Mills J. Development of a new catecholamine to selectively increase cardiac contractility. Circ Res 1975;36: 185–196.

    PubMed  CAS  Google Scholar 

  7. Abou-Mohamed G, Caldwell RW, Ibrahim TM, Tuttle RR. Integrative cardiovascular actions of a novel catecholamine, GP-2–128. J Cardiovasc Pharmacol 1994;23:485–491.

    Article  PubMed  CAS  Google Scholar 

  8. Tuttle RR, Hilman R, Wiesner J, et al. Closed-loop delivery and monitoring a catecholamine, arbutamine, for pharmacological stress testing: Preclinical evaluation (abstr). Pharmacologist 1991;33:177.

    Google Scholar 

  9. Nagarajan R, Abou-Mohamed G, Meyers T, Caldwell RW. A novel catecholamine, (arbutamine) for a pharmacological cardiac stress agent. Cardiovasc Drug Ther 1996;10: 31–38.

    Article  CAS  Google Scholar 

  10. Young M, Pan W, Wiesner J, et al. Characterization of arbutamine: A novel catecholamine stress agent for diagnosis of coronary artery disease. Drug Dev Res 1994;32:19–28.

    Article  CAS  Google Scholar 

  11. Van Rossum JM. Cumulative dose response curves: II-Technique for dose response curve in isolated organs and evaluation of drug parameters. Arch Int Pharmacodyn Ther 1965;143:299–330.

    Google Scholar 

  12. Abou-Mohamed G, Caldwell RW, Carrier GO, Elmazar MM, Tuttle RR. Interaction of a novel catecholamine, GP-128, with adrenergic receptors. J Cardiovasc Pharmacol 1994;23:492–500.

    Article  PubMed  CAS  Google Scholar 

  13. Dooley DJ, Bitiges H, Regmann NC. GGP-20712 A: A useful tool for quantitating β1 − and β2 −adrenergic receptors. Eur J Pharmacol 1986;130:137–139.

    Article  PubMed  CAS  Google Scholar 

  14. Nedrergaard J, Lindberg O. The brown fat cell. Int Rev Cytol 1982;74:186–286.

    Google Scholar 

  15. Lambert M, Neisch AC. Rapid method for estimation of glycerol in fermentation solutions. Can J Res 1950;28: 83–89.

    Google Scholar 

  16. Arunlakashana O, Schild RD. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 1959;14: 48–58.

    Google Scholar 

  17. Furchgott RF, Bursztyn P. Comparison of dissociation constants and relative efficacies of selected agonists acting on parasympathetic receptors. NY Acad Sci 1967;139:882–899.

    Article  Google Scholar 

  18. Cheng YC, Prusoff WH. Relationship between inhibition constant (ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 1973;22:3099–3108.

    Article  PubMed  CAS  Google Scholar 

  19. Winer BJ. Statistical Principles in Experimental Design, 2nd ed. New York: McGraw-Hill, 1971, pp 152–176, 11–196.

    Google Scholar 

  20. Previtali M, Lanzarini L, Ferrario M, Tortorici M, Mussini A, Montemartini C. Dobutamine versus dipyridamole echocardiography in coronary artery disease. Circulation, 1991; 83(Suppl III):27–31.

    Google Scholar 

  21. Minneman KP, Hegstr LR, Molinoff PB. Simultaneous determination of beta1 and beta2 adrenergic receptors in tissues containing both receptor subtypes. Mol Pharmacol 1979;16:34–36.

    PubMed  CAS  Google Scholar 

  22. Brodde OE. β Adrenoceptors. In: Williams M, Glennon RA, Timmermans PB, eds. Receptor Pharmacology and Function. New York: Marcel Dekker, 1989, pp 207–255.

    Google Scholar 

  23. Brodde OE. 47–1 and 47–2 in the human heart: Properties function and alteration in chronic heart failure. J Pharmacol Rev 1991;43:203–342.

    CAS  Google Scholar 

  24. Benfey BG. Function of myocardial α-adrenoceptors. Life Sci 1990;46:743–757.

    Article  PubMed  CAS  Google Scholar 

  25. Arch JRS, Ainsworth AT, Cawthorne MA. Atypical β-receptor on brown adipocytes as target for anti-obesity drugs. Nature 1984;309:163–165.

    Article  PubMed  CAS  Google Scholar 

  26. Walter M, Lemoine H, Kaumann AJ. Stimulant and blocking effects of optical isomers of pindolol on the sinoatrial node and trachea of guinea pig. Role of beta-adrenoceptor subtypes in the dissociation between blockade and stimulation. Naunyn-Schmiedebergs Arch Pharmacol 1984;327:159–175.

    Article  PubMed  CAS  Google Scholar 

  27. Wilson C, Wilson S, Piercy V, Sennitt MV, Arch RSJ. The rat lipolytic β-adrenergic receptors: Studies using novel β-adrenoceptor agonist. Eur J Pharmacol 1984;100:309–319.

    Article  PubMed  CAS  Google Scholar 

  28. Shen Y, Zhang H, Vatner SF. Peripheral vascular effects of beta-3 adrenergic receptor stimulation in conscious dogs. J Pharmacol Exp Ther 1994;268:466–473.

    PubMed  CAS  Google Scholar 

  29. Rand MJ, Tunge LH, Louis WJ, Story D. Cardiac α-adrenoceptors: Postjunctional and prejunctional. J Mol Cell Cardiol 1986;18(Suppl 5):17–32.

    Article  PubMed  CAS  Google Scholar 

  30. Schumann HJ, Wagner J, Knorr A, Reidemeister JC, Sadony V, Sachramm G. Demonstration in human atrial preparations of alpha adrenoceptors mediating positive inotropic effects. Naunyn-Schmiedebergs Arch Pharmacol 1978;302: 333–336.

    Article  PubMed  CAS  Google Scholar 

  31. Wagner J, Brodde OE. On the presence and distribution of alpha adrenoceptor in the heart of various mammalian species. Naunyn-Schmiedebergs Arch Pharmacol 1978;302: 239–254.

    Article  PubMed  CAS  Google Scholar 

  32. Ruffolo RRJr, Morgan EL. Interaction of the novel inotropic agent, ASL-7022, with α- and β-adrenoceptors in the cardiovascular system of the pithed rat: Comparison with dobutamine and dopamine. J Pharmacol Exp Ther 1984; 229:364–371.

    PubMed  CAS  Google Scholar 

  33. Bolter CP, Ledsome JR. Inotropic and chronotropic responses of the in vivo denervated dog myocardium to dobutamine. Can J Physiol Pharmacol 1976;54:618–621.

    PubMed  CAS  Google Scholar 

  34. Vatner SF, McRitchie RJ, Braunwald E. Effects of dobutamine on the left ventricular performance, coronary dynamics and distribution of cardiac output in conscious dogs. J Clin Invest 1974;53:1265–1273.

    Article  PubMed  CAS  Google Scholar 

  35. Sakanashi M, Tomamatsu E, Takeo S, et al. Effect of dobutamine on coronary circulation and cardiac metabolism of the dog. Drug Res 1978;28:798–801.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia

    Gamal Abou-Mohamed, Ravi Nagarajan & Robert W. Caldwell

  2. School of Pharmacy, Mansoura University Mansoura, Egypt

    Tarek M. Ibrahim

Authors
  1. Gamal Abou-Mohamed
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  2. Ravi Nagarajan
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  3. Tarek M. Ibrahim
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  4. Robert W. Caldwell
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Abou-Mohamed, G., Nagarajan, R., Ibrahim, T.M. et al. Characterization of the adrenergic activity of arbutamine, a novel agent for pharmacological stress testing. Cardiovasc Drug Ther 10, 39–47 (1996). https://doi.org/10.1007/BF00051129

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  • DOI: https://doi.org/10.1007/BF00051129

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