Richard Lanzara
Bio Balance Inc., 30 West 86th Street, New York, New York, USA
ABSTRACT
This study was designed to test a receptor model and a method to optimize agonist/antagonist combinations calculated to prevent receptor desensitization, which has relevance for many important drugs, including the β1-adrenergic agonist drugs. Because desensitization is a serious side effect, the β1-adrenergic agonist drugs are no longer the logical treatment for heart failure and have been replaced by antagonist drugs represented by metoprolol (Lopressor). Although the scientific rationale for this remains unclear and because the agonist and antagonist drugs may be administered together in some medical circumstances, it is important to understand the early interactions of β-agonist drugs with the β-antagonist drugs at the level of the initial receptor response. Isoproterenol (Iso) or dobutamine (Dob) were given as intravenous solutions to rats with or without the β1-antagonist, metoprolol (Met), which was given either as a fixed amount or as part of an agonist/antagonist combination. The Iso and Dob solutions alone demonstrated rapid desensitization, whereas the optimal Iso/Met and Dob/Met agonist/antagonist combinations significantly prevented desensitization while maintaining near maximal responses in all of the animals tested. The theory behind the model predicted these responses and fit the experimental data with reasonable biophysical parameters. This study supports the concept that the earliest events of receptor desensitization can be modeled and controlled at the level of the initial receptor response and also suggests that the beneficial effects of metoprolol for heart failure may result from its action on the earliest events of receptor activation.
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How to cite this article
Richard Lanzara, 2005. Optimal Agonist/Antagonist Combinations Maintain Receptor Response by Preventing
Rapid β1-adrenergic Receptor Desensitization. International Journal of Pharmacology, 1: 122-131.
DOI: 10.3923/ijp.2005.122.131
URL: https://scialert.net/abstract/?doi=ijp.2005.122.131
DOI: 10.3923/ijp.2005.122.131
URL: https://scialert.net/abstract/?doi=ijp.2005.122.131
REFERENCES
- Bianchi, M.T., K.F. Haas and R.L. MacDonald, 2001. Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAA receptors. J. Neurosci., 21: 1127-1136.
Direct Link - Sullivan-Hanley, N.R. and J.G. Hensler, 2002. Mechanisms of ligand-induced desensitization of the 5-hydroxytryptamine2A receptor. J. Pharmacol. Exp. Ther., 300: 468-477.
Direct Link - Bender, K., M. Wellner-Kienitz, A. Inanobe, T. Meyer, Y. Kurachi and L. Pott, 2001. Overexpression of monomeric and multimeric GIRK4 subunits in rat atrial myocytes removes fast desensitization and reduces inward rectification of muscarinic K1 current (IK(ACh)) evidence for functional homomeric GIRK4 channels. J. Biol. Chem., 276: 28873-28880.
PubMed - Brouria, F., L. Findjia, O. Mediania, N. Mougenota and N. Hanounb et al., 2002. Toxic cardiac effects of catecholamines: Role of β-adrenoceptor downregulation. Eur. J. Pharmacol., 456: 69-75.
CrossRefDirect Link - Pao, C.S. and J.L. Benovic, 2002. Phosphorylation-independent desensitization of G protein-coupled receptors? Sci. STKE, 2002: pe42-pe42.
CrossRefDirect Link