Desensitization is a serious side effect of many drugs. It is also a fundamental problem for modeling drug-receptor interactions. 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 b1-adrenergic agonist drugs. Because desensitization is a serious side effect, the beta1-adrenergic agonist drugs are no longer the logical treatment for heart failure and have been replaced by antagonist drugs represented by metoprolol (Lopressor).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 beta-agonist drugs with the beta-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 beta1-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 desensitizaton, 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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