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a serious side effect, the β1-adrenergic agonist drugs are no longer the logical treatment for heart failure and have been replaced by antagonist drugs represented by metoprolol (Lopressor).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.