Abstract

We tested the hypothesis that the human β₁-adrenergic receptor displays constitutive activity and that β-adrenergic antagonists differ in their ability to modulate this constitutive activity. Transfection of the cDNAs of the human β₁- and β₂-adrenergic receptors into COS-7 cells caused increases in basal cAMP that were proportional to the receptor levels, thus demonstrating constitutive activity for both subtypes. At comparable receptor levels, the increase in basal cAMP was about 5-fold higher for the β₂- than for the β₁-subtype. As a model for enhanced β-adrenergic signaling at the whole-organ level, we used transgenic mice with heart-specific overexpression of the human β₁-adrenergic receptor. In this model, the β₁-adrenergic receptor displayed constitutive activity as evidenced by a higher spontaneous beating rate of isolated right atria from β₁-transgenic versus wild-type mice. This difference was abolished by the addition of CGP20712A, demonstrating inverse agonist properties of this compound. We then tested whether various β-adrenergic antagonists currently in clinical use for the treatment of heart failure differ in their ability to modulate constitutive activity of the cardiac β₁-adrenergic receptor. The β₁-selective antagonists metoprolol and bisoprolol showed significant inverse agonist activity at the β₁-adrenergic receptor. Carvedilol behaved as a neutral antagonist and xamoterol displayed marked partial agonist activity. We conclude that the human β₁-adrenergic receptor displays constitutive activity that is considerably lower than that of the β₂-subtype. β-Adrenergic antagonists currently in clinical use differ in their ability to exert inverse agonist activity at the human β₁-adrenergic receptor, which may contribute to their therapeutic effects.