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Vol. 60, Issue 4, 712-717, October 2001
1-Adrenergic
Receptor in 1-Receptor Transgenic Mice
Institut für Pharmakologie, Universität Würzburg,
Würzburg, Germany
We tested the hypothesis that the human 
1-adrenergic
receptor displays constitutive activity and that -adrenergic
antagonists differ in their ability to modulate this constitutive
activity. Transfection of the cDNAs of the human 1- and
2-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 2- than for the 1-subtype. As a model
for enhanced -adrenergic signaling at the whole-organ level, we used
transgenic mice with heart-specific overexpression of the human
1-adrenergic receptor. In this model, the
1-adrenergic receptor displayed constitutive activity as evidenced by a higher spontaneous beating rate of isolated right atria
from 1-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 -adrenergic antagonists currently in clinical use for the treatment of heart failure differ in their ability to modulate constitutive activity of the cardiac 1-adrenergic receptor. The
1-selective antagonists metoprolol and bisoprolol showed
significant inverse agonist activity at the 1-adrenergic
receptor. Carvedilol behaved as a neutral antagonist and xamoterol
displayed marked partial agonist activity. We conclude that the human
1-adrenergic receptor displays constitutive activity
that is considerably lower than that of the 2-subtype.
-Adrenergic antagonists currently in clinical use differ in their
ability to exert inverse agonist activity at the human
1-adrenergic receptor, which may contribute to their
therapeutic effects.
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