Selectivity of Dobutamine for Adrenergic Receptor Subtypes: <i>IN VITRO ANALYSIS BY RADIOLIGAND BINDING</i>

R. Sanders Williams; Timothy Bishop

doi:10.1172/JCI110208

Selectivity of Dobutamine for Adrenergic Receptor Subtypes: IN VITRO ANALYSIS BY RADIOLIGAND BINDING

Published June 1, 1981 - More info

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Abstract

The cardiovascular responses elicited by dobutamine are distinctly different from those produced by other adrenergic or dopaminergic agonists. To test the hypothesis that dobutamine could have differential affinities for adrenergic receptor subtypes, and that such subtype selectivity could be related to its relatively unique pharmacologic properties, we assessed the ability of dobutamine to displace adrenergic radioligands from membrane receptors in a number of tissues of previously characterized adrenergic receptor subtype. For beta adrenergic receptors identified by (−) [³H]dihydroalprenolol (DHA), dobutamine had significantly greater affinity for the β₁ subtype (K_D = 2.5 μM in rat heart and 2.6 μM in turkey erythrocyte) than for the β₂ subtype (K_D = 14.8 μM in frog heart and 25.4 μM in rat lung) (P < 0.001). For alpha adrenergic receptors, dobutamine had markedly greater affinity for the α₁-subtype identified by [³H]prazosin (K_D = 0.09 μM in rat heart and 0.14 μM in rabbit uterus) than for the α₂-subtype identified by [³H]dihydroergocryptine (DHE) (K_D = 9.3 μM in human platelet) or by [³H]yohimbine (K_D = 5.7 μM in rabbit uterus) (P < 0.001).

Like other β₁-agonists, in the absence of guanine nucleotide, dobutamine competition curves for DHA binding in rat heart demonstrated two classes of binding sites, with one site of significantly higher affinity (K_D = 0.5 μM, P = 0.008) than the single class of binding sites (K_D = 5.2 μM) identified in the presence of guanine nucleotide. However, unlike β₂- or α₂-agonists, dobutamine displacement of DHA binding in rat lung or of DHE binding in human platelets demonstrated only a single class of binding sites, and guanine nucleotide had only minimal effects.

We conclude that dobutamine is selective for β₁ as opposed to β₂, and for α₁ as opposed to α₂ adrenergic receptors. Furthermore, guanine nucleotide effects on dobutamine binding, and biochemical response data in vitro suggest that dobutamine is a β₁-agonist, but has little intrinsic activity at β₂ and α₂-receptors. This selectivity for adrenergic receptor subtypes may be part of the basis for dobutamine's distinctive pharmacologic properties in vivo.