DIFFERENTIAL ATTENUATION OF THE RESPONSES TO ADENOSINE AND METHOXAMINE IN ISOLATED RABBIT AORTA

This article describes the functional antagonism between the responses to adenosine (through adenosine A2 receptors) and methoxamine (throug h alpha-1 adrenoceptors) in the adventitia- and endothelium-denuded is olated rabbit thoracic aorta. Rings were contracted with different con centrations of methoxamine and cumulative relaxation concentration-res ponse curves (CRC) to adenosine were constructed. This protocol allowe d the authors to rearrange the same data, which yielded contractile CR Cs to methoxamine in the presence of adenosine. A 32-fold increase in the [methoxamine] markedly attenuated the maximal response to adenosin e (80% decrease) and shifted the CRC to adenosine 10-fold to the right . By contrast, a 3000-fold increase in the [adenosine] shifted the CRC to methoxamine 3.25-fold to the right and attenuated the maximal resp onse by a modest 18%. Analysis of these data by the operational model of agonism indicated that the efficacy parameter, tau, for adenosine o r methoxamine was reduced by 99% or 71%, respectively, under these con ditions. The agonist dissociation constant, K(A), for adenosine (80 mu M) or methoxamine (33 muM) by functional antagonism was also estimated . Use of an irreversible alpha-1 adrenoceptor antagonist allowed for t he estimation of the K(A) for methoxamine by the receptor inactivation method using the operational model (40 muM), the Furchgott equation ( 48 muM) and the nested equations (42 muM) described by James et al. Th ese results suggest that this tissue preparation is a good model to st udy functional antagonism quantitatively and that the functional antag onism between the responses mediated by these two receptors allows for the reliable estimation of the agonist dissociation constant for alph a-1 adrenoceptor agonists.