Do low‐affinity states of β‐adrenoceptors have roles in physiology and medicine?

The pharmacology once ascribed to the 'beta4-adrenoceptor' is now believed to be that of a low-affinity state of the beta1-adrenoceptor. The beta2-adrenoceptor may also have a low-affinity state or site, while the beta3-adrenoceptor--the original low-affinity beta-adrenoceptor--can display more than one pharmacology. In this issue, Mallem et al. show that CGP-12177 relaxes thoracic aorta rings from normal rats by stimulating vascular smooth muscle low-affinity beta1-adrenoceptors, apparently linked in part to Gi protein. By contrast, in rings from hypertensive rats, CGP-12177 acts mainly via endothelial beta3-adrenoceptors. This work raises the possibility that low-affinity states of beta-adrenoceptors have physiological roles, and suggests that they might be drug targets.