Attempts to uncover subtypes of α-adrenoceptors and associated mechanisms by using sequential administration of blocking drugs

1. By the sequential administration of α1- and α2-blockers it can be shown, in the pithed rabbit, that the dose/pressor response curve to noradrenaline consists of two separate curves, one for each receptor. α2-mediated responses predominate at low doses and α1-mediated responses predominate at high doses. Pressor responses to sympathetic nerve stimulation have, similarly, an α2 component at low frequencies and a dominant α1-mediated response at high frequencies: a residual response is resistant to combined α1- plus α2-blockade. 2. This α-blocker-resistant pressor nerve response was further analysed in the pithed rat and was found to be partly susceptible to α,β-methylene ATP, which densitizes purinergic responses. However, reserpine pretreatment produced a greater reduction of nerve-mediated pressor responses than did α-blockade, suggesting that part of the ‘α-blocker resistant’ response might be adrenergic. 3. It is concluded that sympathetic vasopressor nerve transmission is mediated for the greater part by α1- and α2-adrenoceptors but that there is evidence for contributions from non-α-adrenergic and ‘purinergic’ elements. An even greater proportion of the responses to circulating catecholamines is attributable to the α-receptors with a relatively small but significant ‘resistant’ component.