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

By the sequential administration of alpha 1- and alpha 2-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. alpha 2-mediated responses predominate at low doses and alpha 1-mediated responses predominate at high doses. Pressor responses to sympathetic nerve stimulation have, similarly, an alpha 2 component at low frequencies and a dominant alpha 1-mediated response at high frequencies: a residual response is resistant to combined alpha 1- plus alpha 2-blockade. This alpha-blocker-resistant pressor nerve response was further analysed in the pithed rat and was found to be partly susceptible to alpha,beta-methylene ATP, which desensitizes purinergic responses. However, reserpine pretreatment produced a greater reduction of nerve-mediated pressor responses than did alpha-blockade, suggesting that part of the 'alpha-blocker resistant' response might be adrenergic. It is concluded that sympathetic vasopressor nerve transmission is mediated for the greater part by alpha 1- and alpha 2-adrenoceptors but that there is evidence for contributions from non-alpha-adrenergic and 'purinergic' elements. An even greater proportion of the responses to circulating catecholamines is attributable to the alpha-receptors with a relatively small but significant 'resistant' component.