Analytical pharmacology and the elucidation of function

James Black believed that analysis of biological assays provides insights into the operation of physiological control systems. In this paper, we illustrate this point in three 'cardiovascular' assays. The first determined the half-life (t½) of 'endothelium-derived relaxing factor' (EDRF), using bradykinin to release EDRF, which produced concentration-related relaxations of a precontracted artery. With the introduction of time delays between the source of EDRF and the assay artery, there were rightward shifts in dose-response curves, which provided the basis of calculating t½. The second assay determined the roles of noradrenaline reuptake and prejunctional α(2)-adrenoceptor activity on transmitter concentration at sympathetic synapses with atria and resistance vessels. In the former, the reuptake role was paramount, whilst prejunctional receptor activity was dominant at vascular synapses, owing to anatomical differences. The third assay provided in vivo estimates of the enhancement of the total peripheral resistance responses to constrictor and dilator stimuli owing to the structural changes in hypertension. Major nonlinearities in the dose-response curve obscured this enhancement. Their effect was avoided by deriving extended dose-response curves from combined constrictor and dilator data, permitting calculation of the enhancement over the range between the nonlinearities.