Extended concentration-response curves used to reflect full agonist efficacies and receptor occupancy-response...

1. An approach is described for generating extended agonist concentration-response curves where the responses are unconstrained by the normal tissue maximum response. Functional antagonism is employed to hold the tissue state in the range where any change in stimulus can be translated into a measurable response. 2. The maximum response of these extended concentration-response curves provides an index of intrinsic activity reflecting the agonist efficacy and the receptor occupancy-response coupling range. 3. The use of this approach is illustrated with extended concentration-response curves for noradrenaline (NA), vasopressin, acetylcholine (ACh), and 5-methylfurmethide in the small mesenteric and tail arteries of the rat. Both NA and vasopressin can maximally activate the arteries, but the new protocol shows that NA can produce more cellular activation than vasopressin in the tail artery. Both ACh and 5-methylfurmethide are full agonists but ACh has a higher intrinsic activity than 5-methylfurmethide. The ACh muscarinic receptors in the mesenteric artery have a larger occupancy-response range than the ACh muscarinic-receptors in the tail artery, and the alpha-adrenoceptors in the tail artery appear to have a larger occupancy-response coupling range than those in the mesenteric artery. 4. This approach extends our ability to compare the efficacies of full agonists, and to compare the occupancy-response coupling ranges of receptors that can normally maximally activate the assay tissue. This is achieved without the use of an irreversible antagonist and should be applicable to many receptors and pharmacological assay systems where responses are stable and functional antagonists are available.