Theoretical and practical problems with the assessment of intrinsic efficacy of agonists: efficacy of reputed beta-1 selective adrenoceptor agonists for beta-2 adrenoceptors.
Agonist effects of the reputedly beta-1 selective adrenoceptor agonists prenalterol, dobutamine and tazolol were compared, in rat uterus, with those of the reportedly beta-2 selective agonist, terbutaline. Butoxamine was a simple competitive antagonist of responses to all agonists with a 10 to 16 times greater potency in rat uterus than in guinea-pig left atria. Similarly, atenolol was 50 to 80 times less potent as an antagonist of all agonists in rat uterus than guinea-pig left atria. The Schild regressions for both antagonists, when subjected to analyses of covariance of regression lines, yielded no evidence to suggest that the reputedly beta-1 selective agonists activated receptors different from those activated by terbutaline in rat uterus. These data indicated that the responses produced by these agonists in rat uterus were due to stimulation of beta-2 adrenoceptors under current classifications. An analysis of the relative intrinsic efficacy of prenalterol on beta-2 as opposed to beta-1 adrenoceptors indicated a nonselective efficacy at the receptor level. The implications of these data in terms of tissue-related efficacy (i.e., intrinsic activity) and receptor-related intrinsic efficacy (as defined by Furchgott) are discussed as a caveat to ascribing tissue selectivity to receptor selectivity without the appropriate data. Specifically, estimates of selective agonist efficacy at receptors should be made on the basis of selective intrinsic efficacy and not on measurements of agonists potency or maximal responses.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D016275:Atrial Function; D004280:Dobutamine / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D007700:Kinetics; D008297:Male; D011217:Practolol / Q000031:analogs & derivatives / Q000494:pharmacology; D011294:Prenalterol; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D013726:Terbutaline / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D001262:Atenolol; C002268:tazolol; D011294:Prenalterol; D013726:Terbutaline; D011217:Practolol