AN INVITRO QUANTITATIVE-ANALYSIS OF THE ALPHA-ADRENOCEPTOR PARTIAL AGONIST ACTIVITY OF DOBUTAMINE AND ITS RELEVANCE TO INOTROPIC SELECTIVITY

  • 1 January 1981
    • journal article
    • research article
    • Vol. 216  (2) , 210-219
Abstract
In rat anococcygeus muscle, dobutamine [D3] produced concentration-related submaximal contractions which were antagonized competitively by phentolamine [PHEN] (pKB [pK for .beta.-receptors] = 8.3) and D antagonized norepinephrine[NE]-induced contractions in a competitive manner with an Kd for the .alpha.-adrenoceptor of 20 nM (pKB = 7.7). Therefore, D satisfied criteria for a partial agonist of .alpha.-adrenoceptors having an affinity for .alpha.-adrenoceptors 25 times that of NE (pKA [pK for .alpha.-receptor] = 6.3) in this tissue. An estimate of the relative efficacy of D showed 1/40 the efficacy of NE at the .alpha.-adrenoceptors. D contracted rabbit aorta and produced concentration-related relaxations at 1000 times greater concentrations after alkylation of .alpha.-adrenoceptors by phenoxybenzamine. In noncontracted canine saphenous vein, D had no visible agonist activity but did produce contractions after propranolol [PRO]. In partially contracted saphenous vein, D produced a small contraction which was converted to a PRO-sensitive relaxation of tone after PHEN. D was a full .beta.-adrenoceptor agonist in guinea-pig trachea under spontaneous tone but a partial agonist after strong contraction by bethanechol. This allowed measurement of the pKB of D at .beta.-adrenoceptors (pKB = 5.35) and estimation of efficacy at .beta.-adrenoceptors relative to isoproterenol [ISO] (eD/eISO = 1/20). No evidence for .beta.-adrenoceptor selectivity was found in studies of potency ratios and relative efficacy using ISO for comparison. D showed a slight (2-fold) selectivity for inotropy in vitro when compared to ISO in guinea-pig right and left atria. This selectivity was removed by PHEN suggesting a cardiac .alpha.-like adrenoceptor effect; this finding was confirmed in PRO-treated guinea-pig left atria. These results are discussed in terms of the in vivo effects of D and its use as a tool for classification of .beta.-adrenoceptors, particularly the putative presynaptic .beta.-adrenoceptor.