Characterization of the beta 1-adrenoceptor stimulatory effects of the partial beta 1-agonists acebutolol, xamoterol, H142/08 and H201/70.

Abstract

The beta 1-adrenoceptor stimulatory effects of the partial beta 1-agonists acebutolol, xamoterol, H142/08 and H201/70 were investigated in the isolated right atrium (frequency response) of the rat. All the partial agonists studied induced a concentration-dependent increase in atrial rate. This effect was antagonized by the beta 1-selective blocker pafenolol. The concentrations of H142/08 and H201/70 needed to produce a half maximal response (-log EC50: pD2) were significantly greater than those required to occupy half the receptor population (-log equilibrium dissociation constant: pKB). These compounds required a fractional receptor occupancy of 80-90% to produce half the maximal stimulatory effect while the corresponding receptor occupancy for the other partial agonists studied was about 20%. The maximal stimulatory effect (intrinsic activity) generated by the compounds in the right atrium was (mean +/- S.D.): xamoterol 60 +/- 11%, H142/08 30 +/- 9%, H201/70 18 +/- 3% and acebutolol 17 +/- 8%. In addition, the stimulatory potency of the partial agonists was calculated as the efficacy (e) of the compounds relative to that of isoprenaline. The relative efficacy, expressed as -log[e(partial agonist/e(isoprenaline)] was: xamoterol 2.2 +/- 0.4, acebutolol 3.0 +/- 0.2, H142/08 3.4 +/- 0.2 and H201/70 3.6 +/- 0.2. It is concluded that partial beta 1-agonists have different relationships between their stimulatory effect and fractional receptor occupancy. There was a poor correlation between the intrinsic activity and relative efficacy of partial beta 1-agonists in the right atrium.