Abstract

The classification of beta adrenoceptor subtypes has apparently received substantial confirmation from the cardioselective properties of practolol, so-called beta₁ receptor blockade. This interpretation assumes that practolol has no relevant pharmacological properties other than beta receptor antagonism; the present report challenges that assumption. Practolol was studied to elucidate the reported alkylating properties of chloropractolol; although no evidence of alkylation was found, the results with chloropractolol are included as a check on the self-consistency of the pharmacological analyses done on rat isolated atria and coronary-perfused hearts. Practolol and chloropractolol had, respectively, 0.3 and 0.4 times the agonist activity of isoprenaline on atrial pacemaker frequency. Using the method of Barlow, Scott, and Stephenson [(1967) Br. J. Pharmacol., 31, 188-196], apparent equilibrium dissociation constants (pK_P) for these partial agonists were calculated to be 6.8 and 7.8, respectively. However, attempts to estimate the apparent pK_P values directly from Schild plots were frustrated by nonlinearity at low dose ratios. The anomalously low level of antagonism seen at low concentrations appeared to be due to concurrent sensitization of the tissue to isoprenaline, which, decaying more slowly than receptor blockade, became manifest after prolonged washing. The degree of sensitization, namely, a dose ratio of 0.5, was equal to that produced maximally by inhibition of extraneuronal uptake of isoprenaline, using 17β-estradiol, and/or inhibition of catechol O-methyltransferase, using U-0521. Neither practolol nor chloropractolol blocked extraneuronal accumulation of isoprenaline measured in perfused hearts, but both depressed the steady-state efflux of 3-methoxyisoprenaline, presumed to be due to catechol O-methyltransferase inhibition. Atria maximally sensitized by U-0521 treatment gave Schild plots for practolol and chloropractolol that were linear, had a slope of unity, and gave apparent pK_P values that agreed with values from studies of agonist activities and those calculated independently by a third method, that of Stephenson [(1956) Br. J. Pharmacol. Chemother., 11, 379-393]. These results are consistent with the predictions of Furchgott’s [(1972) in Handbuch der experimentellen Pharmakologie, Vol. 33, Catecholamines (Blaschko, H. & Muscholl, E., eds.), pp. 203-212, Springer, Berlin] mathematical model for stimultaneous blockade of receptors and agonist uptake, provided that the catechol O-methyltransferase in rat atria is inhibited at slightly lower concentrations than the beta receptors. The relevance of this finding, if any, to the cardioselective properties of practolol will now need to be examined.