Stimulant and blocking effects of optical isomers of pindolol on the sinoatrial node and trachea of guinea pig. Role of ?-adrenoceptor subtypes in the dissociation between blockade and stimulation

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Abstract
The blocking and stimulant potencies of (−)-pindolol and (+)-pindolol were estimated on right atria and tracheae of guinea pig. Blocking affinities were estimated for β-adrenoceptor subtypes by using several agonists. Binding affinities of (−)-pindolol and (+)-pindolol were also estimated for β-adrenoceptors labelled with 3H-(−)-bupranolol in membranes of ventricular myocardium and lung of guinea pig. Both (−)-pindolol and (+)-pindolol caused tracheal relaxation with intrinsic activities of 0.3. The concentration-effect curve for (−)-pindolol exhibits a high-sensitivity and a low-sensitivity relaxant component; the curve for (+)-pindolol was nearly monophasic. The EC50's were (−log mol/l) 9.2 and 6.1 for (−)-pindolol and 7.6 for (+)-pindolol. Using subtype-selective blockers it was found that the relaxant effects of (+)-pindolol and those of the high-sensitivity component of (−)-pindolol are mediated through β 2-adrenoceptors. The low-sensitivity component of relaxation of (−)-pindolol was antagonized by β-blockers less than expected from their affinities for β-adrenoceptors. Both (−)-pindolol and (+)-pindolol caused an increase of atrial beating rate with an intrinsic activity of 0.2. The concentration-effect curve of (−)-pindolol was biphasic; the curve of (+)-pindolol was monophasic. The EC50's were (−log mol/l) 9.1 and 7.0 for (−)-pindolol and 7.5 for (+)-pindolol. From the use of subtype-selective antagonists we conclude that the positive chronotropic effects of (+)-pindolol are mediated predominantly by β 2-adrenoceptors. On the other hand, the high-sensitivity component of the positive chronotropic effects of (−)-pindolol appears to be mediated predominantly through β 1-adrenoceptors, although β 2-adrenoceptors may also participate. The low-sensitivity component of the positive chronotropic effects of (−)-pindolol is resistant to blockade by subtype-selective antagonists at concentrations causing at least 98% β-adrenoceptor occupancy. Only high but nondepressant concentrations of non-selective (−)-bupranolol antagonized the low-sensitivity component of (−)-pindolol. (−)-Pindolol antagonized the effects of several agonists to similar extent in both trachea and right atrium. (+)-Pindolol was less potent as antagonist of the relaxant effects of (−)-noradrenaline on trachea than against those of (−)-adrenalinc, (−)-isoprenaline and (±)-salbutamol. On right atrium (+)-pindolol antagonized non-selectively the positive chronotropic effects of (−)-isoprenaline, (−)-adrenaline and (−)-noradrenaline. The estimated blocking constant K B was (−log mol/l) 9.5–9.6 for (−)-pindolol; the K B's of (+)-pindolol were 6.7–7.2 for β 1- and 7.8 for β 2-adrenoceptors. The evidence is consistent with different steric characteristics of β 1- and β 2-adrenoceptors. (−)-Pindolol and (+)-pindolol competed in a stereoselective manner with 3H-(−)-bupranolol for β-adrenoceptors of ventricle and lung. The affinity ratio of (−)-pindolol/(+)-pindolol was 80 in lung and 200 in ventricle, supporting the concept of different steric properties of β 1- and β 2-adrenoceptors. 3H-(−)-bupranolol labelled a ventricular site that was recognized with low affinity (−log mol/l K D=4.9) by (−)-pindolol. This low-affinity site may be involved in causing the low-sensitivity stimulant effects of (−)-pindolol. The dissociation between blockade (high potency) and stimulation (low potency) observed with (−)-pindolol and racemic pindolol can be accounted by different receptor populations mediating blockade and stimulation of (−)-pindolol.