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

The blocking and stimulant potencies of (-)-pindolol and (+)-pindolol were estimated on right atria and tracheae of guinea pig. Blocking affinities were estimated for beta-adrenoceptor subtypes by using several agonists. Binding affinities of (-)-pindolol and (+)-pindolol were also estimated for beta-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 beta 2-adrenoceptors. The low-sensitivity component of relaxation of (-)-pindolol was antagonized by beta-blockers less than expected from their affinities for beta-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 beta 2-adrenoceptors. On the other hand, the high-sensitivity component of the positive chronotropic effects of (-)-pindolol appears to be mediated predominantly through beta 1-adrenoceptors, although beta 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% beta-adrenoceptor occupancy. Only high but non-depressant 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 (-)-adrenaline, (-)-isoprenaline and (+/-)-salbutamol.(ABSTRACT TRUNCATED AT 400 WORDS)