The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

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Abstract
We compared the α1, α2‐ and β1‐adrenoceptor blocking potencies of labetalol with those of its two stereoisomers (RR and SR) in pithed rats and in homogenized rat cerebral cortex and heart. In pithed rats, labetalol and the RR‐SR combination were given orally either at doses of 25 and 50 mg kg−1 body wt. or intravenously at doses of 1 and 5 mg kg−1 body wt. Prazosin 4 and 20 μg kg−1 body wt. and propranolol 1 and 5 mg kg−1 body wt., were given intravenously for comparison studies of potency at α1‐ and β1‐adrenoceptors, respectively. Effects were studied before and after i.v. administration of either phenylephrine (at doses which increased the mean arterial pressure by approximately 80 mmHg) or isoprenaline (at doses that increased heart rate by approximately 100 beats min−1). In pithed rats, labetalol and the RR‐SR combination antagonized, in a dose‐dependent manner, the pressor effect of phenylephrine (P < 0.05) and the chronotropic effect of isoprenaline (P < 0.05). Following both oral and intravenous dosing, the RR‐SR combination was twice potent as labetalol in terms of α1‐and β1‐adrenoceptor antagonism at equivalent doses. Labetalol and the enantiomers lacked affinity at α2‐adrenoceptors while at α1‐adrenoceptors the order of potency was prazosin ≫ RR‐SR > labetalol. At β1‐adrenoceptors, the affinity of the compound RR‐SR was about 3 times that of labetalol. As labetalol is a mixture of active (RR and SR) and inactive (SS and SR) enantiomers (in terms of α‐ and β‐receptor actions), the combination of RR and SR may be a valuable substitute for labetalol in the treatment of systemic hypertension. Although the potential for non‐specific side effects (common to all four enantiomers) could be expected to be diminished, recent reports by postmarketing surveillance indicate that the RR isomer (dilevalol) can induce liver toxicity. Interestingly, labetalol is devoid of this effect; whether the combination of RR and SR enantiomers could be of clinical importance warrants further investigation.