Metabolic effects of various beta-adrenoceptor blocking agents in rats and dogs

Koe 3290 (N-[3-cyano-4-[3-[(1, 1-dimethyl-2-propynyl)amino]-2-hydroxypropoxy] phenyl]-2-methyl-propionamide), Koe 4299 (N-[3-cyano-4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-hexanamide+ ++ hydrochloride), Koe 4302 (N-[3-cyano-4-[3-[(1, 1-dimethyl-2-propynyl)amino]-2-hydroxypropoxy]phenyl]-hexanamid e hydrochloride) and the well-known compounds propranolol, bunitrolol, atenolol and acebutolol inhibit isoprenaline-stimulated increase of the concentration of free fatty acids (FFA) in the plasma of rats and dogs. In rats, most of the cardioselective blockers (Koe 3290, Koe 4299, Koe 4302, acebutolol) diminish isoprenaline-stimulated lactate, after s.c. injection, in a dose range higher than that required to reduce FFA. With the exception of atenolol, these substances show a relative selectivity between antilipolytic and antiglycolytic activity in favour of the antilipolytic effect. The non-cardioselective substances, propranolol and bunitrolol, either do not or only slightly differentiate between the inhibition of FFA and that of lactate. In dogs, after i.v. injection, only Koe 3290 and acebutolol have a relative metabolic selectivity similar to that seen in rats, but the other beta-adrenoceptor antagonists, with and without cardioselectivity, do not differentiate between the inhibition of isoprenaline-stimulated FFA, and that of lactate and glucose. In contrast, a greater antiglycolytic effect is often seen. Interspecies differences between the rat and the dog and variations among the drugs tested are discussed in detail. Koe 3290 is the only highly cardioselective drug with marked antilipolytic activity which markedly differentiates, in both rats and dogs, between the inhibition of FFA and carbohydrates. This substance, therefore, would appear to offer some additional advantages in the therapy of myocardial ischemia.