Presynaptic alpha-2 adrenoceptor activation and coupling of the receptor-presynaptic effector system in the perfused rat heart: affinity and efficacy of phenethylamines and imidazoline derivatives.

The right sympathetic nerves of perfused rat hearts were stimulated in the presence of inhibitors of neuronal and extraneuronal uptake and propranolol. The inhibition by alpha adrenoceptor agonists of stimulation-evoked (10 pulses, 0.1 Hz) [3H]norepinephrine (NE) overflow into the perfusate was taken as a parameter of presynaptic adrenoceptor activation. Under the present conditions, autoinhibition of NE release is not activated by endogenous NE as evident from ineffectiveness of adrenoceptor antagonists in facilitating evoked [3H]NE overflow. The potency (EC50, -log10), affinity (agonist-presynaptic receptor dissociation constant KA, -log10) and relative efficacies (RE) were determined for phenethylamines (NE or alpha-methylepinephrine) and for imidazoline derivatives. NE (-log EC50, 7.76) was 0.88 log units more potent than alpha-methylepinephrine (-log EC50, 6.88) and about the same difference was observed for the -log KA values (5.92 vs. 4.75). RE were similar (NE, 100%; alpha methylepinephrine, 98%) and 22- to 50-fold higher than efficacies of imidazoline derivatives. Hydroxylations in positions 3 and 4 of the phenyl moiety of phenylaminoimidazoline (-log EC50, less than 5; -log KA, less than 5; RE, less than 1%) resulted in a marked increase in potency (-log EC50, 8.32) of the resulting dihydroxyphenylaminoimidazoline due to a high affinity (-log KA, 8.22) at a low efficacy (2% of NE). In contrast, hydroxylation in positions 3 and 4 of the phenyl ring of tolazoline (no agonist activity under the present conditions; antagonist affinity constant from the literature, 6.4-6.6) produced dihydroxytolazoline, a moderately potent agonist (-log EC50, 7.25) with an efficacy of 3.5% at an affinity (-log KA, 6.92) not much different from that of tolazine.(ABSTRACT TRUNCATED AT 250 WORDS)