title: 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.
abstract: 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)
mesh_terms: D000818:Animals; D001692:Biological Transport; D004558:Electric Stimulation; D006321:Heart / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D013564:Sympathetic Nervous System / Q000502:physiology; D013570:Synaptic Membranes / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010627:Phenethylamines; D011942:Receptors, Adrenergic, alpha; D010643:Phenoxybenzamine; D009638:Norepinephrine