Desensitization of inhibitory prejunctional alpha 2-adrenoceptors and putative imidazoline receptors on rabbit heart sympathetic nerves.

To find out whether sympathetic nerves of the rabbit heart possess pharmacologically relevant prejunctional imidazoline receptors different from alpha-autoreceptors, the inhibition by oxymetazoline, aganodine and BDF 6143 (4-chloro-2-[2-imidazoline-2-ylamino]-isoindoline hydrochloride) of endogenous noradrenaline overflow evoked by stimulation of extrinsic postganglionic sympathetic nerves (0.66 Hz, 80 pulses) was investigated. In addition we wanted to find out whether either type of these prejunctional receptors undergoes desensitization upon pre-exposure to respective agonists. The alpha 2-adrenoceptor agonist oxymetazoline inhibited the evoked noradrenaline overflow (2.9 nmol/l, IC50; about 90%, maximum inhibition). The inhibition was antagonized by rauwolscine (-log KB 8.20). This confirms the presence of alpha 2-autoreceptors. Endogenous noradrenaline activated autoinhibition to a small extent as indicated by a rauwolscine-induced increase in evoked overflow by less than 2-fold. The alpha 2- and imidazoline receptor agonist aganodine inhibited the evoked noradrenaline overflow (2.4 nmol/l, IC50; about 80%, maximum inhibition). The inhibition was antagonized by rauwolscine with a potency (-log KB 6.75), about 1/30 of that found at the alpha 2-autoreceptor. Neither an alpha 2-selective low concentration of rauwolscine nor the alpha 1-adrenoceptor antagonist prazosin, nor SKF 104078, a mixed alpha 1/2-antagonist, reduced the aganodine effect. The alpha 2-adrenoceptor antagonist and imidazoline receptor agonist BDF 6143 inhibited the evoked noradrenaline overflow (18 nmol/l, IC50; about 70% maximum inhibition). The inhibition was insensitive to a low rauwolscine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)