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 alpha2-adrenoceptor agonist oxymetazoline inhibited the evoked noradrenaline overflow (2.9 nmol/l, IC50; about 90%, maximum inhibition). The inhibition was antagonized by rauwolscine (-log K(B) 8.20). This confirms the presence of alpha2-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 alpha2- 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 K(B) 6.75), about 1/30 of that found at the alpha2-autoreceptor. Neither an alpha2-Selective low concentration of rauwolscine nor the alpha1-adrenoceptor antagonist prazosin, nor SKF 104078, a mixed alpha1/2-antagonist, reduced the aganodine effect. The alpha2-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. In hearts pre-exposed for 30 min (followed by washout; rauwolscine 0.1 mumol/l added later on to minimize presynaptic alpha2-adrenoceptor activation or blockade by drugs persisting in the biophase) to oxymetazoline 10 mumol/l, aganodine 2 mumol/l or BDF 6143 10 mumol/l, the inhibitory effects of oxymetazoline 30 nmol/l and aganodine 10 nmol/l were concomitantly reduced. No significant reduction of the agonist effect was seen after pre-exposure to BDF 6143 2 mumol/l. Pre-exposure to BDF 6143 10 mumol/l shifted the concentration for half-maximum inhibition to the right and depressed the maximum effect of both, oxymetazoline and aganodine, but did not affect the inhibitory action of the muscarinic agonist methacholine. It is concluded that inhibitory prejunctional alpha2-autoreceptors and putative imidazoline receptors coexist on postganglionic sympathetic nerves of the rabbit heart. They are both subject to desensitization upon exposure to a high agonist concentration. The findings are compatible with a mutual cross-desensitization under the conditions investigated.
