Desensitization of inhibitory prejunctional α₂-adrenoceptors and putative imidazoline receptors on rabbit heart sympathetic nerves

Summary

To find out whether sympathetic nerves of the rabbit heart possess pharmacologically relevant prejunctional imidazoline receptors different from α-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 α₂-adrenoceptor agonist oxymetazoline inhibited the evoked noradrenaline overflow (2.9 nmol/l, IC₅₀; about 90010, maximum inhibition). The inhibition was antagonized by rauwolscine (−log K_B 8.20). This confirms the presence of α₂-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 α₂- 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 α₂-autoreceptor. Neither an α₂-selective low concentration of rauwolscine nor the α₁-adrenoceptor antagonist prazosin, nor SKF 104078, a mixed α_1/2-antagonist, reduced the aganodine effect. The α₂-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 μmol/l added later on to minimize presynaptic α₂-adrenoceptor activation or blockade by drugs persisting in the biophase) to oxymetazoline 10 μmol/l, aganodine 2 μmol/l or BDF 6143 10 μmol/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 μmol/l. Pre-exposure to BDF 6143 10 μmol/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 α₂-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.