INVOLVEMENT OF PRESYNAPTIC IMIDAZOLINE RECEPTORS IN THE ALPHA-2-ADRENOCEPTOR-INDEPENDENT INHIBITION OF NORADRENALINE RELEASE BY IMIDAZOLINE DERIVATIVES

An involvement of imidazoline recognition sites in the modulation of transmitter release was investigated in the rabbit pulmonary artery and aorta preincubated with [H-3]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Electrical impulses were applied transmurally at 0.66 or 2 Hz. In the absence of further drugs, rauwolscine as well as the imidazoline derivatives BDF 6143 [4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline], idazoxan and phentolamine increased the H-3 overflow from the pulmonary artery, evoked by electrical stimulation at 2 Hz; the effect was due to the alpha-2-autoreceptor blocking property of these drugs. The maximum increase in overflow obtainable with the imidazolines was considerably lower than with rauwolscine. The concentration-response curves of the imidazolines were bell-shaped. At 0.66 Hz, BDF 6143 did not facilitate, but concentration-dependently inhibited, whereas idazoxan failed to change the evoked H-3 overflow. When, at the stimulation frequency of 2 Hz, presynaptic alpha-2-adrenoceptors were blocked by rauwolscine and/or pre-exposure to phenoxybenzamine, the electrically evoked H-3 overflow from the pulmonary artery and/or aorta was inhibited by the following imidazoline derivatives: the alpha-2-adrenoceptor antagonists BDF 6143, idazoxan and phentolamine, the alpha-1-adrenoceptor agonist with alpha-2-blocking property cirazoline as well as the alpha-2-adrenoceptor agonists clonidine and moxonidine. The maximum inhibition caused by BDF 6143 was greater than that due to clonidine and moxonidine; the latter two, hence, behaved as partial agonists. At the stimulation frequency of 0.66 Hz, the imidazolines exhibited a higher potency than, but a similar intrinsic activity to that at 2 Hz. Noradrenaline did not affect the evoked H-3 overflow. The BDF 6143-induced inhibition of evoked H-3 overflow was not modified by metitepine, atropine, theophylline, dipyridamole and indometacin, but was counteracted by the partial agonists clonidine and moxonidine. The results exclude the possibility that alpha-1- and alpha-2-adrenoceptors, 5-HT1 receptors, muscarine receptors, P1 purinoceptors and prostaglandin receptors are involved in the imidazoline-induced inhibition of noradrenaline release. They provide evidence indicating that the inhibitory effect is mediated by imidazoline receptors on the postganglionic sympathetic nerve terminals of the rabbit pulmonary artery and aorta.