Modulation of Norepinephrine Release in Blood Vessels

Abstract

Summary: Various imidazoline and guanidine derivatives with agonistic or antagonistic properties at α2-adrenoceptors may modulate norepinephrine release not only via classic α2-autoreceptors but also via presynaptic imidazoline receptors. This possibility was examined in rabbit pulmonary artery and aorta preincubated with [3H]norepinephrine (NE) and superfused with a physiological salt solution. The release of [3H]NE from the sympathetic nerves contained in the preparations was stimulated by electrical impulses (2 Hz, unless stated otherwise). α2-Adrenoceptor-blocking imidazolines such as phentolamine, tolazoline, idazoxan, and 4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline (BDF 6143) increased the electrically evoked [3H]NE release. Their concentration-response curves were bell-shaped, and the maximum increase obtainable was less than that obtained with rauwolscine, a nonimidazoline α2-adrenoceptor antagonist. When the frequency of stimulation was decreased from 2 to 0.66 Hz (leading to a decreased concentration of NE in the biophase of the α2-autoreceptors and therefore a decreased degree of autoreceptor activation), BDF 6143 no longer facilitated but instead concentration-dependently inhibited [3H]NE release. An inhibition of release without any facilitatory component could also be observed at 2 Hz with all imidazoline derivatives mentioned above when the presynaptic α2-adrenoceptors had been blocked by rauwolscine and/or preexposure to the irreversible α-adrenoceptor antagonist phenoxybenzamine. Clonidine and moxonidine, two imidazolines with α2-adrenoceptor agonistic properties, and cirazoline, an imidazoline devoid of intrinsic activity at α2-adrenoceptors, inhibited [3H]NE release. Rauwolscine apparently was antagonistic not only at presynaptic α2-adrenoceptors but also at presynaptic imidazoline receptors because it antagonized the inhibitory response to BDF 6143 at 0.66 Hz. The pA2 values of rauwolscine for α2-adrenoceptor antagonism in various tissues of several species (reported in the literature) were, as a rule, in the range of 8.0. In the rabbit pulmonary artery and aorta, pA2 values of rauwolscine in this range could be found only for the antagonism against the moxonidine-induced inhibition of [3H]NE release, whereas the pA2 values against clonidine and other putative imidazole receptor agonists were between 6.37 and 6.77. Taken together, the present data suggest that in addition to the classic α2-adrenoceptors, imidazoline receptors are involved in modulation of NE release in the rabbit pulmonary artery and aorta. Comparison of the potencies of all putative imidazoline receptor-ligands investigated in these blood vessels with their potencies in other tissues (including those in the rostral ventrolateral medulla of the brainstem involved in the hypotensive effect of clonidine and moxonidine) revealed that the imidazoline sites are heterogeneous. In the rabbit pulmonary artery and aorta, moxonidine activates predominantly α2-adrenoceptors (but not the coexisting presynaptic imidazoline receptors subtype), whereas it possesses particularly high affinity for the imidazoline receptors in the rat rostral ventrolateral medulla. Thus. moxonidine may be particularly selective for the imidazoline receptor of the brainstem.