PRESYNAPTIC IMIDAZOLINE RECEPTORS AND NON-ADRENOCEPTOR [H-3] IDAZOXANBINDING-SITES IN HUMAN CARDIOVASCULAR TISSUES

1 In segments of human right atrial appendages and pulmonary arteries preincubated with [H-3]-noradrenaline and superfused with physiologica l salt solution containing desipramine and corticosterone, the involve ment of imidazoline receptors in the modulation of [H-3]-noradrenaline release was investigated. 2 In human atrial appendages, the guanidine s aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynap tic imidazoline receptors, inhibited electrically-evoked [H-3]-noradre naline release. The inhibition was not affected by blockade of alpha(2 )-adrenoceptors with 1 mu M rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 mu M; apparent pA(2) ag ainst aganodine and DTG: 5.55 and 5.21, respectively). 3 In the presen ce of 1 mu M rauwolscine, [H-3]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazol ine, but not by agmatine and noradrenaline. The inhibitory effects of 100 mu M idazoxan and 30 mu M cirazoline were abolished by 30 mu M rau wolscine. 4 In the atrial appendages, the rank order of potency of all guanidines and imidazolines for their inhibitory effect on electrical ly-evoked [H-3]-noradrenaline release in the presence of 1 mu rauwolsc ine was: aganodine greater than or equal to BDF 6143 hloro-2-(2-imidaz olin-2-yl-amino)-isoindoline]>DTG greater than or equal to clonidine>c irazoline>idazoxan (BDF 6143 and clonidine were previously studied und er identical conditions). This potency order corresponded to that prev iously determined at the presynaptic imidazoline receptors in the rabb it aorta. 5 When, in the experiments in the human pulmonary artery, ra uwolscine was absent from the superfusion fluid, the concentration-res ponse curve for BDF 6143 (a mixed alpha(2) adrenoceptor antagonist/imi dazoline receptor agonist) for its facilitatory effect on electrically -evoked [H-3]-noradrenaline release was bell-shaped. In the presence o f 1 mu M rauwolscine, BDF 6143 and cirazoline concentration-dependentl y inhibited the evoked [H-3]-noradrenaline release. 6 In human atrial appendages, non-adrenoceptor [H-3]-idazoxan binding sites were identif ied and characterized. The binding of [H-3]-idazoxan was specific, rev ersible, saturable and of high affinity (K-D: 25.5 nM). The specific b inding of [H-3]-idazoxan (defined by cirazoline 0.1 mM) to membranes o f human atrial appendages was concentration-dependently inhibited by s everal imidazolines and guanidines, but not by rauwolscine and agmatin e. In most cases, the competition curves were best fitted to a two-sit e model. 7 The rank order of affinity for the high affinity site (in a few cases for the only detectable site; cirazoline = idazoxan > BDF 6 143 > DTG greater than or equal to clonidine) is compatible with the p harmacological properties of I-2-imidazoline binding sites, but is cle arly different from the rank order of potency for inhibiting evoked no radrenaline release from sympathetic nerves in the same tissue. 8 It i s concluded that noradrenaline release in the human atrium and, less w ell established, in the pulmonary artery is inhibited via presynaptic imidazoline receptors. These presynaptic imidazoline receptors appear to be related to those previously characterized in rabbit aorta and pu lmonary artery, but differ clearly from I-1 and I-2 imidazoline bindin g sites.