Atipamezole, an imidazoline-type alpha(2)-adrenoceptor inhibitor, binds tohuman platelets and inhibits their adrenaline-induced aggregation more effectively than yohimbine

To investigate the usefulness of atipamezole [MPV-1248, 4-(2-ethyl-2,3-dihy dro-1H-inden-2-yl)-1H-imidazole], a novel alpha(2)-adrenoceptor-specific an tagonist, as a tool in platelet studies, the ability of this antagonist: (1 ) to bind to platelet alpha(2)-adrenoceptors, and (2) to inhibit adrenaline -induced platelet aggregation was compared to that of yohimbine, another co mmonly used alpha(2)-adrenoceptor antagonist. It was found that atipamezole binds to platelet alpha(2)-adrenoceptors more effectively than yohimbine: [H-3]atipamezole has more than three times higher alpha(2)-adrenoceptor bin ding affinity in intact gel-filtered human platelets (equilibrium dissociat ion constant (K-d) 0.7+/-0.21 vs. 2.9=/-0.77 nM, p<0.05), but only one-thir d of the binding capacity of [H-3]yohimbine (B-max 27.0+/-3.8 vs. 100+/-19 pM/ 10(5) cells, p<0.0l). Functionally, in comparison with yohimbine, an al most threefold lower concentration of atipamezole inhibited adrenaline (5 m u M)- induced platelet aggregation. A concentration of atipamezole, which i nhibited this aggregation by 50% (IC50), was 0.37+/-0.07 mu M, whereas IC50 for yohimbine was 0.98+/-0.12 mu M, p<0.0001. Thus, atipamezole represents a functionally undisputed alpha(2)-adrenoceptor antagonist, more effective than yohimbine. Its distinct binding profile as a radioligand also suggest s the presence of imidazol(in)e binding sites in platelets. (C) 2000 Elsevi er Science Ltd. All rights reserved.