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

To investigate the usefulness of atipamezole MPV-1248, 4-(2-ethyl-2, 3-dihydro-1H-inden-2-yl)-1H-imidazole], a novel alpha(2)-adrenoceptor-specific antagonist, 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 commonly used alpha(2)-adrenoceptor antagonist. It was found that atipamezole binds to platelet alpha(2)-adrenoceptors more effectively than yohimbine: 3H]atipamezole has more than three times higher alpha(2)-adrenoceptor binding affinity in intact gel-filtered human platelets (equilibrium dissociation constant (K(d)) 0.7+/-0.21 vs. 2.9+/-0.77 nM, p<0.05), but only one-third of the binding capacity of 3H]yohimbine (B(max) 27.0+/-3.8 vs. 100+/-19 pM/10(5) cells, p<0.01). Functionally, in comparison with yohimbine, an almost threefold lower concentration of atipamezole inhibited adrenaline (5 microM)-induced platelet aggregation. A concentration of atipamezole, which inhibited this aggregation by 50% (IC(50)), was 0.37+/-0.07 microM, whereas IC(50) for yohimbine was 0.98+/-0.12 microM, 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 suggests the presence of imidazol(in)e binding sites in platelets.