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.
Mustonen
P
P
Wihuri Research Institute, Helsinki, Finland.
Savola
J
J
Lassila
R
R
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000328:Adult; D001665:Binding Sites; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020927:Dexmedetomidine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D015016:Yohimbine / Q000378:metabolism / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D010656:Phenylephrine; D015016:Yohimbine; D020927:Dexmedetomidine; D011224:Prazosin; D004837:Epinephrine