Jpn. J. Pharmacol. 84 (1), 1-6 (2000)

Positive Inotropic Effects of Imidazoline Derivatives Are Not Mediated via Imidazoline Binding Sites but a1-Adrenergic Receptors

Walter Raasch, K.R. Julian Chun, Andreas Dendorfer and Peter Dominiak

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lčbeck,
Ratzeburger Allee 160, D-23538 Lčbeck, Germany

Abstract: Imidazoline-binding sites are non-adrenergic receptors and classified into I1/I2 subtypes. There is strong evidence that I1-binding sites, located in the rostro-ventrolateral medulla, are involved in regulation of blood pressure. However, less is known about the peripheral participation of I1-binding sites in cardiovascular reactions. Therefore, the aim of this study was to investigate whether specific imidazoline derivatives influence myocardial contractility and whether imidazoline binding sites are expressed in rat heart. Agmatine, clonidine and idazoxan failed to alter inotropy in left atria within the whole concentration range tested (1╩nM-100╩mM), whereas cirazoline (1-100╩mM) and moxonidine (100╩mM) increase inotropy by about 20-30%. After preincubation with the a1-adrenoceptor antagonist prazosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an a1-adrenergic and less an imidazoline binding site mediated mechanism. Radioligand-binding studies in membranes of left ventricles using [3H]-clonidine to specify I1-binding yielded KD╩values of 12.7╩mM, confirming the functional results of an absence of I1-binding sites in ventricles of rats. However, the existence of low affinity I2-binding sites determined by [3H]-idazoxan labeling could not be excluded since a KD of 0.5╩mM was calculated and since competition studies with guanabenz (Ki=0.1╩mM), clonidine (Ki=58.1╩mM) and moxonidine (Ki=129╩mM) confirmed the specificity of the I2-binding.

Keywords: Imidazoline binding site, a1-Adreoceptor, Moxonidine, Agmatine, Cardiac contractility

Copyrightę The Japanese Pharmacological Society 2000

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