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 L歟eck,
Ratzeburger Allee 160, D-23538 L歟eck, 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ﾊnM-100ﾊmM), whereas cirazoline (1-100ﾊmM) and moxonidine (100ﾊ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 K_Dﾊvalues of 12.7ﾊ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 K_D of 0.5ﾊmM was calculated and since competition studies with guanabenz (K_i=0.1ﾊmM), clonidine (K_i=58.1ﾊmM) and moxonidine (K_i=129ﾊmM) confirmed the specificity of the I₂-binding.

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