Positive inotropic effects of imidazoline derivatives are not mediated via imidazoline binding sites but α₁-adrenergic receptors

Imidazoline-binding sites are non-adrenergic receptors and classified into I₁/I₂subtypes. 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 μM), whereas cirazoline (1 - 100 μM) and moxonidine (100 μM) increase inotropy by about 20 - 30%. After pre-incubation with the α₁-adrenoceptor antagonist prazosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an α₁-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) values of 12.7 μM, 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 μM was calculated and since competition studies with guanabenz (K(i) = 0.1 μM), clonidine (K(i) = 58.1 μM) and moxonidine (K(i) = 129 μM) confirmed the specificity of the I₂-binding.