Positive inotropic effects of imidazoline derivatives are not mediated viaimidazoline binding sites but alpha(1)-adrenergic receptors

Imidazoline-binding sites are non-adrenergic receptors and classified into I-1/I-2 subtypes. There is strong evidence that I-1-binding sites, located in the rostro-ventrolateral medulla, are involved in regulation of blood pr essure. However, less is known about the peripheral participation of I-1-bi nding sites in cardiovascular reactions. Therefore, the aim of this study w as to investigate whether specific imidazoline derivatives influence myocar dial contractility and whether imidazoline binding sites are expressed in r at heart. Agmatine, clonidine and idazoxan failed to alter inotropy in left atria within the whole concentration range tested (1 nM- 100 mu M). wherea s cirazoline (1-100 mu M) and moxonidine (100 mu M) increase inotropy by ab out 20-30%. After preincubation with the alpha(1)-adrenoceptor antagonist p razosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an alpha(1)-adrenergic and less an imidazoline binding sit e mediated mechanism. Radioligand-binding studies in membranes of left vent ricles using [H-3]-clonidine to specify I-1-binding yielded K-D values of 1 2.7 mu M, confirming the functional results of an absence of I-1-binding si tes in ventricles of rats. However, the existence of low affinity I-2-bindi ng sites determined by [H-3]-idazoxan labeling could not be excluded since a K-D of 0.5 mu M was calculated and since competition studies with guanabe nz (K-i = 0.1 mu M), clonidine (K-i = 58.1 mu M) and moxonidine (K-i = 129 mu M) confirmed the specificity of the I-2-binding.