W. Raasch et al., Positive inotropic effects of imidazoline derivatives are not mediated viaimidazoline binding sites but alpha(1)-adrenergic receptors, JPN J PHARM, 84(1), 2000, pp. 1-6
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.