Novel imidazoline compounds that inhibit Kir-mediated vasorelaxation in rat middle cerebral artery

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Abstract
The ability of a series of novel imidazoline (IMID) compounds (fluoryl-, methoxy- and methyl-phenyl derivatives of clonidine) to inhibit the vasorelaxation and hyperpolarisation response to exogenous K+ (1–10 mM) was assessed in the rat middle cerebral artery (MCA) using the small vessel myograph. In this preparation, K+-induced relaxation was inhibited by low concentrations of Ba2+ (30 μM) but not affected by the Na+/K+ ATPase inhibitor ouabain (10 μM), or a combination of tetraethylammonium (TEA; 1 mM), 4-aminopyridine (1 mM) and glibenclamide (10 μM). These results are consistent with K+ eliciting a vasorelaxation response through the activation of inwardly rectifying K+ channels (Kir channels) in this tissue. K+-mediated vasorelaxation was assessed in the absence and in the presence of two concentrations of the IMID compounds (1 and 10 μM). The majority of the compounds investigated caused marked inhibition of K+-mediated relaxation at these concentrations. In electrophysiological studies the fluoryl-derivative (IMID-4F; 10 μM) potently inhibited the hyperpolarisation response that accompanies the relaxation response to exogenous K+. In conclusion, we have identified a number of IMID compounds that inhibit relaxation and hyperpolarisation responses mediated via Kir channels in the rat MCA. Many of these compounds have a greater potency as inhibitors of Kir channels than Ba2+, and may be a useful tool in studying Kir channel function.