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

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 microM) but not affected by the Na+/K+ ATPase inhibitor ouabain (10 microM), or a combination of tetraethylammonium (TEA; 1 mM), 4-aminopyridine (1 mM) and glibenclamide (10 microM). 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 microM). 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 microM) 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.

Evidence for Involvement of Both IK Ca and SK Ca Channels in Hyperpolarizing Responses of the Rat Middle Cerebral Artery

“…After equilibration for 20 minutes vessels were tensioned to 1 mN (approximates wall tension at 60 mm Hg). In some experiments vessel tension was increased to 4 mN (approximates wall tension at 140 mm Hg) in order to increase spontaneous myogenic constriction 13 Smooth-muscle tension was recorded with an isometric pressure transducer and Powerlab software (ADI, Australia). Vessel viability was assessed by adding exogenous K ϩ (15 to 55 mmol/L, total K ϩ concentration), vessels with tension of Ն3 mN being used.…”

Astrocyte control of the cerebrovasculature

“…Though barium is commonly used to block Kir channels, this treatment also elicits pronounced depolarizations of astrocytes (Anderson et al, 1995) and can out compete Ca 2+ for the pore of L‐type voltage gated Ca 2+ channels, which are prominent in cerebral SMCs (Alborch et al, 1995). The additional use of an imidazole compound to block Kir channels would help support the author's conclusions (Favaloro et al, 2003). Placing an important role on SMC Kir channels is likely not conflicting with the data from the Newman lab showing that there is no difference in K + induced dilations between wild type and Kir knockout mice because of the difference in the Kir subtypes involved.…”

Effect of type 1 diabetes on the production and vasoactivity of hydrogen sulfide in rat middle cerebral arteries

“…Due to the high level of spontaneous myogenic tone in rat MCA, the following protocol was adopted to standardize the level of passive force applied to each vessel (Favaloro et al 2003 ; Streeter et al 2012 ). First, a 4 mN force was applied to each segment over a 30-min period to allow spontaneous tone to develop.…”