RESUMEN
This study characterises the vasorelaxation and hyperpolarisation effects of the negatively charged quaternary compound tetraphenylboron (TPB) in the rat small mesenteric artery. Segments of rat small mesenteric artery were mounted in a myograph and vessel tone and membrane potential were measured simultaneously. In vessels pre-contracted with vasopressin (0.3-0.6 nM), U46619 (30-90 nM) or methoxamine (0.3-3 microM), TPB (0.1-100 microM) produced a marked endothelium-independent relaxation. However, vasorelaxation responses to TPB were abolished in tissues pre-contracted with K(+) (50 mM), and significantly inhibited by glibenclamide (glib, 10 microM). In the absence of tone, TPB (1-30 microM) caused a concentration-dependent membrane hyperpolarisation of rat mesenteric artery smooth muscle cells, which was not dependent on the endothelium, but sensitive to glibenclamide (10 microM). In methoxamine (0.3-3 microM) pre-contracted vessels, the relaxation response was associated with a marked hyperpolarisation, which was also sensitive to glibenclamide (10 microM), further inhibited by a combination of K(+) channel blockers (glib [10 microM], charybdotoxin [100 nM], apamin [100 nM], 4-aminopyridine [1 mM] and Ba(2+) [30 microM]) and abolished by 50 mM K(+). The results of this study show that TPB causes a vasorelaxation and hyperpolarisation response in the rat small mesenteric artery through a direct action on the vascular smooth muscle. TPB exerts its effects partially via the activation of K(ATP) channels, but also by another mechanism involving K(+)-dependent hyperpolarisation.
Asunto(s)
Arteria Mesentérica Inferior/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Tetrafenilborato/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Membrana Celular/fisiología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Potenciales de la Membrana , Arteria Mesentérica Inferior/fisiología , Músculo Liso Vascular/citología , Músculo Liso Vascular/fisiología , Potasio/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/fisiología , Ratas , Ratas Sprague-Dawley , Tetrafenilborato/administración & dosificaciónRESUMEN
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.