Article
Impaired EDHF-mediated vasodilatation and K+ channel function in chronic renal failure
Defekte EDHF-vermittelte Vasodilatation und K+-Kanalfunktion bei chronischer Niereninsuffizienz
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Published: | August 10, 2005 |
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Background: Chronic renal failure is associated with increased cardiovascular morbidity, abnormal arterial tone, and endothelial dysfunction. Ca2+-activated K+-channels (KCa) are important regulators of endothelial function by controlling endothelial hyperpolarization and thus endothelium-derived hyperpolarizing factor (EDHF)-meditated vasodilations. Here we tested the hypothesis whether an altered function of endothelial KCa and diminished EDHF-meditated vasodilatation contribute to endothelial dysfunction in experimental chronic renal failure (CRF).
Methods: Functional expression of endothelial KCa currents and endothelium-dependent vasodilatations in rat carotid arteries (CA) were assessed by using patch-clamp techniques, single-cell-RT-PCR, and a pressure-myograph, 8 weeks after either subtotal 5/6 nephrectomy in normotensive (5/6NxN) and hypertensive (5/6NxH) or sham-operated (Sham) rats.
Results: Acetylcholine (ACh)-induced EDHF-mediated vasodila-tations were present in Sham, but almost absent in both 5/6NxN and 5/6NxH. 1-EBIO, a selective opener of endothelial small and intermediate KCa induced a substantial vasodilatation in Sham, but induced very small vasodilatation in 5/6NxH and in 5/6NxN. In experiments without blocking NO/prostacyclin synthesis, endothelium-dependent vasodilatation to ACh was significantly reduced in both 5/6NxN and 5/6NxH. In patch-clamp experiments, mean KCa currents were significantly reduced in ECs from 5/6NxH and 5/6NxN when compared to Sham. In 5/6Nx rats compared to Sham, single-cell-RT-PCR analysis revealed a greatly reduced frequency of ECs expressing the KCa genes SKCa3 and IKCa1.
Conclusions: Experimental CRF leads to a loss of EDHF-type vasodilatation which was caused at least in part by an impaired functional expression of endothelial hyperpolarizing KCa. The loss of EDHF-type vasodilatation may contribute to endothelial dysfunction and abnormal arterial tone in CRF.