Referenced in: none

Automatically associated channels: SK3

Title: Impaired EDHF-mediated vasodilation and function of endothelial Ca-activated K channels in uremic rats.

Authors: Ralf Köhler, Ines Eichler, Herdis Schönfelder, Ivica Grgic, Philipp Heinau, Han Si, Joachim Hoyer

Journal, date & volume: Kidney Int., 2005 Jun , 67, 2280-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15882269

Abstract
Chronic renal failure (CRF) is associated with increased cardiovascular morbidity, abnormal arterial tone, and endothelial dysfunction. Ca(2+)-activated K(+)-channels (K(Ca)) are important regulators of endothelial function by controlling endothelial hyperpolarization and thus endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilations. Here we tested the hypothesis whether an altered function of endothelial K(Ca) and diminished EDHF-mediated vasodilation contribute to the endothelial dysfunction in the rat remnant kidney model of chronic renal failure.Functional expression of endothelial K(Ca) currents and endothelium-dependent vasodilations in rat carotid arteries were assessed by using patch-clamp techniques, single-cell reverse transcription-polymerase chain reaction (RT-PCR), and a pressure myograph 8 weeks after either subtotal 5/6 nephrectomy in normotensive or hypertensive, or sham-operated rats.Acetylcholine (ACh)-induced EDHF-mediated vasodilations were present in sham-operated rats, but almost absent in both normotensive 5/6 nephrectomy rats and hypertensive 5/6 nephrectomy rats. In experiments without blocking nitric oxide/prostacyclin synthesis, endothelium-dependent vasodilation to ACh was significantly reduced in both normotensive 5/6 nephrectomy rats and hypertensive 5/6 nephrectomy rats. In sham-operated rats, 1-ethyl-2-benzimidazolinone (1-EBIO), a selective opener of endothelial small and intermediate K(Ca), induced a substantial EDHF-mediated vasodilation, which was greatly reduced in hypertensive 5/6 nephrectomy rats and in normotensive 5/6 nephrectomy rats. In patch-clamp experiments, mean K(Ca) currents were significantly reduced in endothelial cells from hypertensive 5/6 nephrectomy rats and normotensive 5/6 nephrectomy rats when compared to sham-operated rats. Concordantly, single-cell reverse-transcription-polymerase chain reaction (RT-PCR) analysis revealed a greatly reduced frequency of endothelial cells expressing the K(Ca) genes, SKCa3 and IKCa1 in 5/6 nephrectomy rats compared to sham-operated rats.Experimental CRF leads to a loss of EDHF-type vasodilation which was caused at least in part by an impaired functional expression of endothelial hyperpolarizing K(Ca). The loss of EDHF-type vasodilation may contribute to endothelial dysfunction and abnormal arterial tone in CRF.