Impaired EDHF-mediated vasodilation and function of endothelial Ca 2+-activated K+ channels in uremic rats

Abstract

Background. Chronic renal failure (CRF) 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 vasodilation contribute to the endothelial dysfunction in the rat remnant kidney model of chronic renal failure. Methods. Functional expression of endothelial KCa 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. Results. 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 nor-motensive 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 KCa, 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 KCa genes, SKCa3 and IKCa1 in 5/6 nephrectomy rats compared to sham-operated rats. Conclusion. 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. © 2005 by the International Society of Nephrology.