Distal convoluted tubule Cl-concentration is modulated via K+ channels and transporters
Cl-sensitive with-no-lysine kinase (WNK) plays a key role in regulating the thiazide-sensitive Na+-Cl- cotransporter (NCC) in the distal convoluted tubule (DCT). Cl- enters DCT cells through NCC and leaves the cell across the basolateral membrane via the Cl- channel ClC-K2 or K+-Cl- cotransporter (KCC). While KCC is electroneutral, Cl- exit via ClC-K2 is electrogenic. Therefore, an alteration in DCT basolateral K+ channel activity is expected to influence Cl- movement across the basolateral membrane. Although a role for intracellular Cl- in the regulation of WNK and NCC has been established, intracellular Cl- concentrations ([Cl-]i) have not been directly measured in the mammalian DCT. Therefore, to measure [Cl-]i in DCT cells, we generated a transgenic mouse model expressing an optogenetic kidney-specific Cl-Sensor and measured Cl- fluorescent imaging in the isolated DCT. Basal measurements indicated that the mean [Cl-]i was ~7 mM. Stimulation of Cl- exit with low-Cl- hypotonic solutions decreased [Cl-]i, whereas inhibition of KCC by DIOA or inhibition of ClC-K2 by NPPB increased [Cl-]i, suggesting roles for both KCC and ClC-K2 in the modulation of [Cl-]i. Blockade of basolateral K+ channels (Kir4.1/5.1) with barium significantly increased [Cl-]i. Finally, a decrease in extracellular K+ concentration transiently decreased [Cl-]i, whereas raising extracellular K+ transiently increased [Cl-]i, further suggesting a role for Kir4.1/5.1 in the regulation of [Cl-]i. We conclude that the alteration in ClC-K2, KCC, and Kir4.1/5.1 activity influences [Cl-]i in the DCT.
Long-term clinical benefit of sirolimus-eluting stents compared to bare metal stents in the treatment of saphenous vein graft disease
OBJECTIVE:The purpose of this study was to evaluate the efficacy of sirolimus-eluting stents (SES) in the treatment of saphenous vein graft (SVG) disease. BACKGROUND:Percutaneous coronary intervention (PCI) of SVG lesions with bare metal stents (BMS) is associated with frequent in-stent restenosis, progression of disease in nonstented SVG segments, and suboptimal clinical outcomes. While SES have been shown to reduce restenosis rates in various native lesion subsets, the long-term clinical impact of SES use in SVG lesions is less clear. METHODS:We compared our first 59 patients who underwent SES implantation in SVGs with 50 consecutive patients who received BMS in an equivalent time period prior to SES availability. Clinical outcomes were compared in both groups. RESULTS:Baseline clinical variables between the two groups were similar. Mean graft age in the SES cohort was older than that in the BMS cohort (12.9 years vs. 9.4 years). At follow-up, the SES group had a 24.6% absolute lower incidence of major adverse cardiac events (MACE) (25.4% vs. 50.0%), driven by a 20.7% absolute lower incidence of target vessel revascularization (TVR) (15.3% vs. 36.0%). The SES treatment group had a 24.1% lower rate of clinical restenosis (11.9% vs. 36.0%). The use of a SES was an independent negative predictor of MACE at a mean follow-up of 20 months (odds ratio [OR]= 0.48,P = 0.03). CONCLUSIONS:Despite the placement of longer stents in patients with older, smaller SVGs, the use of SES in the treatment of SVG lesions appears to be safe and is associated with less clinical restenosis and more favorable long-term clinical outcomes as compared with BMS.