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Background: Hemodialysis solutions typically contain a high alkali concentration designed to counter interdialytic acidosis, but this could result in persistent alkalosis in some patients. The prevalence and significance of persistent alkalosis were therefore examined at four outpatient centers over a 10‐year period. Methods: Alkalosis was defined as a pre‐dialysis serum [HCO3] ≥ 26 meq/L in >6 months of a 12‐month period and was persistent if present in a majority of months thereafter. Control patients had a serum [HCO3] of 19–23 meq/L > 6 of every 12 months. Standard, citrate‐containing dialysate was used in all patients without adjustment of bicarbonate concentration. Results: 444 of 1271 patients had alkalosis that persisted in 73. Compared to control patients, persistently alkalotic patients were older, but gender, race, starting weight, comorbidities, and mortality did not differ. Dialysis dose was 7% greater, protein catabolic rate was 11% lower, and interdialytic weight gain was 29% lower, all p < 0.001. Persistently alkalotic patients had double the incidence of cardiac arrhythmias (p = 0.07) and a 20% greater intradialytic blood pressure decrease (p < 0.001). Conclusions: Alkalosis is common in hemodialysis patients and can be persistent, likely due to decreased protein catabolic rate and increased dialysis dose, and may have detrimental cardiovascular effects. [ABSTRACT FROM AUTHOR]

Vascular calcification is a multifaceted process involving gain of calcification inducers and loss of calcification inhibitors. One such inhibitor is inorganic pyrophosphate ([PP.sub.i]), and regulated generation and homeostasis of extracellular [PP.sub.i] is a critical determinant of soft-tissue mineralization. We recently described an autocrine mechanism of extracellular [PP.sub.i] generation in cultured rat aortic vascular smooth muscle cells (VSMC) that involves both ATP release coupled to the ectophosphodiesterase/pyrophosphatase ENPP1 and efflux of intracellular [PP.sub.i] mediated or regulated by the plasma membrane protein ANK. We now report that increased cAMP signaling and elevated extracellular inorganic phosphate ([P.sub.i]) act synergistically to induce calcification of these VSMC that is correlated with progressive reduction in ability to accumulate extracellular [PP.sub.i]. Attenuated [PP.sub.i] accumulation was mediated in part by cAMP-dependent decrease in ANK expression coordinated with cAMP-dependent increase in expression of TNAP, the tissue nonselective alkaline phosphatase that degrades [PP.sub.i]. Stimulation of cAMP signaling did not alter ATP release or ENPP1 expression, and the cAMP-induced changes in ANK and TNAP expression were not sufficient to induce calcification. Elevated extracellular [P.sub.i] alone elicited only minor calcification and no significant changes in ANK, TNAP, or ENPP1. In contrast, combined with a cAMP stimulus, elevated [P.sub.i] induced decreases in the ATP release pathway(s) that supports ENPP1 activity: this resulted in markedly reduced rates of [PP.sub.i] accumulation that facilitated robust calcification. Calcified VSMC were characterized by maintained expression of multiple SMC differentiation marker proteins including smooth muscle (SM) [alpha]-actin, SM22[alpha], and calponin. Notably, addition of exogenous ATP (or [PP.sub.i] per se) rescued cAMP + phosphate-treated VSMC cultures from progression to the calcified state. These observations support a model in which extracellular [PP.sub.i] generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification. ectonucleotide pyrophosphatase/phosphodiesterase-1; ANK; adenosine 3',5'-cyclic monophosphate; ATP release doi:10.1152/ajpcell.00419.2009.

Extracellular inorganic pyrophosphate ([PP.sub.i]) is a potent suppressor of physiological calcification in bone and pathological calcification in blood vessels. Ectonucleotide pyrophosphatase/phosphodiesterases (eNPPs) generate [PP.sub.i] via the hydrolysis of ATP released into extracellular compartments by poorly understood mechanisms. Here we report that cultured vascular smooth muscle cells (VSMC) from rat aorta generate extracellular [PP.sub.i] via an autocrine mechanism that involves ATP release tightly coupled to eNPP activity. The nucleotide analog [beta], [gamma]-methylene ATP (MeATP or AMPPCP) was used to selectively suppress ATP metabolism by eNPPs but not the CD39-type ecto-ATPases. In the absence of MeATP, VSMC generated extracellular [PP.sub.i] to accumulate [greater than or equal to] 600 nM within 2 h while steadily maintaining extracellular ATP at 1 nM. Conversely, the presence of MeATP completely suppressed [PP.sub.i] accumulation while increasing ATP accumulation. Probenecid, which inhibits [PP.sub.i] efflux dependent on ANK, a putative [PP.sub.i] transporter or transport regulator, reduced extracellular [PP.sub.i] accumulation by approximately twofold. This indicates that autocrine ATP release coupled to eNPP activity comprises [greater than or equal to] 50% of the extracellular PP,-generating capacity of VSMC. The accumulation of extracellular [PP.sub.i] and ATP was markedly attenuated by reduced temperature but was insensitive to brefeldin A, which suppresses constitutive exocytosis of Golgi-derived secretory vesicles. The magnitude of extracellular [PP.sub.i] accumulation in VSMC cultures increased with time postplating, suggesting that ATP release coupled to [PP.sub.i] generation is upregulated as cultured VSMC undergo contact-inhibition of proliferation or deposit extracellular matrix. adenosine 5'-triphosphate release; vascular calcification; ectonucleotide pyrophosphatase; ectoadenosine 5'-triphosphatase

Warfarin produced a similar proportional increase in progression in ESRD patients, but because of the underlying propensity towards arterial calcification in ESRD, the rate of progression in ESRD patients treated with warfarin was almost 20-fold greater than in women without ESRD not treated with warfarin. One could argue that it could be used in patients with excellent control of their mineral metabolism but our data show that warfarin increases arterial calcification in patients with normal renal function and presumably normal mineral metabolism. Patients with end-stage renal disease (ESRD) often have indications for long-term anticoagulation such as atrial fibrillation, thrombosis of arteriovenous fistulas and grafts, metallic heart valves, and hypercoagulable states. [Extracted from the article]

Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCC1 is activated by vasoconstrictors and inhibited by nitrovasodilators, contributes to smooth muscle tone in vitro, and is upregulated in hypertension. To determine the role of NKCC1 in systemic vascular resistance and hypertension, blood pressure was measured in rats before and after inhibition of NKCC1 with bumetanide. Intravenous infusion of bumetanide sufficient to yield a free plasma concentration above the I[C.sub.50] for NKCC1 produced an immediate drop in blood pressure of 5.2% (P < 0.001). The reduction was not prevented when the renal arteries were clamped, indicating that it was not due to a renal effect of bumetanide. Bumetanide did not alter blood pressure in NKCC1-null mice, demonstrating that it was acting specifically through NKCC1. In third-order mesenteric arteries, bumetanide-inhibitable efflux of [sup.86]Rb was acutely stimulated 133% by phenylephrine, and bumetanide reduced the contractile response to phenylephrine, indicating that NKCC1 influences tone in resistance vessels. The hypotensive effect of bumetanide was proportionately greater in rats made hypertensive by a 7-day infusion of norepinephrine (12.7%, P < 0.001 vs. normotensive rats) but much less so when hypertension was produced by a fixed aortic coarctation (8.0%), again consistent with an effect of bumetanide on resistance vessels rather than other determinants of blood pressure. We conclude that NKCC1 influences blood pressure through effects on smooth muscle tone in resistance vessels and that this effect is augmented in hypertension. resistance arteries; hypertension; bumetanide doi:10.1152/ajpheart.01402.2006