Effects of bone remodelling on calcium mass transfer during haemodialysis

Background. During haemodialysis, calcium balance can affect, or be affected by, mineral metabolism. However, when dialysate calcium concentration (d[Ca]) is chosen or kinetic models are employed to calculate calcium balance, bone remodelling is rarely considered. In this study, we examined whether bone remodelling affects calcium mass transfer during haemodialysis. Methods. We dialysed 23 patients using a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L. Calcium mass transfer was measured and associated with remodelling bone factors. Results. Calcium balance varied widely depending on the d[Ca]. Calcium removal was -578 +/- 389, -468 +/- 563, +46 +/- 400 and +405 +/- 413 mg when a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L was used, respectively (1.0 and 1.25 VS 1.5 and 1.75 mmol/L, P<0.001; 1.5 vs 1.75 mmol/L, P<0.05). Univariate analysis showed that calcium balance correlated with calcium gradient, parathyroid hormone (PTH), osteocalcin and dialysis vintage. Multivariate analysis revealed that calcium balance was dependent on calcium gradient, PTH and osteocalcin. Conclusions. These results suggest that bone remodelling could affect calcium mass transfer during haemodialysis.

Ten-Year Experience with Sevelamer and Calcium Salts as Phosphate Binders

Most patients with chronic kidney disease experience abnormalities in serum calcium, phosphorus, parathyroid hormone, and vitamin D metabolism. These can lead to vascular calcification (VC), which has been associated with increased risk for cardiovascular disease and mortality. Although hyperphosphatemia is believed to be a risk factor for mortality and VC, no randomized trial was ever designed to demonstrate that lowering phosphate reduces mortality. Nonetheless, binders have been used extensively, and the preponderance of evidence shows that sevelamer slows the development of VC whereas calcium salts do not. Four studies have demonstrated a slower progression of VC with sevelamer than with calcium-containing binders, although a fifth study showed nonsuperiority. Conversely, the results on mortality with sevelamer have been variable, and data on calcium-based binders are nonexistent. Improved survival with sevelamer was demonstrated in a small randomized clinical trial, whereas a larger randomized trial failed to show a benefit. In addition, preclinical models of renal failure and preliminary clinical data on hemodialysis patients suggest a potential benefit for bone with sevelamer. Meanwhile, several randomized and observational studies suggested no improvement in bone density and fracture rate, and a few noted an increase in total and cardiovascular mortality in the general population given calcium supplements. Although additional studies are needed, there are at least indications that sevelamer may improve vascular and bone health and, perhaps, mortality in hemodialysis patients, whereas data on calcium-based binders are lacking. Clin J Am Soc Nephrol 5: S31-S40, 2010. doi: 10.2215/CJN.05880809

Vitamin D Receptor and Calcium-Sensing Receptor Gene Polymorphisms in Hypercalciuric Stone-Forming Patients

Background/Aim: Some studies have identified an association of kidney stone formation with vitamin D receptor (VDR) or calcium-sensing receptor (CaSR) polymorphisms. We aimed to evaluate the association between these polymorphisms with urinary calcium excretion (uCa) in calcium-stone-forming patients. Methods: VDR polymorphism, detected by BsmI digestion, and 3 CaSR polymorphisms (G/T at codon 986, G/A at codon 990 and C/G at codon 1011), detected by direct sequencing, were evaluated in 100 hypercalciuric (HCa) and 101 normocalciuric (NCa) calcium-stone-forming patients. Results: The total allelic frequency of VDR polymorphism was: 16% BB, 49% Bb and 35% bb. The prevalence of bb genotype was significantly higher in the HCa when compared to the NCa group (43 vs. 27%). With respect to CaSR polymorphisms, 986S, 990G and 1011E variant alleles were detected, respectively, in 5, 4 and 3% of the whole sample and 5 CaSR haplotypes were identified: 94% ARQ (wildtype), 3% SRQ, 1.5% AGQ, 1.0% ARE and 0.5% AGE. No statistical differences have been observed between NCa and HCa with respect to these CaSR haplotypes. Conclusions: The present study suggested that bb homozygous for VDR polymorphism was overrepresented in hypercalciuric stone formers. Urinary calcium excretion was not associated with CaSR polymorphism in the present sample. Copyright (C) 2009 S. Karger AG, Basel

Calcium channel blockers are independently associated with short sleep duration in hypertensive patients with obstructive sleep apnea

Objective Obstructive sleep apnea (OSA) and hypertension (HYP) frequently coexist and have additive harmful effects on the cardiovascular system. There is also growing evidence that short sleep duration may contribute independently to poor cardiovascular outcome. The aim of this study was to evaluate the potential influence of antihypertensive medication on sleep parameters objectively measured by standard polysomnography in hypertensive patients with OSA. Methods We evaluated consecutive patients with a recent diagnosis of OSA by full polysomnography (apnea hypopnea index >= 5 events/h) and HYP. Smokers, patients with diabetes mellitus, heart failure, or using hypnotics and benzodiazepines were excluded. Results We evaluated 186 hypertensive patients with OSA, 64% men. All patients were on at least one antihypertensive medication, including angiotensin-converting enzyme inhibitors (37%), beta-blockers (35%), angiotensin receptor blockers (32%), diuretics (29%) and calcium channel blockers (21%). Backward multiple regression analysis showed that age (P <= 0.001) and the use of calcium channel blockers (P=0.037) were the only factors inversely associated with lower total sleep time. Sleep efficiency was inversely associated only with age (P <= 0.001), whereas the use of calcium channel blockers had a nonsignificant trend (P=0.092). Use of calcium channel blockers was associated with significant reduction in total sleep time (-41 min, P=0.005) and 8% lower sleep efficiency (P=0.004). No other antihypertensive medication, including diuretics and beta-blockers, was associated with sleep impairment. Conclusion Calcium channel blockers may impact negatively on sleep duration in hypertensive patients with OSA. The mechanisms and significance of this novel finding warrants further investigation. J Hypertens 29: 1236-1241 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Angiotensin II Binding to Angiotensin I-Converting Enzyme Triggers Calcium Signaling

Angiotensin (Ang) I-converting enzyme (ACE) is involved in the control of blood pressure by catalyzing the conversion of Ang I into the vasoconstrictor Ang II and degrading the vasodilator peptide bradykinin. Human ACE also functions as a signal transduction molecule, and the binding of ACE substrates or its inhibitors initiates a series of events. In this study, we examined whether Ang II could bind to ACE generating calcium signaling. Chinese hamster ovary cells transfected with an ACE expression vector reveal that Ang II is able to bind with high affinity to ACE in the absence of the Ang II type 1 and type 2 receptors and to activate intracellular signaling pathways, such as inositol 1,4,5-trisphosphate and calcium. These effects could be blocked by the ACE inhibitor, lisinopril. Calcium mobilization was specific for Ang II, because other ACE substrates or products, namely Ang 1-7, bradykinin, bradykinin 1-5, and N-acetyl-seryl-aspartyl-lysyl-proline, did not trigger this signaling pathway. Moreover, in Tm5, a mouse melanoma cell line endogenously expressing ACE but not Ang II type 1 or type 2 receptors, Ang II increased intracellular calcium and reactive oxygen species. In conclusion, we describe for the first time that Ang II can interact with ACE and evoke calcium and other signaling molecules in cells expressing only ACE. These findings uncover a new mechanism of Ang II action and have implications for the understanding of the renin-Ang system. (Hypertension. 2011;57:965-972.) . Online Data Supplement

Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats

Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The small (SK(Ca)) and intermediate (IK(Ca)) calcium-activated potassium channels play a key role in endothelium-dependent relaxation. Because the repressor element 1-silencing transcription factor (REST) negatively regulates IK(Ca) expression, we hypothesized that augmented REST and decreased IK(Ca) expression contributes to impaired endothelium-dependent vasodilation associated with hypertension. Acetylcholine (ACh) responses were slightly decreased in small mesenteric arteries from male stroke-prone spontaneously hypertensive rats (SHRSPs) versus arteries from Wistar Kyoto (WKY) rats. Incubation with N-nitro-L-arginine methyl ester (L-NAME; 100 mu mol/L) and indomethacin (100 mu mol/L) greatly impaired ACh responses in vessels from SHRSP. lberiotoxin (0.1 mu mol/L), which is a selective inhibitor of large-conductance K(Ca) (BK(Ca)) channels, did not modify EDHF-mediated vasodilation in SHRSP or WKY. UCL-1684 (0.1 mu mol/L.), which is a selective inhibitor of SKCa channels, almost abolished EDHF-mediated vasodilation in WKY and decreased relaxation in SHRSP. 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole (TRAM-34; 10 mu mol/L) and charybdotoxin (0.1 mu mol/L), which are both IKCa inhibitors, produced a small decrease of EDHF relaxation in WKY but completely abrogated EDHF vasodilation in SHRSP. EDHF-mediated relaxant responses were completely abolished in both groups by simultaneous treatment with UCL-1684 and TRAM-34 or charybdotoxin. Relaxation to SK(Ca)/IK(Ca) channels agonist NS-309 was decreased in SHRSP arteries. The expression of SK(Ca) was decreased, whereas IK(Ca) was increased in SHRSP mesenteric arteries. REST expression was reduced in arteries from SHRSP. Vessels incubated with TRAM-34 (10 mu mol/L) for 24h displayed reduced REST expression and demonstrated no differences in IK(Ca). In conclusion, IK(Ca) channel upregulation, via decreased REST, seems to compensate deficient activity of SK(Ca) channels in the vasculature of spontaneously hypertensive rats. (Translational Research 2009; 154:183-193)

Luteinizing hormone (LH) acts through PKA and PKC to modulate T-type calcium currents and intracellular calcium transients in mice Leydig cells

LH increases the intracellular Ca(2+) concentration ([Ca(2+)](i)) in mice Leydig cells, in a process triggered by calcium influx through T-type Ca(2+) channels. Here we show that LH modulates both T-type Ca(2+) currents and [Ca(2+)]; transients through the effects of PKA and PKC. LH increases the peak calcium current (at -20 mV) by 40%. A similar effect is seen with PMA. The effect of LH is completely blocked by the PKA inhibitors H89 and a synthetic inhibitory peptide (IP-20), but only partially by chelerythrine (PKC inhibitor). LH and the blockers induced only minor changes in the voltage dependence of activation, inactivation or deactivation of the currents. Staurosporine (blocker of PKA and PKC) impaired the [Ca(2+)](i) changes induced by LH. A similar effect was seen with H89. Although PMA slowly increased the [Ca(2+)](i) the subsequent addition of LH still triggered the typical transients in [Ca(2+)](i). Chelerythrine also does not avoid the Ca(2+) transients, showing that blockage of PKC is not sufficient to inhibit the LH induced [Ca(2+)](i) rise. In summary, these two kinases are not only directly involved in promoting testosterone synthesis but also act on the overall calcium dynamics in Leydig cells, mostly through the activation of PKA by LH. (c) 2011 Elsevier Ltd. All rights reserved.

Small-World Effect in Epidemics Using Cellular Automata

The spread of an infectious disease in a population involves interactions leading to an epidemic outbreak through a network of contacts. Extending on Watts and Strogatz (1998) who showed that short-distance connections create a small-world effect, a model combining short-and long-distance probabilistic and regularly updated contacts helps considering spatial heterogeneity. The method is based on cellular automata. The presence of long-distance connections accelerates the small-world effect, as if the world shrank in proportion of their total number.