Background: It has been reported that elevated levels of serum uric acid are related to hypertension and cardiovascular disease. Recent studies, however, have found little association between hyperuricemia and hypertension. Methods and Results:The association of serum uric acid with blood pressure was examined in 3,960 Japanese male workers (18-64 years of age; mean age, 42.3±0.2 years). Systolic blood pressure was significantly correlated with serum uric acid. Multiple regression analysis also showed that both systolic and diastolic blood pressures were independently associated with serum uric acid. When subjects were divided into 6 groups according to blood pressure on the basis of the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009), serum uric acid was elevated in a linear fashion as blood pressure increased. A similar relationship was found even in 3,608 subjects who were not taking anti-hypertensive or uric acid-lowering agents. In contrast, no relation was found between serum uric acid and blood pressure in 352 subjects taking anti-hypertensive medicine.Conclusions: Blood pressure is closely associated with serum uric acid. Serum uric acid might be associated with the increase in blood pressure, because there is no relation between serum uric acid and blood pressure in the subjects treated with anti-hypertensive medications. (Circ J 2011; 75: 2827 - 2832
The intracellular signaling pathways responsible for extracellualr uridine-5'-triphosphate (UTPo)-induced chloride (Cl-) currents (I(Cl.UTP)) were studied in mouse ventricular myocytes with the whole-cell clamp technique. UTPo (0.1 to 100 microM) activated a whole-cell current that showed a time-independent activation, a linear current-voltage relationship in symmetrical Cl- solutions, an anion selectivity of Cl-> iodide > aspartate, and an inhibition by a thiazolidinone-derived specific inhibitor (CFTR(inh)-172, 10 microM) of cystic fibrosis transmembrane conductance regulator (CFTR), but not by a disulfonic stilbene derivative (DIDS, 100 microM), these properties matching those of CFTR Cl- channels. The potency order of nucleotides for an activation of the Cl- current was UTP = ATP > uridine-5'-diphosphate (UDP) = ADP. Suramin (100 microM), a P2Y receptor antagonist, strongly inhibited the UTPo -activation of the Cl- current, whereas pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 100 microM), another P2Y receptor antagonist, induced little inhibition of I(Cl.UTP). The activation of I(Cl.UTP) was sensitive to protein kinase C (PKC) inhibitor, phospholipase C (PLC) inhibitor, intracellular GDPbetaS (nonhydrolyzable GDP analogue) or anti-Gq/11 antibody. UTPo failed to activate the Cl- current when the cells were dialyzed with nonhydrolyzable ATP analogues (ATPS or AMP-PNP) without ATP, suggesting that ATP hydrolysis is a prerequisite for the current activation. I(Cl.UTP) was persistently activated with a mixture of ATPgammaS + ATP in the pipette, suggesting the involvement of phosphorylation reaction in the current activation process. Our results strongly suggest that I(Cl.UTP) is due to the activation of CFTR Cl- channels through Gq/11-coupled P2Y2 receptor-PLC-PKC signaling and ATP hydrolysis in mouse heart.
Volume-regulated outwardly rectifying anion channel (VRAC) plays an important role in cellvolume regulation in many types of cells. Little is known about the regulation of VRAC by phosphatidylinositides (PIs), which include phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2). We examined the effect of PIs on the VRAC current activated in hypotonic solution in mouse ventricular cells. VRAC current was inhibited strongly by intracellular application of LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or anti-PIP3 antibody (PIP3-Ab), and less strongly by anti-PIP2 antibody (PIP2-Ab). LY294002 inhibited regulatory volume decrease in hypotonically swollen cells, which was in parallel with the VRAC inhibition. Intracellular PIP3 or PIP2 influenced neither the basal background current in isotonic solution nor the VRAC current in hypotonic solution. However, PIP3, but not PIP2, restored the VRAC current suppressed by LY294002 or PIP2-Ab. These results suggest that the activation of VRAC current requires the presence of intracellular PIP3, that PI3K-mediated increase in PIP3 level is sufficient to fully activate VRAC current, and that PIP3 alone without osmotic stimulation cannot induce VRAC current. We propose that VRAC in mouse ventricular cells is regulated by PIP3 and/or its down stream signaling pathways.
Volume-regulated anion channels (VRACs) play an important role in cell-volume regulation. a1-Adrenoceptor stimulation by phenylephrine (PE) suppressed the hypotonic activation of VRAC current in mouse ventricular cells and regulatory volume decrease (RVD) was also absent in PE-treated cells. We examined whether the effects of a1-adrenoceptor stimuli on VRAC current were modulated by phosphatidylinositol signalling. EXPERIMENTAL APPROACHWhole-cell patch-clamp method was used to record the hypotonicity-induced VRAC current in mouse ventricular cells. RVD was analyzed by videomicroscopic measurement of cell images. KEY RESULTSThe attenuation of VRAC current by PE was suppressed by a1A-adrenoceptor antagonists (prazosin and WB-4101), anti-Gq protein antibody and a specific phosphoinositide-specific phospholipase C (PLC) inhibitor (U-73122), but not by antagonists for a1B-, a1D-or b-adrenoceptor, or protein kinase C inhibitors. The inhibition of VRAC by PE was antagonized by intracellular excess phosphatidylinositol 4,5-bisphosphate (PIP2), while intracellular anti-PIP2 antibody (PIP2 Ab) inhibited the activation of VRAC currents. When cells were loaded with phosphatidylinositol 3,4,5-trisphosphate (PIP3) with or without PIP2 Ab, PE little affected the VRAC current. Extracellular m-3M3FBS (an activator of PLC) suppressed VRAC in the absence of PE, and this effect was reversed by intracellular excess PIP2. CONCLUSIONS AND IMPLICATIONSOur results indicate that the stimulation of a1A-adrenoceptors by PE inhibited the activation of cardiac VRAC current via PIP3 depletion brought about by PLC-dependent reduction of membrane PIP2 level.
The currents through the volume-regulated outwardly rectifying anion channel (VRAC) were measured in single ventricular myocytes obtained from streptozotocin (STZ)-induced diabetic mice, using whole-cell voltage-clamp method. In myocytes from STZ-diabetic mice, the density of VRAC current induced by hypotonic perfusion was markedly reduced, compared with that in the cells form normal control mice. Video-image analysis showed that the regulatory volume decrease (RVD), which was seen in normal cells after osmotic swelling, was almost lost in myocytes from STZ-diabetic mice. Some mice were pretreated with 3-O-methylglucose before STZ injection, to prevent the STZ's beta cell toxicity. In the myocytes obtained from such mice, the magnitude of VRAC current and the degree of RVD seen during hypotonic challenge were almost normal. Incubation of the myocytes from STZ-diabetic mice with insulin reversed the attenuation of VRAC current. These findings suggested that the STZ-induced chronic insulin-deficiency was an important causal factor for the attenuation of VRAC current. Intracellular loading of the STZ-diabetic myocytes with phosphatidylinositol 3,4,5-trisphosphate (PIP3), but not phosphatidylinositol 4,5-bisphosphate (PIP2), also reversed the attenuation of VRAC current. Furthermore, treatment of the normal cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, suppressed the development of VRAC current. We postulate that an impairment PI3K-PIP3 pathway, which may be insulin-dependent, is responsible for the attenuation of VRAC currents in STZ-diabetic myocytes.
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