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Recently, neutrophil‐to‐lymphocyte ratio (NLR) and monocyte‐to‐lymphocyte ratio (MLR) are frequently used to evaluate disease progression and outcome. Here, we aim to analyze the associations between NLR or MLR and kidney function in undiagnosed hypertensive individuals from general population during routine health checkup. Liver function was analyzed for comparison. From 2011 to 2016, 53 939 examiners have registered for health checkup in Yanbian University Hospital, Yanbian, China. Among 15 219 participants who have complete datasets, 4997 individuals were hypertensive (HTN, SBP/DBP: ≥ 140/90 mm Hg). NLR, glucose, lipids (Chol, TG, LDL), kidney (CREA, BUN), and liver (AST, ALT, GGT, ALB, TBIL) functional parameters were significantly higher in HTN. Pearman correlation analysis showed that NLR was positively correlated with SBP and CREA only in HTN. MLR was associated with CREA in both HTN and non‐HTN. NLR or MLR was associated with liver functions similarly in HTN and non‐HTN. The authors then divided NLR or MLR into tertiles (NLR: 0‐1.7276, 1.7276‐3, >3; MLR: 0‐0.1845, 0.1845‐0.3, >0.3). NLR was positively associated with BUN at NLR >1.7276 and with CREA at all tertiles in HTN. MLR was correlated with CREA and BUN at high MLR in non‐HTN. Further analysis showed that age or gender did not affect the associations of NLR and MLR with kidney function in HTN, but strong association was observed in male or aged (>65 years old) non‐HTN group. These results showed that NLR could be used as a cost‐effective predictor of kidney abnormality in HTN patients even in a general population.

Neuronal nitric oxide synthase (nNOS or NOS1) is the major endogenous source of myocardial nitric oxide (NO), which facilitates cardiac relaxation and modulates contraction. In the healthy heart it regulates intracellular Ca2+, signalling pathways and oxidative homeostasis and is upregulated from early phases upon pathogenic insult. nNOS plays pivotal roles in protecting the myocardium from increased oxidative stress, systolic/diastolic dysfunction, adverse structural remodelling and arrhythmias in the failing heart. Here, we show that the downstream target proteins of nNOS and underlying post-transcriptional modifications are shifted during disease progression from Ca2+-handling proteins [e.g. PKA-dependent phospholamban phosphorylation (PLN-Ser16)] in the healthy heart to cGMP/PKG-dependent PLN-Ser16 with acute angiotensin II (Ang II) treatment. In early hypertension, nNOS-derived NO is involved in increases of cGMP/PKG-dependent troponin I (TnI-Ser23/24) and cardiac myosin binding protein C (cMBP-C-Ser273). However, nNOS-derived NO is shown to increase S-nitrosylation of various Ca2+-handling proteins in failing myocardium. The spatial compartmentation of nNOS and its translocation for diverse binding partners in the diseased heart or various nNOS splicing variants and regulation in response to pathological stress may be responsible for varied underlying mechanisms and functions. In this review, we endeavour to outline recent advances in knowledge of the molecular mechanisms mediating the functions of nNOS in the myocardium in both normal and diseased hearts. Insights into nNOS gene regulation in various tissues are discussed. Overall, nNOS is an important cardiac protector in the diseased heart. The dynamic localization and various mediating mechanisms of nNOS ensure that it is able to regulate functions effectively in the heart under stress.

4-Hydroxynonenal (4-HNE) is considered as a harmful signaling molecule. The accumulation of 4-HNE is implicated under oxidative stress such as ischemia/reperfusion injury. Previously we have report...

4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current (ITO,1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-à-go-go-related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study ITO,1. Under voltage clamp, whole cell HERG current (IHERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 +/- 0.5 mM. Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 mM 4-AP inhibited peak IHERG during an applied action potential clamp waveform by ~59 %. It also significantly prolonged action potentials and inhibited resurgent IK tails from guinea-pig isolated ventricular myocytes, which lack an ITO,1. We conclude that by blocking the alpha-subunit of the IKr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on ITO,1.

Arterioles and small arteries change their tone in response to transmural pressure changes, called myogenic tone (MT). In comparison to the branches of cerebral arteries (CA) showing prominent MT, the third branches of mesenteric arteries (MA) with similar diameters show weaker MT. Here, we aimed to analyze the electrophysiological differences responsible for the weaker MT in MA (MT MA ) than MT in CA (MT CA ). We measured ionic current using patch clamp in isolated MA smooth muscle cells (MASMCs) and CA smooth muscle cells (CASMCs) of rats. MT was analyzed using video analysis of pressurized small arteries. Quantitative‐PCR (q‐PCR) and immunofluorescence confocal microscopy were used to compare the mRNA and protein expression level of big‐conductance Ca 2+ ‐activated K + channel (BK C a ) subunits (Slo1 α and Slo β 1). Whole‐cell patch clamp study revealed higher density of voltage‐operated Ca 2+ channel current (I C aV ) in the MASMCs than in CASMCs. Although voltage‐gated K + channel current (I K v ) was also higher in MASMCs, treatment with Kv inhibitor (4‐aminopyridine) did not affect MT MA . Interestingly, BK C a current density and the frequency of spontaneous transient outward currents (STOCs) were consistently higher in MASMCs than in CASMCs. Inside‐out patch clamp showed that the Ca 2+ ‐sensitivity of BK C a is higher in MASMCs than in CASMCs. Iberiotoxin, a selective BK C a inhibitor, augmented MT MA by a larger extent than MT CA . Although q‐PCR analysis did not reveal a significant difference of mRNAs for Slo1 α and Slo β 1, immunofluorescence image suggested higher expression of Slo1 α in MASMCs than in CASMCs. Despite the large I C aV density, the high activities of BK C a including the more frequent STOCs in MASMCs veils the potentially strong MT MA .

The trivalent cation, gadolinium (Gd3+) is commonly used to inhibit stretch-activated channels. In this report, we show that Gd3+ also inhibits ionic current (INaCa), carried by the Na+-Ca2+ exchanger protein. Under selective recording conditions, Gd3+ inhibited both outward and inward INaCa from guinea-pig isolated ventricular myocytes in a dose-dependent manner, with half-maximal inhibition concentrations (IC50) of 30.0±4.0 μM at +60 mV (Hill-coefficient, h=1.04±0.13) and 20.0±2.7 μM at −100 mV (h=1.13±0.16), respectively (P>0.05, n=5–9). Thus, inhibition was not voltage-dependent. The time from Gd3+ application to steady-state effect was slow compared to the divalent blocker Ni2+. The slow time course appeared to reflect gradual Gd3+ accumulation at its binding site on the exchanger, rather than a use-dependent blocking mechanism. This study indicates that for experiments in which Gd3+ is used, its inhibitory effect on INaCa should be taken into account. British Journal of Pharmacology (2000) 130, 485–488; doi:10.1038/sj.bjp.0703353

1. Stretch-activated channels (SACs) were studied in isolated rat atrial myocytes using the whole-cell and single-channel patch clamp techniques. Longitudinal stretch was applied by using two patch electrodes. 2. In current clamp configuration, mechanical stretch of 20 % of resting cell length depolarised the resting membrane potential (RMP) from -63.6 +/- 0.58 mV (n = 19) to -54.6 +/- 2.4 mV (n = 13) and prolonged the action potential duration (APD) by 32.2 +/- 8.8 ms (n = 7). Depolarisation, if strong enough, triggered spontaneous APs. In the voltage clamp configuration, stretch increased membrane conductance in a progressive manner. The current-voltage (I-V ) relationship of the stretch-activated current (ISAC) was linear and reversed at -6.1 +/- 3.7 mV (n = 7). 3. The inward component of ISAC was abolished by the replacement of Na+ with NMDG+, but ISAC was hardly altered by the Cl- channel blocker DIDS or removal of external Cl-. The permeability ratio for various cations (PCs:PNa:PLi = 1.05:1:0.98) indicated that the SAC current was a non-selective cation current (ISAC,NC). The background current was also found to be non-selective to cations (INSC,b); the permeability ratio (PCs:PNa:PLi = 1.49:1:0.70) was different from that of ISAC,NC. 4. Gadolinium (Gd3+) acted on INSC,b and ISAC,NC differently. Gd3+ inhibited INSC,b in a concentration-dependent manner with an IC50 value of 46.2 +/- 0.8 microM (n = 5). Consistent with this effect, Gd3+ hyperpolarised the resting membrane potential (-71.1 +/- 0.26 mV, n = 9). In the presence of Gd3+ (0.1 mM), stretch still induced ISAC,NC and diastolic depolarisation. 5. Single-channel activities were recorded in isotonic Na+ and Cs+ solutions using the inside-out configuration. In NMDG+ solution, outward currents were abolished. Gd3+ (100 microM) strongly inhibited channel opening both from the inside and outside. In the presence of Gd3+ (100 microM) in the pipette solution, an increase in pipette pressure induced an increase in channel opening (21.27 +/- 0.24 pS; n = 7), which was distinct from background activity. 6. We concluded from the above results that longitudinal stret in rat atrial myocytes induces the activation of non-selective cation channels that can be distinguished from background channels by their different electrophysiology and pharmacology.