Human blood-pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian-syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon-Syndrome(GS), the phenotypic inverse of the salt-wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low dose thiazide diuretics or a low salt diet. Variants within at least four genes (the With-No-lysine-(K)-kinases, WNKs1&4, Cullin3 and KeLch-like3) can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide sensitive Na-Cl Cotransporter (NCC) and hence salt retention. We discuss the key role of a kinase, STE20(sterile 20)/SPS1-related proline/Alanine-rich Kinase(SPAK), that functions as an intermediary between the WNK kinases and NCC and whose loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop Thiazide-Induced-Hyponatraemia(TIH) may give-further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. We discuss the key features of TIH including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water-retention. Taken together, the study of Gordon syndrome and TIH may increase understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new anti-hypertensive drug targets and avoidance of hyponatraemic side-effects. This article is protected by copyright. All rights reserved.

AIM:

A number of studies have examined if WCHT is associated with increased cardiovascular risk but with definitions of WCHT that were not sufficiently robust, and results have been inconsistent. This review aims to standardise the evidence by only including studies which used a definition of WCHT consistent with international guidelines.

METHOD:

Published studies were reviewed for data on vascular dysfunction, target organ damage, risk of future sustained hypertension and cardiovascular events.

FINDINGS:

WCHT has a population prevalence of approximately 15% and is associated with non-smoking and slightly elevated clinic blood pressure. Compared to normotensives, subjects with WCHT are at increased cardiovascular risk due to a higher prevalence of glucose dysregulation, increased left ventricular mass index and increased risk of future diabetes and hypertension.

CONCLUSION:

Management of a subject with WCHT should focus on cardiovascular risk factors, particularly glucose intolerance, not blood pressure alone. This article is protected by copyright. All rights reserved.

In his article, Professor Ludbrook nicely illustrates the different reasoning behind a one tailed test by comparing different experiments. The logic appears clear, so why is one-tailed testing unpopular?. Scientists generally approach statistics with trepidation seeking rules and clear pronouncements. Statistical terms pose a substantial problem for many, because everyday words gain a patina of additional or special meaning. This article is protected by copyright. All rights reserved.

In a recent paper Ludbrook repeats and attempts to defend the ancient shibboleth that one-tailed tests should be used whenever one hopes or predicts that the direction (sign) of an effect will be in a particular direction.(1) Most of the historical literature on the one- versus 2-tailed testing controversy is ignored. He cites 29 works all but two of which deal with this issue only briefly and superficially. This article is protected by copyright. All rights reserved.

Vascular reactivity is a surrogate marker for atherosclerosis and is predictive of cardiovascular outcome. Noncardiovascular surgery is associated with perioperative cardiovascular complications in high risk patients. To evaluate the impact of noncardiovascular surgery on reactive hyperaemia and arterial endothelial function, and to investigate the relationships between invasive (laparotomy) versus minimally invasive (laparoscopic) surgery and endothelial dysfunction, we prospectively evaluated 106 patients undergoing abdominal surgery under general anaesthesia (71 laparotomy, 35 laparoscopy). Measurements of blood pressure, heart rate and pain (by visual analogue scale, VAS) were undertaken. Brachial endothelium-dependent flow-mediated dilation (FMD), endothelium-independent dilation(nitroglycerin-induced dilation, NTG)and reactive hyperaemia were measured with high resolution B-mode ultrasound at preoperative day 1 (baseline), and postoperatively at 2 hours, one day and 7 days. Blood pressure and heart rate were significantly higher 2 hours postoperatively. VAS were higher (P<0.01), and reactive hyperaemia and FMD were significantly lower (P<0.001) at 2 hours and one day post-opreation compared with baseline and with postoperative day 7. FMD at postoperative day 7 recovered to baseline level. Patients undergoing laparoscopic surgery had less FMD reduction at day 1 (7.5±1.5%) and day 7 (7.9±1.5%), compared with laparotomy (6.4±1.6%, p=0.001 and 7.0±1.6%, P=0.006 respectively), consistent with potential cardiovascular benefit. NTG responses were stable throughout. On backward multivariate linear regression analysis, FMD was independently related to age and VAS (model R=0.486, F value=6.4, P<0.001). Reactive hyperaemia and arterial endothelial function are significantly reduced in the early postoperative period, particularly after laparotomy compared with laparoscopy, which may be related to post-operative cardiovascular events. This article is protected by copyright. All rights reserved.

autonomic control of the cardiovascular system in chronic kidney disease (CKD) contributes to an increased risk of cardiovascular events. We aimed to determine if and when autonomic dysfunction occurs in a conscious, telemetered, rodent model of CKD. In Lewis Polycystic Kidney (LPK; n=8) and Lewis (n=8) rats, blood pressure (BP), heart rate (HR), HR variability (HRV), systolic BP variability (SBPV) and baroreflex sensitivity (BRS) were determined from 10-16 weeks of age. LPK rats had higher systolic BP (average across all ages: 230 ± 10 vs 123 ± 0.3 P<0.001), increased SBPV (average across all ages: 13.9 ± 1.9 vs. 5.2 ± 0.2 mmHg(2) , P<0.01) and reduced low frequency HRV power (average across all ages: 1.5 ± 0.3 vs. 2.6 ± 0.2 msec(2) , P<0.05). Between 10 and 12 weeks of age, SBPV increased two-fold in the LPK rat (8.13 ± 1.05 vs. 16.10 ± 1.31 mmHg(2) , 10 vs. 12 weeks of age P<0.001), coinciding with a ~40% reduction in BRS (1.32 ± 0.14 vs. 0.79 ± 0.11 msec/mmHg, 10 vs. 12 weeks of age P<0.05). There was no difference in BRS between the LPK and Lewis rat at 10 weeks of age; however, from 12 weeks onwards BRS was reduced in the LPK rat (0.75 ± 0.01 vs. 1.17 ± 0.04 msec/mmHg, P<0.01). Baroreceptor regulation of HR becomes impaired between 10 and 12 weeks of age in the LPK rat, coinciding with an increase in SBPV. Preventing baroreflex dysfunction in CKD may reduce SBPV and the associated mortality risks. This article is protected by copyright. All rights reserved.

Chronic intermittent hypoxia (CIH) contributes to the development of cardiovascular diseases in patients with obstructive sleep apnoea. Many studies have shown an association between increased circulating endothelin (ET)-1 levels and CIH. The aim of the present study was to determine the role of ET receptors in altered aortic function in an animal model of CIH Rats were subjected to CIH (Fi o2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/week) for 3 weeks. After 3 weeks, the rats were killed and their aortas retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry and western blotting. Aortas from rats subjected to CIH exhibited marked endothelial dysfunction and increased responsiveness to ET-1. Furthermore, CIH induced increased ET-1 and ETA receptor expression, whereas ETB receptor expression was decreased. Aortic contractile responses to ET-1 were inhibited by the ETA and ETB receptor antagonists BQ-123 and BQ-788, respectively. Acetylcholine-induced relaxation responses were significantly attenuated in aortas from rats subjected to CIH, whereas CIH had no significant effect on aortic responses to sodium nitroprusside. The results of the present study suggest that increased expression of ETA receptors, which mediate a potent vasoconstrictor response, plays an important role in the pathogenesis of CIH. In addition, decreased endothelial ETB receptor expression, which is associated with the functional decline of endothelium-dependent vasodilation, also contributes to the pathogenesis of CIH. It appears that the ETB receptor-induced buffering of ET-1 responsiveness is mediated via a nitric oxide-dependent mechanism. This article is protected by copyright. All rights reserved.

Identified over a decade ago, the With-No-Lysine[K] (WNK)s have been the subsequent focus of intense research into the renal handling of Na(+) , Cl(-) , K(+) and several rare monogenetic diseases. However the potential extra-renal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca(2+) and PO4 (3-) homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggests a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels including the vascular resistance vessels where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel (TRPC) 3 and/or phosphorylation of the Na(+) -K(+) -2Cl(-) cotransporter (NKCC1) in vascular smooth muscle (VSM) cells. The WNKs and many of the cation-coupled Cl(-) cotransporters they regulate are highly expressed in the central nervous system and recent work has suggested that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy type 2 (HSAN2). Finally, the WNK-Sterile 20 kinase (STE20) signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation. This article is protected by copyright. All rights reserved.

Summary Obesity is associated with high chronic cardiac workload, due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in SHR/NDmcr-cp, an experimental model of obesity hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp, and Wistar Kyoto rats (WKY). We also assessed age-related changes in concentrations of adipocytokines in plasma and left ventricles in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the left ventricle was noted in SHR/cp relative to other strains. In the myocardium, adiponectin level was significantly lower and resistin level and the expression of proinflammatory cytokines (TNF-α and IL-6) were significantly higher in SHR/cp than in SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week-old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of the metabolic syndrome. This article is protected by copyright. All rights reserved.