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Aquaporin-2 (AQP2) mediates vasopressin-regulated collecting duct water permeability. Chronic heart failure (CHF) is characterized by abnormal renal water retention. We hypothetized that upregulation of aquaporin-2 water channel could account for the water retention in CHF. Male rats underwent either a left coronary artery ligation, a model of CHF, or were sham operated. 31-33 d after surgery, mean arterial pressure (MAP) and cardiac output were measured in conscious animals, and the animals were killed 24 h later. Cardiac output (CO) and plasma osmolality were significantly decreased and plasma vasopressin increased in the CHF as compared to the sham-operated rats. Both mRNA and protein AQP2 were significantly increased in the kidneys of the CHF rats. The effect of oral administration of a nonpeptide V2 vasopressin receptor antagonist, OPC 31260, was therefore investigated. OPC 31260 induced a significant increase in diuresis, decrease in urinary osmolality, and rise in plasma osmolality in the OPC 31260-treated CHF rats as compared to untreated CHF rats. The mRNA and protein AQP2 were significantly diminished in both cortex and inner medulla of the treated CHF rats. In conclusion, an early upregulation of AQP2 is present in CHF rats and this upregulation is inhibited by the administration of a V2 receptor antagonist. The results indicate a major role for vasopressin in the upregulation of AQP2 water channels and water retention in experimental CHF in the rat. Water retention is characteristic of advanced congestive heart failure (CHF) 1 (1). Moreover, hyponatremia is a well-defined predictor of mortality of heart failure (2, 3). Plasma arginine vasopressin (AVP) concentrations have been found to be elevated in hyponatremic patients with CHF (4) and are not suppressed during an acute water loading (5). The hypothalamic messenger RNA for vasopressin has also been shown to be increased in experimental CHF (6). Recently, the aquaporin-2 (AQP2) water channel has been cloned and located in the principal cells of the collecting duct (7). Regulation of water transport across the renal principal cells depends on two mechanisms. ( a ) The rapid action of AVP to increase the water permeability of the apical membrane of principal cells by translocating the AQP2 water channels from cytosolic vesicles to the plasma membranes (8). This short-term effect is mediated by the V2 receptor-dependent increase of adenosine 3 Ј 5 Ј -cAMP and may involve cAMP-dependent phosphorylation of AQP2 (9). ( b ) Long-term regulation of collecting duct water permeability is characterized by a increase in AQP2 mRNA and protein content during fluid restriction and AVP infusion into diabetes insipidus (Brattelboro) rats (10-12). Therefore, in a pathophysiological situation such as CHF, a chronic increase in plasma AVP concentration could upregulate the expression of AQP2.This study was therefore undertaken to determine the AQP2 expression in a rat model of CHF induced by the ligation of the left coronary artery. For this purpose, AQP2 mRNA...

Reexpansion of collapsed lung creates intrapulmonary shear forces. In an earlier study we showed that application of a negative end-expiratory airway pressure (NEEP) to normal rabbit lungs in vivo produced tidal collapse and reexpansion with transient changes in compliance and gas exchange but no histologic damage. In the present study we examined NEEP in a model of surfactant perturbation produced by an inhaled aerosol of 2% and 5% dioctyl sodium sulfosuccinate (DOSS). DOSS increased alveolocapillary permeability without affecting compliance or oxygenation. Repeated collapse and reexpansion (RECOREX), caused by NEEP for 3 h was compared with ventilation with positive-end expiratory pressure (PEEP). Groups ventilated with PEEP maintained normal lung mechanics and morphology even if pretreated with DOSS. NEEP disturbed lung mechanics and gas exchange with persistent dose-related histologic damage in animals pretreated with DOSS. Lungs subjected to NEEP without DOSS had normal morphology. We conclude that perturbation of the surfactant system makes lungs vulnerable to injury by RECOREX. The combination of DOSS and NEEP might lead to leakage of plasma proteins into alveoli, causing inactivation of surfactants and increased shear forces with resulting lung damage. Similar mechanisms may accelerate lung damage in the respiratory distress syndrome.

Water retention is characteristic of pregnancy but the mechanism(s) of the altered water metabolism has yet to be elucidated. The collecting duct water channel, aquaporin 2 (AQP2), plays a pivotal role in the renal water regulation, and we hypothesized that AQP2 expression could be modified during pregnancy. Sprague-Dawley female rats were studied on days 7 (P7), 14 (P14), and 20 (P20) of pregnancy, and expression of AQP2 in papillae was examined. Nonpregnant (NP) littermates were used as controls. Plasma osmolalities were significantly lower in pregnant rats by day 7 of gestation (P7 283.8+/-1.82, P14 284.3+/-1.64, P < 0.001, P20 282. 4+/-1.32, P < 0.0001, vs. NP 291.8+/-1.06 mosmol/kgH2O). However, plasma vasopressin concentrations in pregnant rats were not significantly different than in nonpregnant rats (NP 1.03+/-0.14, P7 1.11+/-0.21, P14 1.15+/-0.21, P20 1.36+/-0.24 pg/ml, NS). The mRNA of AQP2 was increased early during pregnancy: AQP2/beta actin: P7 196+/-17.9, P14 200+/-6.8, and P20 208+/-15.5%, P < 0.005 vs. NP (100+/-11.1%). AQP2 protein was also increased during pregnancy: AQP2 protein: P7 269+/-10.0, P14 251+/-12.0, P < 0.0001, and P20 250+/-13.6%, P < 0.001 vs. NP (100+/-12.5%). The effect of V2 vasopressin receptor antagonist, OPC-31260, was then investigated. AQP2 mRNA was suppressed significantly by OPC-31260 administration to P14 rats (AQP2/beta actin: P14 with OPC-31260 39.6+/-1.7%, P < 0.001 vs. P14 with vehicle) and was decreased to the same level of expression as NP rats receiving OPC-31260. Similar findings were found with the analysis of AQP2 protein. The decreased plasma osmolality of P14 rats was not modified by OPC-31260. The results of the study indicate that upregulation of AQP2 contributes to the water retention in pregnancy through a V2 receptor-mediated effect. In addition to vasopressin, other factors may be involved in this upregulation.

ObjectiveTo investigate the prognostic effect of newly diagnosed diabetes mellitus (NDM) and impaired glucose tolerance (IGT) post myocardial infarction (MI).Research Design and MethodsRetrospective cohort study of 768 patients without preexisting diabetes mellitus post-MI at one centre in Yorkshire between November 2005 and October 2008. Patients were categorised as normal glucose tolerance (NGT n = 337), IGT (n = 279) and NDM (n = 152) on pre- discharge oral glucose tolerance test (OGTT). Primary end-point was the first occurrence of major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal MI, severe heart failure (HF) or non-haemorrhagic stroke. Secondary end-points were all cause mortality and individual components of MACE.ResultsPrevalence of NGT, impaired fasting glucose (IFG), IGT and NDM changed from 90%, 6%, 0% and 4% on fasting plasma glucose (FPG) to 43%, 1%, 36% and 20% respectively after OGTT. 102 deaths from all causes (79 as first events of which 46 were cardiovascular), 95 non fatal MI, 18 HF and 9 non haemorrhagic strokes occurred during 47.2 ± 9.4 months follow up. Event free survival was lower in IGT and NDM groups. IGT (HR 1.54, 95% CI: 1.06–2.24, p = 0.024) and NDM (HR 2.15, 95% CI: 1.42–3.24, p = 0.003) independently predicted MACE free survival. IGT and NDM also independently predicted incidence of MACE. NDM but not IGT increased the risk of secondary end-points.ConclusionPresence of IGT and NDM in patients presenting post-MI, identified using OGTT, is associated with increased incidence of MACE and is associated with adverse outcomes despite adequate secondary prevention.

LALANI, ATUL P., BALAVENKATESH KANNA, JOSEPH JOHN, KEVIN J. FERRICK, MICHAEL S. HUBER, AND LAWRENCE E. SHAPIRO. Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res. 2000:8:20 -28. Objective: The occurrence of small high-frequency electrocardiogram (ECG) potentials (1 to 20 V) seen at the end of the QRS complex and into the ST segment have been correlated with increased risk for ventricular arrhythmias and sudden cardiac death. Computer-assisted analysis of these "late potentials" by signal-averaged electrocardiography (SAECG) has been studied and utilized to predict the likelihood of ventricular arrhythmias in various clinical states. Obesity is associated with significant cardiovascular morbidity and sudden death. Ventricular arrhythmias are postulated causes. We studied the occurrence of late potentials in a randomly selected group of obese patients and healthy volunteers. Research Methods and Procedures:We performed SAECG on 105 subjects. Of these, 62 were obese ambulatory patients with body mass index (BMI) of Ͼ30 kg/m 2 , whereas 43 were healthy asymptomatic volunteers with a BMI of Ͻ30 kg/m 2 . Patients with a history of clinical heart disease and pulmonary disease, electrolyte abnormalities, recent hospitalizations, or abnormal screening ECG or taking medications known to alter the QRS interval were excluded. At least 250 beats were analyzed with a noise level of Ͻ0.50 V. Criteria of a late potential include QRS duration Ͼ114 ms, high-frequency low amplitude Ͼ38 ms, and root-mean-square voltage Ͻ20 V. Patients were divided into four subgroups based on BMI values. The prevalence of SAECG abnormalities in each BMI subgroup was studied. We utilized multiple logistic regression analysis to study the effect of obesity, hypertension, and diabetes mellitus on abnormal SAECG results. Results: Compared to age-and sex-matched healthy volunteers with BMI of Ͻ30 kg/m 2 , obese patients with BMI of Ͼ30 kg/m 2 had significantly more abnormalities on SAECG (4.6% vs. 55%). In the obese group, the prevalence and number of abnormalities increased with increase in BMI (35% in the BMI 31 to 40 kg/m 2 subgroup, 86% in the BMI 41 to 50 kg/m 2 subgroup, and 100% in patients with BMI of Ͼ50 kg/m 2 ). Multiple logistic regression analysis shows that BMI is an independent predictor variable of abnormal SAECG results in obese patients (n ϭ 62) with BMI of Ͼ30kg/m 2 as well as in all study subjects (n ϭ 105). BMI also predicts abnormality of each abnormal SAECG criterion in both obese and all subjects. Hypertension was found to influence the QRS duration alone in obese and all subjects. Discussion: Obesity is associated with increased occurrence of abnormal SAECG results. These abnormalities are found both in obese patients with and without hypertension and/or diabetes. Obesity is an independent predictor variable of abnormal SAECG results. A history of hypertension predicts abnormality of QRS duration only.

The abrupt increase in mortality with HbA1c may make it a useful risk stratification tool in non-diabetic patients with LVEF

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