Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability

We demonstrated recently that chronic administration of aldosterone to rats induces glomerular mesangial injury and activates mitogen-activated protein kinases including extracellular signal-regulated kinases 1/2 (ERK1/2). We also observed that the aldosterone-induced mesangial injury and ERK1/2 activation were prevented by treatment with a selective mineralocorticoid receptor (MR) antagonist, eplerenone, suggesting that the glomerular mesangium is a potential target for injuries induced by aldosterone via activation of MR. In the present study, we investigated whether MR is expressed in cultured rat mesangial cells (RMCs) and involved in aldosterone-induced RMC injury. MR expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. Cell proliferation and micromechanical properties were determined by [3H]-thymidine uptake measurements and a nanoindentation technique using an atomic force microscope cantilever, respectively. ERK1/2 activity was measured by Western blotting analysis with an anti-phospho-ERK1/2 antibody. Protein expression and immunostaining revealed that MR was abundant in the cytoplasm of RMCs. Aldosterone (1 to 100 nmol/L) dose-dependently activated ERK1/2 in RMCs with a peak at 10 minutes. Pretreatment with eplerenone (10 micromol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation and decreased the elastic modulus, indicating cellular proliferative and deforming effects of aldosterone, respectively. These aldosterone-induced changes in cellular characteristics were prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor, PD988059 (100 micromol/L). The results indicate that aldosterone directly induces RMC proliferation and deformability through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.     

Novel approach of laparoscopic and endoscopic cooperative surgery (LECS) for cholecystectomy

Background: Endoscopic submucosal dissection (ESD) techniques, such as generating an artificial space between digestive tract layers for safer dissection, were thought to be safer for the resection of organs in cholecystectomy. We investigated whether combinations of endoscopic techniques and laparoscopic techniques could be performed more safely and rapidly.

Material and methods: Laparoscopic and endoscopic cooperative-cholecystectomy (LEC-chole) and conventional laparoscopic cholecystectomy (Lapa-chole) were performed in six dogs. Operation time was defined as the time from the creation of the first port to the retrieval of the resected gallbladder (GB); and GB bed dissection time was the time from local injection of natural saline to the clipping of the cystic duct. The main roles of the endoscope in LEC-chole were to obtain a sufficient cutting space via local injection of natural saline to the GB bed and to monitor the operative view without laparoscopic camera, thus omitting the umbilical port.

Results: The operation times were 60?±?18.3?minutes for LEC-chole and 95?±?7.0 for Lapa-chole (p?=?.036). The GB bed dissection times were 31?±?8.54?minutes in LEC-chole and 50.6?±?7.37?minutes in Lapa-chole (p?=?0.048). There were significant differences in liver damage and bleeding (p?=?0.116), but there were no significant differences in one-month survival.

Conclusions: The application of LEC-chole may be expanded to cholecystectomy.     

Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II‐infused rats

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II‐dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague–Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II‐induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II‐mediated increase in plasma and heart aldosterone 2.3‐ and 1.8‐fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1‐mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4‐hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress‐associated cardiovascular damage in Ang II‐dependent hypertension.     

Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren‐2 transgenic hypertensive rats with aorto‐caval fistula

The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren‐2 transgenic rats (TGR), a model of angiotensin II (ANG II)‐dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto‐caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin‐angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy]benzoic acid (c‐AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin‐converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.     

Orthostatic hypotension in elderly persons during passive standing: a comparison with young persons

BACKGROUND: The present study was aimed at clarifying the mechanism of orthostatic hypotension (OH) that occurs in elderly persons and at investigating assisting methods to prevent OH by evaluating changes in autonomic nervous system (ANS) activity and cerebral circulation of elderly persons when engaged in passive standing. METHODS: Eight elderly volunteers and 9 young volunteers gave informed consent to participate in the study. Two experimental conditions were established: (i) "active standing," in which the subjects stood on their own with guidance from an assistant, and (ii) "passive standing," in which the subjects were placed in a standing position completely by an assistant. ANS was determined before and after standing by measuring the heart rate variability. The reaction of the ANS was evaluated on the basis of low-frequency power (LF: 0.05--0.15 Hz) and high-frequency power (HF: 0.15--0.4 Hz), which were separated from the R-R interval data by power spectral analysis using the fast Fourier transformation. Cerebral perfusion was measured over the right frontal region using a near-infrared spectroscopy cerebral oxygen monitor. RESULTS: The main findings were: (i) Transient decreases in blood pressure occurred immediately after standing in both the young and elderly subjects. (ii) The LF:HF ratio increased significantly ( p <.05) immediately after active standing in the young subjects, whereas this ratio increased in the elderly subjects after some delay. (iii) The LF:HF ratio increased significantly ( p <.01) immediately after passive standing in the young subjects, whereas this ratio decreased significantly ( p <.05) in the elderly subjects. (iv) In the elderly subjects, the total hemoglobin (HbT) and oxyhemoglobin showed the greatest decrease during the 15-second period after standing. The maximum changes in the HbT with passive standing differed significantly ( p <.01) from those observed during active standing. CONCLUSIONS: Our findings emphasize the need to devise bioengineered means that allow elderly persons to exert themselves, to maintain or improve muscle contractility and ANS function, while providing minimum assistance for standing.     

Blood pressure distribution and determinants of higher levels of blood pressure in Japanese rural adolescents

The blood pressures (BP) and anthropometric values of 1,014 Japanese rural school children aged 12-17 years old were measured at one-year interval. The strongest correlation for systolic BP (SBP) was weight and for diastolic BP (DBP) it was age. Larger values of weight, body mass index, triceps skinfold thickness and smaller increment of height showed significant discriminative powers in differentiating the subjects who had been above the age-sex specific 80th percentile value (H-H group) from those who had been below the 20th percentile value (L-L group) for both SBP and DBP. Subjects with a family history of hypertension (FHH) had higher SBP than those without a FHH, and were more prevalent in H-H group for SBP. These results indicate that larger body size and more mature stature are determinants of higher levels of BP during adolescence, and that FHH affects SBP only in this period.     

Determination of the site of the accessory pathway in WPW syndrome by an electrocardiographic inverse solution

The initial portion of the QRS complex in WPW syndrome might be represented by a single dipole, since the delta wave corresponds to the localized ventricular activation propagated over the accessory atrioventricular pathway. In order to examine whether the site of the accessory pathway in WPW syndrome could be localized by an equivalent dipole method, the dipole positions during the delta wave were determined in 30 patients using a three dimensional model of the torso and were then compared with the sites of accessory pathways localized by body surface maps. The single dipole approximation during the delta wave appeared to be appropriate since the index of the nondipolarity of the potentials was as low as 28% on average. The dipole positions determined on the atrioventricular ring during the delta wave were compatible with the sites of accessory pathways localized by body surface maps in 22 of the 30 patients. The dipole positions were adjacent to the sites of accessory pathways in 7 of the remaining 8 patients. Thus the equivalent dipole method might be an additional noninvasive tool to determine the site of the accessory pathway in WPW syndrome.