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Obesity is known to be associated with a number of effects on skin physiology. KK A obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KK A obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KK A obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of MG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng·kg-1·min-1 iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically L-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by L-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity. [ABSTRACT FROM AUTHOR]

Although myocardial flow reserve (MFR) in congestive heart failure (CHF) has been reported to be impaired, the mechanism has not been fully shown in humans. Therefore, we performed positron emission tomography to measure myocardial blood flow (MBF) in patients with CHF and compared it with hemodynamic parameters. Sixteen normal coronary patients with CHF and ten normal controls were enrolled. 15O-labeled water positron emission tomography was performed at rest and during peak hyperemia induced by adenosine triphosphate. MFR was calculated as the ratio of peak hyperemic to baseline MBF. All CHF patients underwent cardiac catheterization. Baseline MBF was similar between CHF patients and normal controls (0.73 ± 0.25 vs. 0.80 ± 0.12 mL/min/g, p = NS). Hyperemic MBF was significantly reduced in CHF patients than in controls (1.68 ± 1.09 vs. 3.21 ± 0.69 mL/min/g, p < 0.05). therefore, MFR was significantly reduced in CHF patients than in controls (2.30 ± 1.30 vs. 4.03 ± 0.90, p < 0.05). There was no significant correlation between baseline MBF and either pulmonary capillary wedge pressure or left ventricular end-diastolic pressure, while both hyperemic MBF and MFR significantly correlated with both pulmonary capillary wedge pressure ( r = −0.67 and r = −0.75, respectively) and left ventricular end-diastolic pressure ( r = −0.51 and r = −0.60, respectively). Despite elevated preload, MBF at rest in CHF patients was compensated to the similar level as that in controls. However, this compensation may exhaust vasodilatory reserve in the failing human heart. Thus, preload at rest is a determinant of myocardial vasodilator reserve and preload reduction may ameliorate coronary vasodilator response in CHF patients. [ABSTRACT FROM AUTHOR]

Objectives: Long-term intravenous infusion of high-dose C-type natriuretic peptide (CNP) is known to prevent neointimal formation after vascular injury. Ultrasound (US) irradiation during microbubbles (MBs) infusion (US/MBs) has been used for local delivery of bioactive agents. We examined whether short-term infusion of CNP could also inhibit neointimal development and whether combined US/MBs treatment at the beginning of the CNP infusion could enhance its effect. Methods: In the rat carotid artery-balloon injury model, the intima/media area (I/M) ratio 14 days after injury was compared among various short-term post-injury treatments. For combined US/MBs, a commercial echocardiograph (1.8 MHz, mechanical index 1.0) and albumin-coated octafluoropropane gas MBs were used. Results: Infusion of high-dose CNP (1.0 μg/kg/min) immediately after injury for only 24 h successfully reduced the I/M ratio (0.18±0.05) to 18% of the ratio in control rats (1.00±0.13) that underwent only balloon injury. Although low-dose CNP (0.1 μg/kg/min for 24 h) alone was not effective in reducing the I/M ratio (0.83±0.18), combined US/MBs treatment for the first 80 min of the infusion markedly reduced the I/M ratio (0.17±0.07), which persisted until 28 days after injury (0.16±0.04). Conclusions: The effects of CNP on the events occurring early after arterial injury may be important in preventing subsequent neointimal development. Thus, intravenous infusion of CNP with US/MBs at its initiation may provide a clinically feasible anti-restenosis therapy applicable immediately after vascular interventions. [Copyright &y& Elsevier]

Objective: Cardiac complications in diabetes mellitus (DM) are frequently ascribed to microangiopathy. Therefore, we sought to directly correlate the serial changes in coronary arterial function with the extent of coronary arteriolar remodeling in a model spontaneously developing type II DM. Methods: Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were used. At 5, 15 and 30 weeks of age, ten rats in each group were subjected to systemic and coronary hemodynamic measurements using the colored microsphere technique before and during maximal coronary hyperemia and histological assessment with Azan-Mallory stain of the coronary arterioles. Results: As early as 15 weeks of age, at which time fasting plasma glucose concentration remained normal, OLETF rats exhibited a lower coronary flow reserve and a greater coronary vascular resistance during hyperemia than did LETO rats. On histomorphometry, OLETF rats exhibited a greater wall-to-lumen ratio and a greater degree of perivascular fibrosis of arterioles at 15 weeks of age and thereafter, both of which exhibited a significant correlation with the minimal coronary vascular resistance. Conclusions: The degree of functional deterioration in coronary circulation was directly correlated with the severity of coronary arteriolar structural remodeling during the development of microangiopathy in early stage of DM. [Copyright &y& Elsevier]

Reports on a study on the improvement of left ventricular diastolic dynamics in prediabetic stage of a Type II diabetic rat model after troglitazone treatment. Hypoglycemic effects of troglitazone in insulin-resistant animal models; Performance of echocardiography; Finding that troglitazone improves left ventricular diastolic dynamics at prediabetic stage.

Recent clinical trials have demonstrated that combination therapy with renin-angiotensin system inhibitors plus calcium channel blockers (CCBs) elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB) against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-Ay mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB) disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day) reduced blood pressure in saline-drinking KK-Ay mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day) exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Deterioration of adipocyte function due to increased oxidative stress predisposes patients to metabolic disorders in advanced age. However, the roles of tumor suppressors in such conditions remain largely unknown. Therefore, we aimed to address their dynamics in aged adipocytes using a long-term culture model. We compared 3T3-L1 adipocytes at 17-19 days (long-term) with those at 8-10 days (short-term) after initiation of adipogenic induction for mimicking 'aged' and 'young' adipocytes, respectively. H 2 O 2 release and dihydroethidium (DHE) staining was increased, while superoxide dismutase (SOD) activity was reduced in long-term cultured adipocytes, which is suggestive of enhanced oxidative stress in this group. Moreover, qRT-PCR revealed increased mRNAs of Nox4 (a subunit of NADPH oxidase complex), Ccl2 (a proinflammatory chemokine) and Il6 [a marker of senescence-associated secretory phenotype (SASP)] along with decreased levels of Pparγ, Adipoq and Slc2a4 (genes related to glucose metabolism). These alterations were associated with increased expression of the tumor suppressors alternate-reading-frame protein p19 Arf (Arf) and p16 Ink4a . However, silencing of Arf reduced mRNAs of Adipoq and Slc2a4 and enhanced release of Il6. The effect was opposite in Arf overexpressing adipocytes, which showed reduced superoxide production as assessed with DHE staining and SOD activity. Western blots showed that Arf negatively regulates the phosphorylation of Akt. Luciferase assay in Hela cells additionally suggested that Arf negatively regulates Il6 transcriptional activity through a PI3 K/Akt mediated pathway. These findings strongly suggest that the enhanced Arf expression in oxidative stress plays compensatory protective roles against aging-related dysregulation of gene expression in adipocytes.

Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states.

Background: The impact of nicorandil as adjunctive therapy for percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) is controversial. We performed 15 O-labeled water positron emission tomography (PET) to quantify regional myocardial perfusion in patients with STEMI who received nicorandil or no adjunctive therapy during PCI., Methods: PCI was performed within 8 h after STEMI onset in 33 patients. 14 patients received intracoronary nicorandil 2 mg immediately after recanalization of the culprit lesion (Nico group). After 3-4 weeks, PET was performed in which myocardial blood flow (MBF) was measured at baseline and during adenosine triphosphate (ATP)-induced hyperemia. Myocardial vascular resistance (MVR) was calculated for all segments. Data were obtained from the reperfused (Rep) and normal segments (Cont) in each patient., Results: In patients not given nicorandil (No-Nico group), the MBF was significantly lower in Rep than that in Cont at baseline and during hyperemia (Cont vs. Rep: 0.82 ± 0.14 vs. 0.68 ± 0.11, P  = 0.001, ATP-Cont vs. ATP-Rep: 2.00 ± 0.72 vs. 1.52 ± 0.61, P  = 0.017), which was restored in the Nico group (Cont vs. Rep: 0.79 ± 0.17 vs. 0.78 ± 0.20; ATP-Cont vs. ATP-Rep: 2.02 ± 0.84 vs. 1.84 ± 0.62). MVR was elevated in Rep at baseline and during hyperemia in the No-Nico group. MVR elevation in Rep was prevented in the Nico group., Conclusions: 15 O-labeled water PET was feasible for segmental analysis of MBF during the subacute phase of STEMI. It revealed that intracoronary administration of nicorandil to STEMI patients who underwent PCI prevented MVR elevation and thus restored MBF in the reperfused segments to a level similar to that in the normal segments.

A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg(-1) twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.

Angiotensin II (Ang II) infusion into rats elevates local angiotensin II levels through an AT1 receptor-dependent pathway in the kidney. We examined whether treatment with an angiotensin-converting enzyme (ACE) inhibitor, temocapril, or an AT1-receptor blocker, olmesartan, prevented elevation of Ang II levels in the kidney of angiotensin I (Ang I)-infused rats. Rats were infused with Ang I (100 ng/min) and treated with temocapril (30 mg/kg per day, n = 10) or olmesartan (10 mg/kg per day, n = 9) for 4 weeks. Ang I infusion significantly elevated blood pressure compared with vehicle-infused rats (n = 6). Treatment with temocapril or olmesartan suppressed Ang I-induced hypertension. Temocapril suppressed both plasma and renal ACE activity. Ang I infusion increased Ang II content in the kidney. Interestingly, temocapril failed to reduce the level of Ang II in the kidney, while olmesartan markedly suppressed an increase in renal Ang II levels. These results suggest a limitation of temocapril and a benefit of olmesartan to inhibit the renal renin-angiotensin system and suggest the possible existence of an ACE inhibitor-insensitive pathway that increases Ang II levels in rat kidney.

The purpose of this study was to examine the usefulness of (11)C-acetate positron emission tomography (PET) for assessing the efficacy of cardiac resynchronization therapy (CRT). Enrolled in this study were 20 patients with severe heart failure. All patients underwent 11C-acetate PET within 1 week after CRT. The oxygen consumption was measured by the monoexponential clearance rate of 11C-acetate (K(mono)) for both CRT-off and -on. Cardiac efficiency (CE) was determined using the concept of the work metabolic index (WMI). WMI was calculated as WMI = (stroke volume index) x (systolic blood pressure) x (heart rate)/K(mono). The patients were divided into two groups: 14 patients with improved CE (from 5.27 +/- 0.91 to 6.77 +/- 1.12) and 6 patients with deteriorated CE (from 5.35 +/- 0.92 to 4.86 +/- 0.84) by CRT-on. K(mono) decreased from 0.053 +/- 0.006 to 0.046 +/- 0.003 by CRT-on in the improved CE group (p = 0.028), but increased from 0.049 +/- 0.006 to 0.050 +/- 0.006 in the deteriorated-CE group (p = 0.036). Stroke volume index, systolic blood pressure, and heart rate did not change by CRT-on for either group. At the one-year follow-up, there were significantly higher rates of major cardiac adverse events in the deteriorated-CE group than in the improved-CE group (p = 0.032). Therefore, the improvement of CE, as assessed by 11C-acetate PET in the early period after CRT, is produced by the decrease in oxygen consumption in patients showing good responses to CRT. The decrease in oxygen consumption in the early period after CRT is thus a useful marker for predicting a good clinical outcome after CRT.

Twelve species of deep-sea fishes collected in 2005 from the western North Pacific, off-Tohoku, Japan were analyzed for organohalogen compounds. Among the compounds analyzed, concentrations of DDTs and PCBs (up to 23,000 and 12,400 ng/g lipid wt, respectively) were the highest. The present study is the foremost to report the occurrence of brominated flame retardants such as PBDEs and HBCDs in deep-sea organisms from the North Pacific region. Significant positive correlations found between delta(15)N ( per thousand) and PCBs, DDTs and PBDEs suggest the high biomagnification potential of these contaminants in food web. The large variation in delta(13)C (per thousand) values observed between the species indicate multiple sources of carbon in the food web and specific accumulation of hydrophobic organohalogen compounds in benthic dwelling carnivore species like snubnosed eel. The results obtained in this study highlight the usefulness of deep-sea fishes as sentinel species to monitor the deep-sea environment., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Ultrasonic destruction of microbubbles (US/MB) in the microcirculation causes local inflammatory cell infiltration, which has been shown to induce angiogenesis. Granulocyte colony-stimulating factor (G-CSF), which mobilizes myelomonocytic cells from the bone marrow and enhances vascular endothelial growth factor (VEGF) release from these cells, has also been applied to therapeutic angiogenesis induction. In the present study, we sought to examine the potential of G-CSF pretreatment to enhance the angiogenic effect of US/MB. Ischemic hindlimbs in mice were treated with either a predetermined minimal effective dose (300 mug/kg) of G-CSF, US/MB alone or G-CSF pretreatment followed by US/MB at seven days after removal of the femoral artery. Ultrasonic destruction of microbubbles was performed as intermittent pulsed local insonation using a diagnostic ultrasound scanner at a peak negative pressure of 1.4 MPa after intravenous injection of perfluorocarbon microbubbles. At 21 days after the treatment, we quantified the surface vascularity using a grid method and the capillary density using an alkaline phosphatase stain. Relative to the capillary density in normal muscle, the capillary density in the treated limbs was restored to 74 +/- 13% by G-CSF alone and 90 +/- 20% by US/MB alone (p < 0.05 vs. both untreated and G-CSF alone), and further increased to 101 +/- 21% by G-CSF pretreatment. The collateral growth induced by the combination of G-CSF pretreatment and US/MB was 2.8- and 1.4-fold greater than the growth induced by G-CSF alone and US/MB alone, respectively (p < 0.05 for both). Thus, pretreatment with a single minimal effective dose of G-CSF can augment the angiogenic effect of US/MB.

Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng x kg(-1) x min(-1) iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically L-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by L-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity.

Elevated activities of the sympathetic nerve and renin-angiotensin systems are common features of heart failure. This study was designed to investigate the roles of the AT1 receptor in cardiac hypertrophy and oxidative stress during excessive beta-adrenoceptor stimulation using an AT1 receptor antagonist (ARB) and AT1a receptor-deficient (AT1aR(-/-)) mice. Isoproterenol (ISO) was given to C57BL mice with or without ARB (olmesartan) treatment and to AT1aR(-/-) mice by a subcutaneously implanted osmotic mini-pump for 11 days at a rate of 15 mg/kg/day. Chronic ISO infusion to C57BL mice caused concentric cardiac hypertrophy (sham; 4.1+/-0.1, ISO; 5.2+/-0.2 mg/g heart to body weight ratio), accompanied by enhancement of cardiac collagen accumulation, lipid peroxidation, superoxide generation and NADPH oxidase activity. The AT1a and beta-1,2 receptor mRNA expressions were down-regulated in the heart of ISO-infused mice. Olmesartan markedly suppressed cardiac mass enlargement as well as increases of oxidative indicators without any effects on heart rate. Olmesartan did not affect the cardiac angiotensin and beta-adrenergic receptor mRNA expression patterns. The AT1a receptor contribution to ISO-induced cardiac hypertrophy was reproduced in AT1aR(-/-) mice. These data suggest that the AT1 receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress under excessive beta-adrenergic stimulation, and that ARB treatment is beneficial for sympatho-excitatory cardiac hypertrophy and failure in mice.

Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-beta pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n = 9); aldosterone (0.75 microg/h, subcutaneously; n = 9); or aldosterone + fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n = 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in alpha-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased alpha-smooth muscle actin staining, numbers of monocytes/macrophages, mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor and monocyte chemoattractant protein-1, and Smad2/3 activity in renal cortical tissues. These results provide evidence, for the first time, that Rho-kinase is substantially involved in aldosterone-induced renal injury through activation of a TGF-beta-dependent pathway.

Objective: Although echocardiography is used for diagnosing right ventricular (RV) infarction produced by right coronary artery (RCA) occlusion, there has been no data on the spatial distribution of RV perfusion abnormalities following acute RCA occlusion. We examined this distribution by myocardial contrast echocardiography (MCE) and blue dye staining in canine models., Methods: The RCA was occluded in 10 open-chest dogs. MCE was performed with 0.27 g/min Levovist infusion by harmonic power Doppler with electrocardiogram gated intermittent triggered imaging at baseline and at 90 min after RCA occlusion. The opacification defects were assessed at the basal, middle, and apical levels of the RV free wall by short-axis view. The extent of the risk area of the occluded RCA, expressed as a percentage of the RV free wall, was measured at each level by injecting blue dye at the end of the experiments. In 10 other dogs, the left anterior descending coronary artery (LAD) was occluded by ligating the proximal portion of the LAD to examine the territory of the LAD on the same levels of the RV free wall by injecting blue dye., Results: Although patchy opacification defects accompanying RV dilation were observed at the basal and middle levels during RCA occlusion, no apical defects were observed in any dogs by MCE. The risk area of the occluded RCA, as delineated by blue dye, was larger in the basal than apical level of the RV free wall in all 10 dogs (basal: 79 +/- 9%; middle: 48 +/- 14%; apical: 3 +/- 6%, p < 0.0001). The risk area of the occluded LAD (basal: 17 +/- 7%; middle: 12 +/- 6%; apical: 6 +/- 6%) was smaller than the risk area of the occluded RCA at the basal and middle levels of the RV free wall (p < 0.0001), and no significant difference was observed at the apical level., Conclusions: RV perfusion abnormalities produced by RCA occlusion are larger in the basal than apical level of the RV free wall. This finding elucidates the spatial distribution of the territory of the RCA on the RV free wall, and may help in identifying and assessing RV ischemia by echocardiography in humans. Moreover, the data in the current study indicate that RV infarction may be produced by occlusion of the coronary arteries except RCA, because the territory of the LAD on the RV free wall is clearly delineated.

Objective: The objective of the present study was to compare the digital and video data of myocardial contrast echocardiography (MCE) to assess altered myocardial blood flow produced by graded coronary stenoses., Methods: Three grades of left anterior descending (LAD) coronary artery stenosis and occlusion were created in eight open-chest canine models. MCE was performed with BR1 infusion by harmonic power Doppler with ECG gated intermittent triggered imaging at pulsing intervals ranging from 1:1 to 1:10. For images that were recorded simultaneously on both a videotape (video data) and an optical disk (digital data), myocardial signal intensity in the LAD region was plotted vs. pulsing intervals and was fitted to an exponential function: y = A(1 - e(-bt)), where A is the peak plateau signal intensity, and b is the rate of signal intensity rise for quantification of myocardial blood flow., Results: Both values for A and b progressively decreased with a greater level of stenosis. The correlation of A with myocardial blood flow (determined by use of fluorescent microspheres) was weak with digital data (r = 0.38, p = 0.037), and was insignificant with video data (r = 0.16, p = 0.38). The correlation of b with microsphere-derived myocardial blood flow was better than that of A with both video and digital data, and was similar between the two kinds of data (video: r = 0.69, p < 0.0001; digital: r = 0.68, p < 0.0001)., Conclusions: Video and digital MCE data are equivalent in their ability to quantify altered myocardial blood flow produced by graded coronary stenoses.

Objective: The present study compared the regional variation of myocardial signal intensity in visualizing myocardial perfusion by myocardial contrast echocardiography (MCE) between harmonic gray scale and power Doppler imaging., Methods: MCE was performed in 12 patients by electrocardiographic (ECG)-gated intermittent triggered MCE with harmonic gray scale and power Doppler imaging following slow intravenous injection of 0.5 ml contrast agent (Optison). The interval between the ECG triggers (pulsing interval) was increased from every heart beat (1:1) to every 2 (1:2), 4 (1:4), and 8 (1:8) cardiac cycles to allow incremental microbubble (contrast agent) replenishment. The MCE images were recorded when attenuation produced by the left ventricular cavity was minimal. The background-subtracted videointensity was measured in 7 segments in an apical 4-chamber view: 3 (apical, mid, and basal) septal segments, 3 (apical, mid, and basal) lateral segments, and 1 apex segment (apical cap)., Results: The background-subtracted videointensity for each segment was greater with the power Doppler than the gray scale imaging (p < 0.01). With the gray scale imaging, the background-subtracted videointensity in the basal septal segment demonstrated a negative value at all pulsing intervals, and the value (-9 +/- 13) was significantly lower than that (22 +/- 20) in the apical lateral segment at a pulsing interval of 1:8 (p < 0.01). With power Doppler imaging, the background-subtracted videointensity was high even in the basal septal segment (112 +/- 33), and no significant difference was observed among each segment., Conclusions: The findings indicate that quantitative assessment of myocardial perfusion based upon background-subtracted video-intensity may be difficult in the far field with harmonic gray scale imaging although the attenuation is not apparent by visual analysis. Harmonic power Doppler is more sensitive for detecting basilar perfusion in the far field compared with harmonic gray scale imaging.