Hiroaki Matsuoka

Cardioprotective Mechanism of Telmisartan via PPAR-γ-eNOS Pathway in Dahl Salt-Sensitive Hypertensive Rats

BACKGROUNDnRecently, some investigators have shown that telmisartan, an angiotensin II (Ang II)-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We investigate whether telmisartan improves cardiovascular remodeling associated with the production of endothelial nitric oxide synthase (eNOS) through PPAR-gamma, inhibits the Rho-kinase pathway, and suppresses oxidative stress in Dahl salt-sensitive (DS) hypertensive rats.nnnMETHODSnTelmisartan (1 mg/kg per day) or telmisartan plus PPAR-gamma inhibitor, GW9662 (1 mg/kg per day) was administered from the age of 6-11 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group.nnnRESULTSnThe levels of eNOS and PPAR-gamma expression, and eNOS phosphorylation were significantly lower in DS rats than in DR rats. Chronic telmisartan treatment in DS rats significantly increased these parameters, but not telmisartan plus GW9662. Telmisartan effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not telmisartan plus GW9662. Moreover, upregulated RhoA protein, Rho-kinase mRNA, and myosin light-chain phosphorylation in DS rats was decreased by telmisartan to a similar degree as observed after treatment with Y-27632, a selective Rho-kinase inhibitor. In addition, NAD(P)H oxidase p22phox, p47phox, gp91phox expression, and mitogen-activated protein kinase and its downstream effector p70 S6 kinase phosphorylation in DS rats was also inhibited by telmisartan.nnnCONCLUSIONSnThese results suggest that the cardioprotective mechanism of telmisartan may be partly due to improvement of endothelial function associated with PPAR-gamma-eNOS, oxidative stress, and Rho-kinase pathway.

Comparison of Atherosclerotic Indicators Between Cardio Ankle Vascular Index and Brachial Ankle Pulse Wave Velocity

Background: Aortic pulse wave velocity has been used for evaluating atherosclerosis. Recently, the development of the volume plethysmographic method has made it possible to easily measure the index of the pulse wave velocity. The brachial ankle pulse wave velocity and cardio ankle vascular index are used for estimating the extent of atherosclerosis. The diagnostic usefulness of these indexes in predicting coronary artery disease was examined. Methods: The brachial ankle pulse wave velocity, the cardio ankle vascular index, and the high-sensitivity C-reactive protein were measured in 696 patients who had chest pain and underwent coronary angiography. Measurement values of brachial ankle pulse wave velocity were compared with those of cardio ankle vascular index in terms of the baseline covariates and the number of major coronary vessels involved (vessel disease). Results: The brachial ankle pulse wave velocity was significantly correlated with age, systolic blood pressure, and diastolic blood pressure but not with the high-sensitivity C-reactive protein. The cardio ankle vascular index was correlated only with age and the high-sensitivity C-reactive protein. The average of both brachial ankle pulse wave velocity and cardio ankle vascular index values was greater in 3 vessel disease group than in 0 vessel disease group. The receiver operating characteristic curve showed that the diagnostic accuracy of coronary artery disease was significantly higher in the cardio ankle vascular index than in the brachial ankle pulse wave velocity (area under the curve ± standard error: 0.691 ± 0.025 vs. 0.584 ± 0.026; P < .05). Conclusions: As a means of estimating the extent of atherosclerosis in large arteries, our results show that both brachial ankle pulse wave velocity and cardio ankle vascular index are useful and that cardio ankle vascular index may have some advantages in its application to patients taking blood pressure—lowering medication because of the minimum effect of blood pressure on its measurement values. The cardio ankle vascular index has increased performance over brachial ankle pulse wave velocity in predicting the coronary artery disease.

Efonidipine reduces proteinuria and plasma aldosterone in patients with chronic glomerulonephritis.

Efonidipine, a dihydropirydine calcium channel blocker, has been shown to dilate the efferent glomerular arterioles as effectively as the afferent arterioles. The present study compared the chronic effects of efonidipine and amlodipine on proteinuria in patients with chronic glomerulonephritis. The study subjects were 21 chronic glomerulonephritis patients presenting with spot proteinuria greater than 30 mg/dL and serum creatinine concentrations of ≤1.3 mg/dL in men or ≤1.1 mg/dL in women. All patients were receiving antihypertensive medication or had a blood pressure ≥130/85 mmHg. Efonidipine 20–60 mg twice daily and amlodipine 2.5–7.5 mg once daily were given for 4 months each in a random crossover manner. In both periods, calcium channel blockers were titrated when the BP exceeded 130/85 mmHg. Blood sampling and urinalysis were performed at the end of each treatment period. The average blood pressure was comparable between the efonidipine and the amlodipine periods (133±10/86±5 vs. 132±8/86±5 mmHg). Urinary protein excretion was significantly less in the efonidipine period than in the amlodipine period (1.7±1.5 vs. 2.0±1.6 g/g creatinine, p=0.04). Serum albumin was significantly higher in the efonidipine period than the amlodipine period (4.0±0.5 vs. 3.8±0.5 mEq/L, p=0.03). Glomerular filtration rate was not significantly different between the two periods. Plasma aldosterone was lower in the efonidipine period than in the amlodipine period (52±46 vs. 72±48 pg/mL, p=0.009). It may be concluded that efonidipine results in a greater reduction of plasma aldosterone and proteinuria than amlodipine, and that these effects occur by a mechanism independent of blood pressure reduction. A further large-scale clinical trial will be needed in order to apply the findings of this study to the treatment of patients with renal disease.

Stimulatory and Inhibitory regulation of lipolysis by the NPR-A/cGMP/PKG and NPR-C/Gi pathways in rat cultured adipocytes.

OBJECTIVEnRecent studies have suggested the abundant expression of natriuretic peptide receptor in adipose tissue. This study was designed to investigate the levels of natriuretic receptor-A (NPR-A) and NPR-C gene expression during the process of preadipocyte differentiation and its role in adipogenesis and lipid metabolism.nnnMETHODSnWe measured mRNA levels of NPR-A and NPR-C during the process of rat preadipocyte differentiation in vitro. We also measured the effects of ANP and C-ANP, a ligand for NPR-C, on preadipocyte differentiation. In addition, we assessed the effects of ANP and C-ANP on lipolysis and the cellular mechanism.nnnRESULTSnThe mRNA levels of NPR-A and NPR-C on day 3, 6, 10 are (-26%, +226%), (+6%, +568%), and (+207%, +3232%) respectively as compared with day 1. ANP (10(-)(7) M) and 8-bromo-cGMP (10(-)(4) M) significantly increased Oil Red positive area and cell number of matured-adipocytes. ANP and 8-bromo-cGMP also increased the mRNA levels of adipocyte-related genes such as PPARgamma, leptin, and adiponectin on day 3, whereas C-ANP did not change these parameters. ANP (10(-)(9)-10(-)(6) M) increased intracellular cGMP levels and promoted lipolysis in adipocytes and the effects were abolished by HS-142-1, and KT5823. Conversely C-ANP (10(-)(6) M) decreased intracellular cAMP levels and lipolysis and its effect was inhibited by PTX.nnnCONCLUSIONnResults suggest that ANP may promote adipocyte differentiation and lipolysis via the NPR-A/cGMP/PKG pathway. Direct action of ANP via NPR-C in adipogenesis may be either absent or barely present, but ANP may play a counter regulatory role in lipolysis via NPR-C/Gi pathway.

Effects of Imidapril on Left Ventricular Mass in Chronic Hemodialysis Patients

Left ventricular hypertrophy is considered to be a major cardiovascular risk factor in hemodialysis patients. Not only high blood pressure but also humoral factors such as angiotensin II and aldosterone are thought to contribute to the increase in left ventricular mass. We examined the effects of an angiotensin converting enzyme (ACE) inhibitor, imidapril, on left ventricular mass in patients with end-stage renal diseases on maintenance hemodialysis. Thirty patients on chronic hemodialysis were randomly divided into 2 groups of 15 patients each and given placebo or 2.5 mg imidapril once daily for 6 months. Before and after the 6-month period, left ventricular mass was evaluated by echocardiography, and circulating factors of the renin-angiotensin-aldosterone system were measured. Background characteristics such as age, gender ratio, causes of renal failure, duration of hemodialysis, body mass index and pre-dialysis blood pressure were comparable between the placebo and the imidapril groups. Systolic and diastolic blood pressures were not significantly changed in either group during the study period. In the imidapril group, serum ACE was reduced (12±1 to 5±2 U/l, p<0.01) and plasma renin activity was increased (3.3±0.8 to 8.1±3.2 ng/ml/h, p<0.01), but plasma angiotensin II and aldosterone were not significantly changed after 6 months (13±3 to 17±3 pg/ml and 365±125 to 312±132 pg/ml, respectively). On the other hand, left ventricular mass index was significantly decreased in the imidapril group (132±10 to 109±6 g/m2, p<0.05) but was unchanged in the placebo group (129±6 to 126±5 g/m2). These results suggest that an ACE inhibitor reduces left ventricular mass in hemodialysis patients by a mechanism that is independent of changes in blood pressure.

Natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system has inhibitory effects in renal fibrosis in mice

OBJECTnThis study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanism involved.nnnMETHODSnThree groups were studied: untreated UUO in wild-type mice; untreated UUO in NPR-A KO mice; and ANP treated (0.05 microg/kg/min) UUO in wild-type mice. We measured histological and immunohistochemical findings (alpha-SMA and F4/80), tissue cGMP levels, various mRNA expression levels by real-time PCR analysis, and transcription factor levels (AP-1 and NF-kappaB) in renal tissue.nnnRESULTSnCompared with wild-type UUO mice, NPRA-KO UUO mice had abnormal morphological findings (fibrous area: +26%, alpha-SMA expression: +30%) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta, collagen I, collagen III, PAI-1, renin and angiotensinogen, whereas there were no differences in F4/80 positive cells or the mRNA expression levels of ICAM-1, osteopontin, or MCP-1 between the two groups. In contrast, ANP pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta, collagen I, collagen III, PAI-1, ICAM-1, osteopontin, MCP-1, renin, and angiotensinogen. NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and ANP pre-treatment reduced AP-1 and NF-kappaB activity.nnnCONCLUSIONnThe endogenous natriuretic peptide/NPR-A system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous ANP pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways.

Cardioprotective Effects of Pitavastatin on Cardiac Performance and Remodeling in Failing Rat Hearts

BACKGROUNDnActivation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling by statins increases the activity of endothelial nitric oxide synthase (eNOS). We investigate whether statins (pitavastatin) improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, Rho-kinase (ROCK) pathway, and the development of oxidative stress in Dahl salt-sensitive (DS) hypertensive rats with heart failure (DSHF).nnnMETHODSnPitavastatin (3 mg/kg per day), or pitavastatin plus specific PI3K inhibitor, wortmannin (1 mg/kg per day), or wortmannin alone were administered from the age of 11-18 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group.nnnRESULTSnDecreased end-systolic elastance (Ees) and percent fractional shortening (%FS) in failing rats was significantly ameliorated by pitavastatin, but not pitavastatin plus wortmannin or wortmannin alone. Upregulation of eNOS and Akt phosphorylation by pitavastatin was suppressed by pitavastatin plus wortmannin or wortmannin alone. Pitavastatin effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not pitavastatin plus wortmannin or wortmannin alone. Activated RhoA and myosin light chain phosphorylation and RhoA, ROCK expression was inhibited by pitavastatin or a specific ROCK inhibitor, Y-27632, and downregulated eNOS expression and Akt phosphorylation was ameliorated by Y-27632. Increased expression of NAD(P)H oxidase subunits and activated p65 nuclear factor (NF)-kappaB, p44/p42 extracellular signal-regulated kinases and its downstream effector p90 ribosomal S6 kinase phosphorylation in failing rat hearts was inhibited by pitavastatin.nnnCONCLUSIONSnThese findings suggest that pitavastatin may improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, the ROCK pathway and oxidative stress.

Association of Smoking With Aortic Wave Reflection and Central Systolic Pressure and Metabolic Syndrome in Normotensive Japanese Men

BACKGROUNDnThe influences of smoking habits on blood pressure (BP) may have been underestimated substantially on the basis of conventional measurements. We compared the radial augmentation index (AI), brachial and central pressures, and prevalence of the metabolic syndrome (MetS) among never smokers, former smokers, and current smokers in a population of Japanese healthy men.nnnMETHODSnA total of 443 normotensive men who entered the health checkup program was divided into four groups according to smoking status; i.e., never smokers (n = 117), former smokers (n = 165), current mild to-moderate smokers (n = 105), and current heavy smokers (n = 56). Radial pulse waveforms were obtained using radial tonometry (HEM-9000AI), and the AI and late systolic pressure in the radial artery, an estimate of central systolic pressure, were measured.nnnRESULTSnThe AI was significantly higher in current smokers than both never and former smokers. Central systolic pressure was significantly higher in both current and former smokers than never smokers, although brachial systolic pressure was not significantly different among these groups. The MetS was more prevalent in current smokers than never smokers.nnnCONCLUSIONnSmoking habits have substantially different effects on the AI and central systolic pressure despite a similar level of brachial systolic pressure. Along with higher prevalence of the MetS, elevated AI and central systolic pressure may be potential mechanisms responsible for an increased risk of cardiovascular disease in smokers.

Right atrial abnormalities in a patient with arrhythmogenic right ventricular cardiomyopathy without ventricular tachycardia

We describe a 59-year-old woman with sick sinus syndrome (SSS) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Diagnosis of SSS was made because she had frequent episodes of sinus arrest with prolonged ventricular asystole. Cardiac images showed a dilated right atrium (RA) and a right ventricle (RV). Electroanatomical mapping of the RA showed extensive scarring with no recordable electrical potentials. Although she had frequent premature ventricular contractions, neither spontaneous ventricular tachycardia (VT) nor induced VT was observed. Microscopic examination of the RV indicated fibrofatty myocardium. Atrial arrhythmias associated with SSS may be the cause of symptoms in some cases of ARVC.

Valsartan improves l-NAME-exacerbated cardiac fibrosis with TGF-β inhibition and apoptosis induction in spontaneously hypertensive rats

This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N(G)-nitro-l-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-ß(1) (TGF-ß(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-ß(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.