Hemodynamically adjusted infrahepatic inferior venous cava clamping can reduce postoperative deterioration in renal function: a retrospective observational study.

PURPOSE: Infrahepatic inferior vena cava (IIVC) clamping is beneficial for reducing the amount of bleeding during hepatic surgery, although the associated systemic circulatory deterioration is noticeable. The relationship between changes in the degree of IIVC clamping and postoperative renal function was retrospectively evaluated. METHODS: A total of 59 patients who underwent elective hepatic surgery with surgical IIVC clamping in the two years were analyzed. In 2016, constant 80% clamping of the IIVC was performed (29 cases), and in 2017, hemodynamically adjusted IIVC clamping was performed (30 cases). Intraoperative parameters, including total blood loss and number of blood transfusions, were examined. The use of each vasoactive agents was analyzed. Renal function in the acute postoperative phase was evaluated using serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) values. RESULTS: Comparison of the two groups showed that bolus doses of both ephedrine and phenylephrine were significantly higher in the 2016 group (P = 0.0221, 0.0017). Continuous doses of dopamine were significantly higher in the 2016 group, while those of noradrenaline were not. Postoperative serum Cr levels relative to baseline (%) were significantly higher in the 2016 group immediately after surgery and on postoperative day (POD) 1 (P = 0.0143, 0.0012). Postoperative eGFR relative to baseline (%) was significantly higher in the 2016 group immediately postoperatively and on PODs 1 and 2 (P = 0.0042, 0.0003, 0.0382). CONCLUSION: Hemodynamically adjustable IIVC clamping might be superior to uniformly fixed clamping in preserving renal function without compromising the desired effect on hemostasis.

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats.

BACKGROUND: Noxious stimulus-induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system. METHODS: We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin. RESULTS: NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005). CONCLUSIONS: These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

[Masked hypertension].

Patients with masked hypertension show normal office blood pressure but elevated out-of-office blood pressure. Out-of-office blood pressure is evaluated by ABPM (ambulatory blood pressure monitoring) or HBPM (home blood pressure measurements). HBPM is more popular in Japan because its simplicity. However, ABPM is essential to measure night blood pressure. Patients with masked hypertension have increased cardiovascular morbidity risk as high as seen in those with established hypertension. Many factors, including life style (smoking, excessive alcohol drinking, etc), variability of blood pressure (morning surge, non-dipper, riser) and inappropriate treatment of hypertension, are involved in masked hypertension. Life style modification, strict and sophisticated blood pressure control, and treatment of underlying diseases are necessary to treat masked hypertension.

Variations in the Blood Phenytoin Levels during Long-Term Combined Treatment with S-1 and Phenytoin.

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 µg/ml, but it increased during S-1 therapy, reaching 22.9 µg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 µg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l(-1)), fasudil (1 g l(-1)) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, alpha-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (-23%, -15%), DHE-positive area (-13%, -11%), alpha-SMA-positive area (-22%, -15%), F4/80-positive area (-42%, -34%) and the expression of various mRNA, most of which were significant (P<0.05). The combination of imidapril and fasudil further improved fibrotic area (-52%), DHE-positive area (-26%), alpha-SMA-positive area (-33%), F4/80-positive area (-62%) and the expression of various mRNA (all P<0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-beta/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.

Radiological and histological analysis of synthetic bone grafts in recurring giant cell tumour of bone: a retrospective study.

PURPOSE: To review the radiology and histology of synthetic bone grafts resected from patients with recurrent giant cell tumour (GCT) of bone. METHODS: 22 patients underwent curettage and grafting for GCT of bone using autogenous cancellous bone mixed with apatite-wollastonite-containing glass ceramic (AWGC), hydroxyapatite (HA), or a mixture of HA and tricalcium phosphate (TCP). Patients were followed up every 3 to 6 months. Three men and 3 women aged 20 to 33 (mean, 27) years developed local recurrence. The mean interval from surgery to recurrence was 35 (range, 12-89) months. Specimens containing the recurring GCT of bone and the surrounding synthetic bone and new bone were evaluated. RESULTS: No complication related to the use of the synthetic bone (such as toxicity, fracture or deformity) occurred. The synthetic bone incorporated well into the surrounding host bone, but was not completely absorbed. HA was more bioactive than AWGC in human bone. HA/TCP were more bioresorbable and osteoconductive in human bone than HA or AWGC. In most areas of AWGC grafts, intervening layers of fibrous connective tissue were seen between the granules and the bone. In most areas of HA grafts, the granules were completely surrounded by viable bone, with bone ingrowth into the pores of the granules, as well as venules and fibrous tissue ingrowth in the pores of portions of the grafts. CONCLUSION: A mixture of synthetic bone and autogenous cancellous bone is safe and useful for grafting after curettage for GCT of bone.

Tracheal intubation with the PENTAX-AWS (airway scope) reduces changes of hemodynamic responses and bispectral index scores compared with the Macintosh laryngoscope.

The PENTAX-AWS, a novel video laryngoscope, allows indirect visualization of the vocal cords on a color monitor display and enables tracheal intubation without upward lifting force required to expose the glottis. This study compared hemodynamic changes, bispectral index scores, and postoperative sore throat before and after laryngoscopy between the Macintosh laryngoscope and the airway scope (AWS). Forty patients (American Society of Anesthesiologists I-II), randomly assigned to either the Macintosh group (n=20 each) or AWS group, were enrolled in this study. After induction with fentanyl (0.001 mg/kg), propofol (1.5 mg/kg), and vecuronium (0.1 mg/kg), tracheal intubation was performed. Hemodynamic parameters were compared before and after laryngoscopy. Patients were assessed for postoperative sore throat at 24 hours after extubation. No significant differences in patient characteristics were observed between groups. Significant increases in both systolic blood pressure (P<0.05 vs. baseline) and heart rate (P<0.001 vs. baseline) after laryngoscopy were seen using the Macintosh blade, whereas the AWS provided no increases in either parameter. The AWS also caused a lesser increase in bispectral index (P<0.05 vs. Macintosh group). Postoperative sore throat was observed in both groups (2 out of 20 in AWS and 6 out of 20 in Macintosh), although this difference did not reach statistically significant level (P=0.23). In conclusion, the AWS offers a reduced degree of hemodynamic stimulation compared with the Macintosh laryngoscope, suggesting that tracheal intubation with the AWS is advantageous to prevent hypertension after laryngoscopy in neurosurgical patients.

Association of smoking with aortic wave reflection and central systolic pressure and metabolic syndrome in normotensive Japanese men.

BACKGROUND: The 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: Smoking 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.

Cardioprotective effects of pitavastatin on cardiac performance and remodeling in failing rat hearts.

BACKGROUND: Activation 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). METHODS: Pitavastatin (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. RESULTS: Decreased 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. CONCLUSIONS: These 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.

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

OBJECTIVE: Recent 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: Results 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.

Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes.

We investigated the levels of adrenomedullin (AM) system during the process of preadipocyte differentiation and its role in lipid metabolism and cellular signaling mechanism in differentiated adipocytes. We cultured rat preadipocytes and measured the following during the process of differentiation: two molecular forms of AM in the culture medium using a specific immunoradiometric assay and gene expression of AM and its receptor component using RT-PCR analysis. In differentiated adipocytes, we measured the effects of AM on the intracellular cAMP level, lipolysis, glucose incorporation, and the protein levels. Two molecular forms of AM were secreted into the medium, and the AM-mature/AM-total ratio was increased after 6 days of differentiation. Cultured rat preadipocytes highly expressed the genes of AM and its receptor components at day 1, and they increased at day 10. Administration of AM to preadipocytes increased the number of Oil Red O-positive adipocytes and spectrophotometric absorbance of Oil Red O. AM dose dependently increased cAMP level and lipolysis, and its effect was blocked by CGRP(8-37). Isoproterenol increased lipolysis, and AM had additive effects on isoproterenol-induced lipolysis. KT5720 and U0126 significantly inhibited the AM-induced lipolysis, whereas KT5720, but not U0126, significantly inhibited the isoproterenol-induced lipolysis. AM increased glucose incorporation and its effect was blocked by wortmannin. Western blot analysis revealed that AM increased phospho PKA, ERK, and Akt. These results indicate that AM and its receptor component are highly expressed in cultured adipocytes and may play a role in lipid metabolism via a different signaling pathway.

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.

Cardioprotective mechanism of telmisartan via PPAR-gamma-eNOS pathway in dahl salt-sensitive hypertensive rats.

BACKGROUND: Recently, 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. METHODS: Telmisartan (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. RESULTS: The 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. CONCLUSIONS: These 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.

Cardioprotective effect of benidipine on cardiac performance and remodeling in failing rat hearts.

BACKGROUND: We have known that endothelial nitric-oxide synthase (eNOS) and oxidative stress may play a key role in cardiac performance in failing rat hearts. However, the interactions between eNOS or oxidative stress and bradykinin (BK) under treatment of calcium channel blockers (CCBs) remain unknown. To elucidate the mechanism underlying the cardioprotective effect of long-acting dihydropyridine CCBs, we evaluated the effect of benidipine on the BK-eNOS and NAD(P)H oxidase pathway in Dahl salt-sensitive (DS) rats with heart failure. METHODS: 11-week-old DS rats were treated with one of the following drug combinations for 7 weeks until the onset of the failing stage: vehicle, BK B2 receptor antagonist (FR172357 (FR)) alone, hydralazine, benidipine, and benidipine plus FR. The left ventricular end-systolic pressure-volume relationship (ESPVR) (contractility: Ees) was evaluated using a conductance catheter. RESULTS: Downregulated Ees and per cent of fractional shortening (%FS) assessed by echocardiography and eNOS expression in the failing stage were both significantly increased by using benidipine; this result was not found, however, when using FR alone or hydralazine or benidipine plus FR. Upregulated expression of NAD(P)H oxidase p22phox and p47phox and lectin-like oxidized low-density lipoprotein receptor-1, and downregulated superoxide dismutase-1 (SOD-1) were significantly ameliorated by benidipine, but not by FR alone or by hydralazine or benidipine plus FR. Benidipine effectively inhibited vascular lesion formation and suppressed atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGF-beta1), but this was not the case when using FR alone or hydralazine or benidipine plus FR. CONCLUSIONS: These results suggest that benidipine may be useful for cardioprotective agents in preventing the cardiac dysfunction and remodeling associated with the BK-eNOS and oxidative stress pathway.

Combination therapy with telmisartan and spironolactone alleviates L-NAME exacerbated nephrosclerosis with an increase in PPAR-gamma and decrease in TGF-beta(1).

To investigate whether the receptor blockades of angiotensin II type 1 and aldosterone receptors can prevent renal tissue injury in relation to the renal tissue mRNA levels of peroxisome proliferation-activated receptors-gamma (PPAR-gamma) and transforming growth factor-beta (1) (TGF-beta(1)) in spontaneously hypertensive rats (SHR) given N(G)-nitro-L-arginine methyl ester (L-NAME), which is considered a model of malignant hypertension. This study was performed in 5 groups of 17-week-old male SHR treated for 3 weeks as follows: group 1, control; group 2, L-NAME (50 mg/L in drinking); group 3, L-NAME plus aldosterone antagonist, spironolactone (SPRL, 100 mg/kg/day); group 4, L-NAME plus angiotensin II type 1 receptor blocker, telmisartan (TELM, 3 mg/kg/day); group 5, L-NAME plus combination therapy (COMB) with low-dose TELM (1 mg/kg/day) and SPRL (100 mg/kg/day). Urinary protein excretion and the glomerular injury score were significantly reduced in the SPRL, TELM, and COMB groups as compared with the L-NAME group, while significant blood pressure reduction was observed only in the TELM group. In the TELM and COMB groups, the perivascular cell infiltration and fibrosis area were significantly reduced together with the PPAR-gamma mRNA increase and TGF- beta(1) mRNA decrease. The urinary excretion of nitric oxides was significantly recovered and the wall to lumen ratio of the interlobular artery was significantly reduced only in the COMB group compared with the L-NAME group. Combined administration of 1 mg/kg/day telmisartan and 100 mg/kg/day spironolactone is thought to be effective in alleviating hypertensive renal injuries independently of blood pressure changes. The anti-inflammatory and antifibrotic effects due to PPAR-gamma activation and TGF-beta(1) inhibition may participate in the renoprotection of this combination therapy.

Long-term efficacy of combination therapy with losartan and low-dose hydrochlorothiazide in patients with uncontrolled hypertension.

We evaluated the long-term efficacy of losartan and low-dose hydrochlorothiazide combination therapy in the treatment of hypertension. We enrolled 15 Japanese hypertensive outpatients whose 24-hour ambulatory blood pressure was >or= 135/80 mmHg after candesartan 8 mg (CND group; n = 10) monotherapy or amlodipine 5 mg (AML group; n = 5) monotherapy for 2 months or more. The monotherapy was then switched to losartan 50 mg and hydrochlorothiazide 12.5 mg combination therapy. Ambulatory blood pressure and indices of glucose and lipid metabolism were measured at the end of the monotherapy and after 3 and 12 months of the combination therapy. In the CND group, 24-hour blood pressure decreased significantly from 137 +/- 9/89 +/- 4 to 126 +/- 8/81 +/- 7 mmHg after 3 months (P < 0.05/ P < 0.001) and to 123 +/- 7/81 +/- 4 mmHg after 12 months (P < 0.01/P < 0.001). In the AML group, 24-hour blood pressure decreased significantly from 137 +/- 11/81 +/- 7 to 125 +/- 12/75 +/- 6 mmHg after 3 months (P < 0.05/P < 0.05) and to 124 +/- 9/77 +/- 7 mmHg after 12 months (P < 0.05/NS). There were significant decreases in systolic blood pressure during the daytime (6:00-21:30), nighttime (22:00-5:30) and early morning (6:00-8:00) after 12 months in both groups. No adverse changes in the indices of glucose or lipid metabolism were observed in either group. In conclusion, long-term combination therapy with losartan and low-dose hydrochlorothiazide was effective in the treatment of hypertensive patients whose blood pressure was not controlled by candesartan or amlodipine monotherapy alone.

Globular adiponectin activates nuclear factor-kappaB and activating protein-1 and enhances angiotensin II-induced proliferation in cardiac fibroblasts.

Adiponectin is present in the serum as a trimer, hexamer, or high-molecular weight form. A proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), also circulates in human plasma. The biological activities of these isoforms are not well characterized. Pressure overload in adiponectin-deficient mice results in enhanced concentric cardiac hypertrophy and increased mortality, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium. Therefore, we examined whether gAd exerts the same effects on myocardium signaling. Nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation were examined using cardiac fibroblasts prepared from the ventricles of 1- to 2-day-old Wistar rats and grown in culture. gAd activated NF-kappaB and enhanced tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activity. gAd also activated AP-1 and enhanced angiotensin II (Ang II)-induced AP-1 activity. gAd induced mRNA expression of c-fos and c-jun and activated extracellular signal-regulated kinase. Thus, gAd enhanced Ang II-induced DNA and collagen synthesis. Antibodies against adiponectin receptor (AdipoR)1 and AdipoR2 elicit activation of NF-kappaB or AP-1, two redox-sensitive transcription factors. Thus, rather than having an antihypertrophic effect, gAd might contribute to the activation of myocardium signaling, leading to myocardial hypertrophy.

Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney.

BACKGROUND: Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF). METHODS: Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks. RESULTS: DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl CONCLUSION: The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.