Biomedical subjects

Fumiki Yoshihara

Publications and source records attributed to Fumiki Yoshihara.

At least 19 recordsLinked to original sources

PubMed2006

Reverse white-coat effect as an independent risk for microalbuminuria in treated hypertensive patients.

BACKGROUND: The influence of the converse phenomenon of white-coat hypertension called 'reverse white-coat hypertension' or 'masked hypertension' on hypertensive target organ damage has not been fully elucidated. The present study assessed the hypothesis that this phenomenon may specifically associate with microalbuminuria, a marker of early renal damage, in treated hypertension. METHODS: A total of 267 treated essential hypertensive patients (133 men and 134 women; mean age, 66 years) without renal insufficiency or macroalbuminuria were enrolled in this study. Patients were classified into three groups by the difference between office and day-time ambulatory systolic blood pressure (BP) levels; i.e. subjects with white-coat effect (W group: office--day-time systolic BP > or =20 mmHg, n = 48), with reverse white-coat effect (R group: office - day-time systolic BP < - 10 mmHg, n = 43) and without white-coat or reverse white-coat effect (N group: -10 mmHg < or = office--day-time systolic BP <20 mmHg, n = 176). The urinary albumin (U-Alb) level was measured as the albumin to creatinine excretion ratio in the urine. Microalbuminuria was defined as U-Alb of > or =30 and <300 mg/g Cr. RESULTS: R group had a well-controlled office BP (130/77 mmHg), but their day-time BP (148/87 mmHg) was elevated compared with the other two groups. The levels of U-Alb excretion in N group, W group and R group were 12.3 (8.4, 25.6), 16.0 (10.5, 31.7) and 24.3 (10.2, 79.7) mg/g Cr [median (interquartile range)], respectively. Both U-Alb level and prevalence of microalbuminuria were significantly greater in R group than in N group. Multivariate analyses revealed that the presence of reverse white-coat effect, but not white-coat effect, was a significant predictor for microalbuminuria, independent of various clinical variables including ambulatory BP levels (odds ratio 2.63 vs N group, P = 0.02). CONCLUSION: These findings suggest that the presence of reverse white-coat effect may be an independent risk for early renal damage in treated hypertensive patients.

Adult↗

PubMed2006

Renal function in patients with abdominal aortic aneurysm. Comparison with hypertensive patients.

AIMS: Renal dysfunction occurs occasionally after the repair of abdominal aortic aneurysm (AAA), and preoperative renal function is considered as one of the potential causes. The present study was designed to evaluate and compare renal function and risk factors of AAA patients with those of hypertensive patients. METHODS: We prospectively examined 95 patients with AAA and 72 patients with essential hypertension (HT) without other cardiovascular diseases (CVD). Renal function, urinary albumin excretion (UAE) and renal scintigraphy were compared. Kidney size was calculated using ultrasonography. RESULTS: Serum creatinine and creatinine clearance in AAA patients was worse than in HT patients. Smoking status was more apparent in AAA patients. Renal artery stenosis occurred in 8 patients with AAA. Renal scintigraphy showed normal function in 19%, hypofunction in 69% and severe dysfunction in 12% of the AAA patients, and normal function in 42% and hypofunction in 58% of the HT patients (p < 0.0001). Multivariate linear regression analysis showed that renal function was related to age, UAE, CVD, smoking status and kidney size for all patients, UAE, CVD, smoking status and kidney size for AAA patients, and age and kidney size for HT patients. CONCLUSION: Renal function of AAA patients was worse than HT patients without other CVD. The risk factors for renal dysfunction were different between AAA and HT patients. These preoperative conditions may relate to the postoperative renal dysfunction seen in AAA patients.

Aged↗

PubMed2006

Masked hypertension and target organ damage in treated hypertensive patients.

BACKGROUND: Recent studies have shown that an elevated ambulatory or home blood pressure (BP) in the absence of office BP-a phenomenon called masked hypertension-is associated with poor cardiovascular prognosis. However, it remains to be elucidated how masked hypertension modifies target organ damage in treated hypertensive patients. METHODS: A total of 332 outpatients with chronically treated essential hypertension were enrolled in the present study. Patients were classified into four groups according to office (<140/90 or >or=140/90 mm Hg) and daytime ambulatory (<135/85 or >or=135/85 mm Hg) BP levels; ie, controlled hypertension (low office and ambulatory BP), white-coat hypertension (high office but low ambulatory BP), masked hypertension (low office but high ambulatory BP), and sustained hypertension (high office and ambulatory BP). Left ventricular mass index, carotid maximal intima-media thickness, and urinary albumin levels were determined in all subjects. RESULTS: Of the patients, 51 (15%), 65 (20%), 74 (22%), and 142 (43%) were identified as having controlled hypertension, white-coat hypertension, masked hypertension, and sustained hypertension, respectively. Left ventricular mass index, maximal intima-media thickness, and urinary albumin level in masked hypertension were significantly higher than in controlled hypertension and white-coat hypertension, and were similar to those in sustained hypertension. Multivariate regression analyses revealed that the presence of masked hypertension was one of the independent determinants of left ventricular hypertrophy, carotid atherosclerosis, and albuminuria. CONCLUSIONS: Our findings indicate that masked hypertension is associated with advanced target organ damage in treated hypertensive patients, comparable to that in cases of sustained hypertension.

Aged↗

PubMed2006

[Adrenomedullin].

Explore the source record for details and available documents.

Adrenomedullin↗

PubMed2005

Relationship between renal artery stenosis and intrarenal damage in autopsy subjects with stroke.

BACKGROUND: In patients with cardiovascular disease (CVD), renal dysfunction is a risk factor for the prognosis, but substantial evidence is still lacking about the relationship between clinical characteristics and renal histology. The aim of our study was to evaluate the relationship between the extent of renal parenchymal damage, renal artery stenosis (RAS) and clinical characteristics in autopsy subjects with stroke. METHODS: During the 17-year period 1980-1997, 2167 subjects were autopsied at the National Cardiovascular Center. We studied retrospectively all the autopsy cases aged 40 years and older who had a history of stroke. Thus, 346 subjects remained and they were classified into two groups. Thirty-six subjects had RAS (group A). Three hundred and ten subjects had no RAS, and we randomly chose 102 subjects among them (group B). We evaluated renal parenchymal damage using a semi-quantitative chronic damage score. RESULTS: The average overall chronic damage score was significantly higher in the stenosed kidneys of group A than in the non-stenosed kidneys of group B (9.0+/-2.6 vs 7.0+/-2.7). The contralateral kidneys of group A had a tendency to have milder renal damage than stenosed kidneys. Furthermore, the total score was higher in the subjects with hypertension, diabetes mellitus, proteinuria, renal insufficiency and CVD than in the subjects without such complications. The total score had a significant association with RAS, proteinuria, renal insufficiency, CVD and weight of the kidney. CONCLUSIONS: In autopsy subjects with stroke, we demonstrated that co-existing renal parenchymal damage was more severe in the subjects with RAS, hypertension, diabetes mellitus, proteinuria and renal insufficiency than those without such complications. The presence of RAS, impaired renal function and proteinuria was closely correlated with the severity of renal parenchymal damage.

Adult↗

PubMed2005

Chronic administration of adrenomedullin attenuates the hypertension and increases renal nitric oxide synthase in Dahl salt-sensitive rats.

Adrenomedullin reduces systemic blood pressure and increases urinary sodium excretion partly through the release of nitric oxide. We hypothesized that chronic adrenomedullin infusion ameliorates salt-sensitive hypertension and increases the expression of renal nitric oxide synthase (NOS) in Dahl salt-sensitive (DS) rats, because the reduced renal NOS expression promotes salt sensitivity. DS rats and Dahl salt-resistant (DR) rats were fed a high sodium diet (8.0% NaCl) for 3 weeks. The high sodium diet resulted in an increase in blood pressure and a reduction of urinary sodium excretion in association with increased renal adrenomedullin concentrations and decreased expression of renal neuronal NOS (nNOS) and renal medullary endothelial NOS (eNOS) in DS rats compared with DR rats. Chronic adrenomedullin infusion partly inhibited the increase of blood pressure and proteinuria in association with a restoration of renal nNOS and medullary eNOS expression in DS rats under the high sodium diet. The immunohistochemical analysis revealed that the restored renal nNOS expression induced by chronic adrenomedullin infusion may reflect the restoration of nNOS expression in the macula densa and inner medullary collecting duct. These results suggest that adrenomedullin infusion has beneficial effects on this hypertension probably in part through restored renal NOS expression in DS rats.

Adrenomedullin↗

PubMed2005

A novel immunosuppressant FTY720 ameliorates proteinuria and alterations of intrarenal adrenomedullin in rats with autoimmune glomerulonephritis.

FTY720 has been originally developed as a new immunosuppressive agent, which prolongs graft survival in organ transplantation. Adrenomedullin (AM) participates in the regulation of sodium homeostasis and has renoprotective effects. The possible involvement of renal AM in the pathophysiology of glomerulonephritis (GN) and the effect of FTY720 has been evaluated in rats. HgCl2 (1 mg/kg body weight) was inoculated subcutaneously 3 times/week for a total of 2 weeks. FTY720 (3 or 10 mg/kg) was inoculated subcutaneously daily. The proteinuria, urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion and serum total cholesterol levels were increased and serum albumin level was reduced in rats with HgCl2-induced GN compared with controls. FTY720 reduced proteinuria (3 mg/kg: -25%; 10 mg/kg: -41%), urinary NAG excretion (-11%; -52%) and total cholesterol level (-21%; -55%) in a dose-dependent manner. Renal AM level and its mRNA expression were increased in rats with GN compared with controls (Peptide Cortex: +69%; Medulla: +82%; mRNA Cortex: +25%). Interestingly, FTY720 additionally increased these levels (Peptide Cortex: +38%; Medulla: +39%; mRNA Cortex: +20%). Renal AM levels correlated with urinary NAG excretion and creatinine clearance. These results suggest that FTY720 suppresses the renal damage in rats with GN and renal AM may participate in the pathophysiology of GN and the renoprotective effects of FTY720.

Adrenomedullin↗

PubMed2005

Upregulation of intracardiac adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy.

Specific adrenomedullin receptors have been identified as calcitonin receptor-like receptor (CRLR)/receptor activity-modifying proteins (RAMP2 and RAMP3) complexes. Although we have demonstrated that adrenomedullin is increased in volume overload-induced cardiac hypertrophy, it remains unknown whether the adrenomedullin receptor is altered or not. This study sought to investigate the significance of intracardiac adrenomedullin and its receptor system in volume overload-induced cardiac hypertrophy. Left ventricular adrenomedullin levels were higher in aortocaval shunt (ACS) rats than in controls (+58%). The left ventricular gene expressions of adrenomedullin, CRLR, RAMP2 and RAMP3 were increased (+27%, +76%, +108% and +131%, respectively) and the left ventricular collagen gene expressions were also increased (type I: +138%, type III: +87%). The left ventricular adrenomedullin level correlated with the gene expression of type III collagen (R=0.42). These results suggest that intracardiac adrenomedullin and its receptor system are upregulated and may participate in the regulation of cardiac remodeling in volume overload-induced cardiac hypertrophy.

Adrenomedullin↗

PubMed2005

Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts.

Insulin-like growth factor (IGF)-1 appears to play an important role in cardiac hypertrophy or remodeling. However, the role of endogenous IGF-1 in the growth of cardiac myocytes and fibroblasts remains unclear. This study investigated the major site of the production of cardiac IGF-1 and the local effects of endogenous IGF-1 secreted from cardiac cells. A significant expression of IGF-1 mRNA was found in cultured neonatal and adult rat cardiac fibroblasts, but not in myocytes. In addition, an in vivo examination by in situ hybridization histochemical analyses demonstrated the IGF-1 transcripts in the interstitial fibrotic tissue of the ventricle. Time-dependent secretion of IGF-1 protein was also observed in cultured cardiac fibroblasts. An antibody against IGF-1 decreased collagen synthesis in cardiac fibroblasts under basal conditions. Fibroblast-conditioned medium, as well as exogenous IGF-1, increased protein synthesis in cardiac myocytes, and this increase was inhibited by antibodies against IGF-1 and IGF-1 receptor, IGF binding protein-3, and IGF-1 receptor antagonist. These observations suggest that IGF-1 is produced and released mainly from cardiac fibroblasts and that endogenous IGF-1 promotes collagen synthesis by cardiac fibroblasts and hypertrophy of myocytes as an autocrine and a paracrine factor. Cardiac IGF-1 may function as an endogenous modulator of cardiac hypertrophy or remodeling.

Animals↗

PubMed2005

Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic.

OBJECTIVE: We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. METHOD: We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. RESULTS: SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. CONCLUSION: Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.

Adrenomedullin↗

PubMed2005

Asymptomatic renal infarction, due to fibromuscular dysplasia, in a young woman with 11 years of follow-up.

We report a 27-year-old woman with renovascular hypertension, renal infarction, and hepatic artery aneurysm due to fibromuscular dysplasia. The patient was first noted to have renal artery aneurysm and hepatic artery aneurysm at the age of 17. The renal infarction was asymptomatic and was incidentally detected by magnetic resonance imaging (MRI) examination. Because of the rather peripheral location of the aneurysms, percutaneous transluminal renal artery angioplasty was considered inappropriate. This case suggests the need for long-term and periodical follow-up of patients with fibromuscular dysplasia.

Adult↗

PubMed2005

QTc dispersion in haemodialysis patients with cardiac complications.

BACKGROUND AND AIMS: QTc dispersion (Maximum - Minimum QTc interval on a standard 12-lead electrocardiogram (ECG)) is a useful predictor of tachyarrhythmic events and related sudden cardiac death. Recent studies have reported that QTc dispersion is prolonged in patients receiving haemodialysis (HD), and it is often further prolonged following HD treatment. In the present study, we examine whether the patients who are susceptible to prolongation of QTc dispersion by HD are prone to life-threatening cardiovascular events and related deaths. METHODS: Forty-eight patients with cardiac symptoms such as chest pain (n = 32), arrhythmia (n = 2) or heart failure (n = 14) and receiving chronic HD treatment (40 males and eight females) were subjected to the present study. Twenty-six of a total 48 patients were given a diagnosis of ischaemic heart disease (IHD) by coronary angiography. Ten patients had cerebrovascular accidents and 11 patients had peripheral vascular disease. After the ECG recording, a prospective follow up was conducted for 37 +/- 24 months. RESULTS: During the follow-up period, 30 patients had cardiac events, and 23 including 18 cardiovascular deaths occurred as outcomes. Throughout the total period, patients who showed prolongation of QTc dispersion after HD had cardiovascular deaths with higher incidence than those did not show the prolongation. CONCLUSIONS: We consider that prolongation of QTc dispersion after HD treatment can predict the prognosis of patients with renal failure bearing cardiac complications. Great care is necessary for such patients if they show longer QTc dispersion and/or susceptibility for further prolongation after HD treatment.

Adult↗

PubMed2005

Adrenomedullin reflects cardiac dysfunction, excessive blood volume, and inflammation in hemodialysis patients.

BACKGROUND: Plasma adrenomedullin (AM) reflects cardiac dysfunction and predicts survival after myocardial infarction. The present study was designed to investigate whether the mature AM (mAM) reflects status of cardiac function, systemic blood volume, or inflammation in hemodialysis patients with cardiovascular disease, and whether mortality and additional cardiovascular morbidity can be predicted by mAM. METHODS: Plasma levels of mAM, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), norepinephrine (NE), and C-reactive protein (CRP) before hemodialysis were measured in 67 chronic hemodialysis patients with cardiovascular disease, along with 2-dimensional and Doppler echocardiographic variables. RESULTS: By univariate regression analysis, mAM correlated negatively with pulmonary venous flow velocity ratio and left ventricular (LV) ejection fraction and positively with LV inflow velocity ratio, LV end-diastolic, end-systolic volume indexes, plasma CRP level, and removal fluid volume by ultrafiltration. Multivariate stepwise regression analysis revealed that mAM reflected all variables better than log [ANP], log [BNP], and log [NE]. During a 1-year follow-up period, 7 patients died and 8 had additional cardiovascular events. Event-free Kaplan-Meier curves based on the median mAM (4.55 pmol/L) showed that patients with high plasma mAM levels had higher mortality and morbidity than those with low plasma mAM levels (P = 0.0056). By Cox multivariate proportional hazard analysis, mAM was related to mortality and morbidity [hazard ratio (HR) 4.55, 95% CI 1.2-16.8, P= 0.023). CONCLUSION: Plasma mAM reflects cardiac dysfunction, excessive blood volume, and inflammation better than ANP, BNP, and NE, resulting in a predictor of mortality and cardiovascular morbidity in hemodialysis patients with cardiovascular disease.

Adrenomedullin↗

PubMed2005

Life-threatening hyperkalemia during a combined therapy with the angiotensin receptor blocker candesartan and spironolactone.

We describe a hypertensive nephrosclerosis patient presenting with severe hyperkalemia due to a combination therapy of the angiotensin receptor blocker (ARB) candesartan and spironolactone despite mildly decreased renal function. Recently, ARBs are replacing the ACE inhibitors. The combined therapy with ARB and spironolactone will eventually become the standard regimen. The strict attention and close monitoring of serum potassium should be mandatory in combination therapy to prevent hyperkalemia. Assessment of trans-tubular potassium gradient (TTKG) and fractional excretion of potassium (FEK) before starting the therapy would help in identifying the patients at higher risk of developing hyperkalemia. Co-administration of thiazide or loop diuretics is recommended to reduce the risk of hyperkalemia.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2004

Orthostatic hypotension at the introductory phase of haemodialysis predicts all-cause mortality.

BACKGROUND: Since the predictive value of orthostatic hypotension (OH) at the introductory phase of haemodialysis (HD) is unknown, we examined the association between OH and all-cause death in patients who started HD between 1987 and 2001. METHODS: More than three consecutive blood pressure measurements before HD treatments (pre-HD BP) were made on each of 304 patients who had recently been started on HD and were in a stable condition. OH was defined as a drop in systolic BP of >20 mmHg or in diastolic BP of >10 mmHg after standing. RESULTS: Of 304 patients, 42% had OH. OH was significantly associated with pre-HD supine systolic BP; its severity was significantly associated with a past history of cerebrovascular disease and pre-HD supine systolic BP. During a mean follow-up of 4.0+/-3.0 years (range 0.1-13.2 years), 136 deaths were recorded. A multivariate Cox proportional hazards model analysis demonstrated that OH and a past history of cerebrovascular disease were independent predictors of all-cause death. The comparison by Kaplan-Meier analysis of the overall survival of patients with and without OH was significant. CONCLUSIONS: Our findings validate OH at the introductory phase of HD as a novel independent predictor of all-cause mortality among HD patients.

Aged↗

PubMed2004

Mycophenolate mofetil prevents autoimmune glomerulonephritis and alterations of intrarenal adrenomedullin in rats.

We studied the effects of mycophenolate mofetil, a specific inhibitor of inosine monophosphate dehydrogenase, on the mercuric chloride induced autoimmune glomerulonephritis in Brown Norway rats and also on the renal contents of adrenomedullin. In the rats with autoimmune glomerulonephritis, plasma and renal tissue adrenomedullin levels were increased significantly. Coadministration of mycophenolate mofetil resulted in prevention of autoimmune glomerulonephritis and also in maintaining of plasma and renal tissue adrenomedullin levels at control levels. Adrenomedullin mRNA expressions in the renal cortex were also higher in the rats with autoimmune glomerulonephritis. Significant positive correlations were found between renal cortical adrenomedullin levels and urinary Na+ and N-acetyl-beta-D-glucosaminidase excretion. A significant negative correlation between renal cortical adrenomedullin levels and creatinine clearance was also found. These results suggest that mycophenolate mofetil suppresses the renal damage in rats with autoimmune glomerulonephritis and renal adrenomedullin may participate in the pathophysiology of autoimmune glomerulonephritis.

Adrenomedullin↗

PubMed2004

Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways.

C-type natriuretic peptide (CNP) is known to play a role in the local regulation of vascular tone. We recently found that CNP is also produced by cardiac ventricular cells. However, its local effect on myocyte hypertrophy remains to be elucidated. The present study investigated the effects of CNP on cultured cardiac myocyte hypertrophy and the interaction between CNP and endothelin-1 (ET-1) signaling pathways. CNP attenuated basal and ET-1-augumented protein synthesis, atrial natriuretic peptide secretion, hypertrophy-related gene expression, GATA-4 and MEF-2 DNA binding activities, Ca(2+)/calmodulin-dependent kinase II activity, and ERK phosphorylation. CNP also inhibited ET-1-induced increase in intracellular Ca(2+) concentration. These effects of CNP were mimicked by a cGMP analog, 8-bromo cGMP. However, the inhibitory effects of CNP on the hypertrophic response of myocytes were significantly diminished at high concentrations of ET-1. Although CNP increased intracellular cGMP levels in myocytes, ET-1 suppressed CNP-induced cellular cGMP accumulation. A protein kinase C activator and Ca(2+) ionophore mimicked this suppressive effect of ET-1. We further examined the effect of CNP on the paracrine action of ET-1 secreted from cardiac nonmyocytes. CNP and 8-bromo cGMP significantly inhibited ET-1 secretion from nonmyocytes. Although nonmyocyte-conditioned medium increased the protein synthesis in myocytes through endogenous ET-1 action, this increase was significantly attenuated by pretreatment of nonmyocytes with CNP and 8-bromo cGMP. These findings demonstrate that CNP inhibits ET-1-induced cardiac myocyte hypertrophy via a cGMP-dependent mechanism, and conversely, ET-1 inhibits CNP signaling by a protein kinase C- and Ca(2+)-dependent mechanism, suggesting mutual interference between CNP and ET-1 signaling pathways.

Animals↗

PubMed2004

Ventricular nonmyocytes inhibit doxorubicin-induced myocyte apoptosis: involvement of endogenous endothelin-1 as a paracrine factor.

A cross-talk between cardiac myocytes and nonmyocytes via humoral factors plays an important role in the development of cardiac growth. However, it remains to be elucidated whether humoral factors produced from nonmyocytes have a protective effect on acute myocardial injury. The present in vitro study investigated the antiapoptotic effect of nonmyocytes on doxorubicin (DOX)-induced myocyte apoptosis and its molecular mechanism. Myocyte-nonmyocyte coculture and treatment with nonmyocyte-conditioned media significantly attenuated DOX-induced myocyte apoptosis. Treatment with nonmyocyte-conditioned media stimulated the phosphorylation of ERK, Akt, and cAMP response element-binding protein (CREB) in myocytes. Nonmyocyte-conditioned media also increased protein levels of Bcl-2 but not Bcl-xL and decreased caspase-3 activation induced by DOX. MAPK kinase-specific inhibitor PD98059, phosphatidylinositol-3 kinase-Akt inhibitor LY294002, and CREB antisense oligonucleotide significantly blocked the antiapoptotic effect of nonmyocyte-conditioned media. A considerable amount of endothelin (ET)-1 production was detected in nonmyocytes but not in myocytes. Exogenous ET-1 mimicked nonmyocyte-conditioned media-mediated ERK and CREB phosphorylation and Bcl-2 protein increase but not Akt phosphorylation. In addition, ET-A receptor antagonists BQ123 and BQ485 partially blocked nonmyocyte-conditioned media-mediated antiapoptotic effect, ERK and CREB phosphorylation, and Bcl-2 protein increase. Nonmyocyte-conditioned media and exogenous ET-1 unchanged protein levels of manganese superoxide dismutase and oxidative stress-related product levels augmented by DOX. The present findings demonstrate that cardiac nonmyocytes inhibit DOX-induced myocyte apoptosis, at least in part, via ET-1 secretion-mediated CREB activation independent of the decrease in oxidative stress.

Apoptosis↗