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E Kusano

Publications and source records attributed to E Kusano.

At least 19 recordsLinked to original sources
PubMed2006

Histone deacetylase inhibitor FK228 suppresses the Ras-MAP kinase signaling pathway by upregulating Rap1 and induces apoptosis in malignant melanoma.

Histone deacetylase (HDAC) inhibitors are expected to be effective for refractory cancer because their mechanism of action differs from that of conventional antineoplastic agents. In this study, we examined the effect of the HDAC inhibitor FK228 on malignant melanoma, as well as its molecular mechanisms. FK228 was highly effective against melanoma compared with other commonly used drugs. By comparing the gene expression profiles of melanoma cells and normal melanocytes, we defined a subset of genes specifically upregulated in melanoma cells by FK228, which included Rap1, a small GTP-binding protein of the Ras family. The expression of Rap1 mRNA and protein increased in FK228-treated melanoma cells in both a dose- and a time-dependent manner. A decrease in the phosphorylation of c-Raf, MEK1/2, and ERK1/2 was accompanied by an increase in Rap1 expression in both FK228-treated and Rap1-overexpressing cells. Inhibition of Rap1 upregulation by small interfering RNA (siRNA) abrogated the induction of apoptosis and suppression of ERK1/2 phosphorylation in FK228-treated melanoma cells. These results indicate that the cytotoxic effects of FK228 are mediated via the upregulation of Rap1. Furthermore, we found that Rap1 was overexpressed and formed a complex with B-Raf in melanoma cell lines with a V599E mutation of B-Raf. The siRNA-mediated abrogation of Rap1 overexpression increased the viability of these cells, suggesting that Rap1 is also an endogenous regulator of Ras-MAP kinase signaling in melanomas.

Animals↗
PubMed2006

Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of arteriosclerosis. Clinical studies show that uremic toxins deteriorate the arteriosclerosis in renal failure patients. Indoxyl sulfate (IS) is a strong protein-bound uremic toxin, but the effect of IS on VSMC proliferation has not been studied. We examined the effect of IS on rat VSMC proliferation, assessed by a cell counting kit (4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] assay) and by [(3)H]thymidine incorporation in vitro. We further evaluated a contribution of mitogen-activated protein kinase (MAPK; p44/42 MAPK) to VSMC proliferation by IS. Immunohistochemical staining was performed for VSMCs using antirat organic anion transporter (OAT)3 antibody. The mRNA expressions of platelet-derived growth factor (PDGF)-A and -C chains, and PDGF-beta receptor were evaluated by real-time PCR. IS stimulated the proliferation of VSMCs in a concentration-dependent manner and activated p44/42 MAPK. Concentration of IS needed to stimulate the proliferation of rat VSMC was about 250 microM, which is compatible with that in the serum of end-stage renal failure patients. PD98059 (10 microM), a selective inhibitor of MAPK/extracellular signal-regulated kinase, inhibited the IS-induced (250 microM) VSMC proliferation and phosphorylation of MAPK. Probenecid (0.5 mM), an inhibitor and substrate of OAT, inhibited the IS-induced (250 microM) VSMC proliferation. Rat OAT3 was detected in VSMCs. The mRNA expressions of PDGF-C chain and PDGF-beta receptor were significantly increased by IS. We conclude that IS directly stimulates rat VSMC proliferation and activates MAPK in vitro. This might be one of the mechanisms underlying the progression of atherosclerotic lesions in end-stage renal disease patients.

Animals↗
PubMed2006

Reversible hypocalcemic heart failure with T wave alternans and increased QTc dispersion in a patient with chronic renal failure after parathyroidectomy.

Despite the crucial role of calcium in myocardial contractility, hypocalcemia has very rarely been reported as a reversible cause of heart failure. In this article, we describe a case of a 51-year-old woman with advanced stages of chronic renal failure after parathyroidectomy who exhibited congestive heart failure, severe hypocalcemia, hypomagnesemia and hypokalemia. Severe hypocalcemia resulted from discontinuation of taking calcium supplements after parathyroidectomy and from reduced 1.25(OH)2D3 synthesis by damaged kidneys. The patient presented with reduced left ventricular ejection fraction (EF) and ECG abnormalities (T wave alternans and increased QTc dispersion), both of which improved after correction of serum calcium levels. Her serum levels of total calcium corrected for serum albumin, but not serum levels of magnesium or potassium, positively and negatively correlated with EF and QTc dispersion, respectively. In the present case, both heart failure and the ECG abnormalities are directly associated with hypocalcemia.

Calcium↗
PubMed2006

Complete remission of minimal-change nephrotic syndrome induced by apheresis monotherapy.

We report a case of a 17-year-old male with relapse of minimal-change nephrotic syndrome (MCNS), in whom apheresis monotherapy without steroids or immunosuppressants resulted in complete remission. The patient initially developed nephrotic syndrome in February 1998. The first renal biopsy confirmed the diagnosis of MCNS. The patient was also found to be a carrier of hepatitis B virus. Steroid therapy was started with oral prednisolone 60 mg/day. Complete remission was achieved in 3 months, and the steroid treatment was tapered off in May 2001. During the steroid tapering, temporal exacerbation of liver function was noted. In July 2002, the patient was admitted to our hospital again due to relapse of nephrotic syndrome. Second biopsy reconfirmed the diagnosis of MCNS. Since the serum titer of HBV was elevated, apheresis monotherapy was selected to avoid the risk of steroid-induced fulminant hepatitis. Four sessions of low-density lipoprotein apheresis (LDL-A) and 5 sessions of double-filtration plasmapheresis (DFPP) reduced the proteinuria from 9.2 g/day to 0.2 g/day over 38 days without any additional medication. Proteinuria remained suppressed below 0.2 g/day for more than 12 months and no exacerbation of liver function was observed up to the final follow-up in September 2003. The present case suggested the potential of apheresis monotherapy to induce and maintain complete remission of MCNS and an important role of circulating factors in the pathogenesis of MCNS.

Adolescent↗
PubMed2006

Fanconi's syndrome and distal (type 1) renal tubular acidosis in a patient with primary Sjögren's syndrome with monoclonal gammopathy of undetermined significance.

Tubulointerstitial nephritis is a well-recognized complication in primary Sjögrens syndrome. Fanconi's syndrome is a far less frequent complication compared with distal tubular dysfunction. We here describe a 49-year-old woman with primary Sjögren's syndrome. In 1997, she was diagnosed with primary Sjögren's syndrome with tubulointerstitial nephritis, and was then treated with oral prednisolone for the tubulointerstitial nephritis. In 2002, she was referred to our hospital because of progressive fatigue. At that time, biclonal spike on serum protein (IgG-kappa and IgA-kappa) and Bence-Jones protein in urine were found. Bone marrow aspiration showed 1.0% plasma cell infiltration. Thus, a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) was made. In 2004, she was again admitted to our hospital because of mild renal dysfunction and hypokalemia. Laboratory evaluation showed inappropriate, alkaline urine in hyperchloremic metabolic acidosis and a positive urine anion gap, indicating the presence of distal (Type 1) renal tubular acidosis (RTA). The urine concentration defect was also found. Further studies revealed proximal tubular dysfunction, including renal glycosuria, generalized aminoaciduria, phosphaturia, uricosuria and proximal RTA. The kidney biopsy represented diffuse and severe tubulointerstitial nephritis with dense infiltrates of lymphocytes and IgA and K light chain-positive plasma cells. No findings of multiple myeloma or malignant lymphoma were observed. In conclusion, our patient had Sjögren's syndrome with MGUS and exhibited dysfunction of both proximal tubule (Fanconi's syndrome) and distal tubule, which may be attributed to diffuse tubulointerstitial nephritis.

Acidosis, Renal Tubular↗
PubMed2003

Combined treatment with nafamostat mesilate and aspirin prevents heparin-induced thrombocytopenia in a hemodialysis patient.

We report on the management of a 36-year-old hemodialysis patient with heparin-induced thrombocytopenia (HIT, type II) and clot formation in extracorporeal circulation. Platelet aggregation test and measurement of anti-platelet factor 4/heparin complex antibody by enzyme-linked immunosorbent assay revealed to us that our patient had developed HIT. Instead of heparin, we used nafamostat mesilate (NM) as an anticoagulant during hemodialysis, but could not completely prevent HIT-induced thrombocytopenia or clot formation in the extracorporeal circuit. Combined use of NM and aspirin completely inhibited platelet aggregation, decrease in platelet count and clot formation in the extracorporeal circuit.

Adult↗
PubMed2002

Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis.

It is well known that long-term glucocorticoid treatment causes osteoporosis, but the precise mechanism remains unclear. Recently, osteoprotegerin (OPG) has been identified as a cytokine that inhibits osteoclast differentiation. We have previously demonstrated that serum OPG is suppressed by glucocorticoids. Therefore, the present study was carried out to clarify the interrelationships between OPG and other markers of bone metabolism during glucocorticoid treatment. Thirteen patients (7 men, 6 women; 44.1 +/- 5.9 years old) with chronic glomerulonephritis who were to be treated with glucocorticoids for the first time were chosen for this study. Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (bAP), parathyroid hormone (PTH), tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment period. Glucocorticoids significantly reduced BMD of the lumbar spine in the 6 month treatment period (p < 0.01). Serum OPG was decreased significantly by glucocorticoids within 2 weeks (p < 0.001), and serum TRAP, a marker of bone resorption, was markedly increased (p < 0.001). On the other hand, there were no remarkable changes in serum PTH. Serum OC and bAP, markers of bone formation, were transiently reduced during the treatment period (p < 0.01). Furthermore, only serum OPG was positively and independently correlated with percentage BMD of age-matched reference (%AMR). These findings imply that glucocorticoid-induced bone loss develops rapidly via enhanced bone resorption and suppressed bone formation. Moreover, the increased bone resorption caused by glucocorticoids may be, at least in part, mediated by inhibition of OPG, not increment of PTH.

Adult↗
PubMed2002

Optically stimulated luminescence in an imaging plate using BaFi:Eu.

BaFI:Eu phosphors are fabricated using a new method of synthesis: liquid phase synthesis, in which the phosphor particles are formed through the association of Ba2+ ions, F-ions and Eu2+ ions in solution. An intense optically stimulated luminescence (OSL) peak at about 410 nm is observed by stimulating X ray irradiated BaFI:Eu phosphor with about 550-750 nm light. It is found that the peak wavelength of the optically stimulation spectrum is about 690 nm. This result suggests that the semiconductor laser can be used as the stimulating light source. It is also found that the OSL intensity is increased with increasing the X ray dose. The BaFI:Eu phosphor as a photostimulable material for the imaging plate of a computed radiography system provides the following advantages; (1) high X ray absorption coefficient, (2) high monodispersion in size which would contribute to sharp images, (3) high OSL and thus low luminescence mottle and (4) high DQE (detective quantum efficiency).

Barium Compounds↗
PubMed2002

Effect of ticlopidine hydrochloride on erythropoietin-induced rise in blood pressure in patients on maintenance hemodialysis.

BACKGROUND/AIMS: A recent observation that antiplatelet-aggregation drugs, including ticlopidine hydrochloride, may prevent erythropoietin (EPO)-induced rise in blood pressure in hemodialysis (HD) patients remains a subject of particular interest. The aim of the present study was to determine the effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure of HD patients with special reference to blood levels of vasoactive substances. METHODS: HD patients who showed hypertension or aggravation of preceding hypertension with EPO treatment were selected for this study. Ticlopidine hydrochloride was administered at a dose of 200 mg daily for 4 weeks. Blood pressure and serum levels of nitric oxide (NO), atrial natriuretic peptide (ANP) and endothelin (ET) were determined before and after drug administration. Patients were divided into two groups, one of which showed a drop in mean blood pressure (MBP) of >10 mm Hg (group I) and one which did not (group II), and a comparison was made between them with respect to the blood parameters. RESULTS: Five of 15 patients showed a drop of MBP of >10 mm Hg (group I), and 10 patients did not show any change in MBP (group II). In group I, there was a significant increase in blood NO levels compared to the concentrations before ticlopidine administration, while there was no change in group II. With respect to ANP and ET, there was no significant change in either of the groups. CONCLUSION: The findings suggest that the preventive effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure may partly be related to the enhancement of NO production in patients on maintenance HD.

Adult↗
PubMed2002

Cellular component of vascular calcification. Fibroblasts are essential for calcium deposition in cultured cells.

It has been reported that calcium deposition and calcium content in cultured human aortic smooth muscle cells (SMC) increased when the cells are incubated in a medium with a high phosphate concentration (2 mM). To determine the cellular components or soluble factors contributing to the deposition, we cultured commercially available SMC, fibroblasts (Fb) and endothelial cells (Ed). These cells and their mixtures were incubated for 10 days in normal or high-phosphate media. Calcium crystals were stained by the von-Kossa staining and counted in the defined area. Calcium content was measured by a colorimetric assay. SMC were incubated in high-phosphate media (up to 2 mM) or beta-glycerophosphate (beta-GP) media, resulting in no obvious deposition of calcium crystals, irrespective of the coating of type I collagen on the dish. Next, various combinations of cells were cultured, and a significant number of depositions were observed only when Fb were included in the combination. The calcium content was significantly higher in cultures of SMC and Fb. The calcium deposition on single or mixture of the cells did not increase compared with control when cells were incubated in a high concentration of phosphate, cultured in the existence of beta-GP or uremic serum. We therefore conclude that Fb, rather than SMC or Ed, are essential for calcium deposition and calcium accumulation in culture. Phosphate concentration in the medium and uremic serum did not influence the deposition of calcium.

Calcification, Physiologic↗
PubMed2001

Immunotactoid glomerulopathy characterized by steroid-responsive massive subendothelial deposition.

We report a case of immunotactoid glomerulopathy with unique histologic findings in serial biopsies. A 73-year-old man complained of developing general edema. Laboratory data on admission presented moderate renal dysfunction with nephrotic syndrome. There was no evidence of systemic disease that might cause secondary glomerulopathy. Light microscopy of the renal specimen revealed lobulation of glomerular tufts and massive endothelial deposition of hyaline-like periodic acid-Schiff-positive substance with neutrophilic infiltration. The deposits were positive for immunoglobulin by immunohistochemical stains but negative for Congo red stain. Electron microscopy disclosed the deposition of microtubular structure (60 nm in diameter) predominantly in the subendothelial area and to some extent in the subepithelial and mesangial areas. Some of the tubules were extremely large (100 to 130 nm in diameter) and displayed a unique scroll structure in cross-section. The patient was treated with two sessions of plasma exchange and subsequent oral prednisolone (30 mg/d). Proteinuria and renal dysfunction improved significantly in the following 2 months. Second and third renal biopsies revealed disappearance of the deposit along with the improvement of proteinuria and renal dysfunction. Because similar microtubular structures were found in neutrophils in the glomerulus as well as in the urinary sediment, phagocytosis was suggested as a possible mechanism for removal of the deposit.

Aged↗
PubMed2001

Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis.

BACKGROUND: Osteoporosis is a well known side-effect of long-term treatment with glucocorticoids. However, the precise mechanism of this disorder is unclear. Recently, osteoprotegerin (OPG) [osteoclastogenesis inhibitory factor (OCIF)] has been identified as a novel cytokine, which inhibits differentiation and activation of osteoclast. In the present study, in order to clarify the roles of OPG in the development of glucocorticoid-induced osteoporosis, we measured circulating OPG before and after glucocorticoid therapy. METHODS: The study subjects were 12 patients (five males, seven females, 53.4 +/- 4.8 [SE] years) with various renal diseases that required glucocorticoid therapy. All patients received glucocorticoids for the first time. Treatment was initiated at an average dose of 32.5 +/- 3.0 mg per day. Serum OPG was measured using enzyme-linked immunosorbent assay (ELISA). Laboratory data, markers of bone metabolism and circulating OPG were compared before and after treatment for 4 weeks. RESULTS: Serum OPG prior to glucocorticoid therapy was positively and independently correlated with serum creatinine. Serum OPG decreased significantly (P: < 0.0001) from 1.03 +/- 0.14 to 0.77 +/- 0.12 ng/ml after short-term administration of glucocorticoids. Furthermore, serum osteocalcin as a marker of bone formation was also reduced markedly (P: = 0.001). On the other hand, there were no remarkable changes in serum calcium, total alkaline phosphatases, creatinine and intact parathyroid hormone in response to glucocorticoid administration. CONCLUSION: These findings indicate that short-term administration of glucocorticoids significantly suppresses serum OPG and osteocalcin. It might participate in the development of glucocorticoid-induced osteoporosis via an enhancement of bone resorption and suppression of bone formation.

Female↗
PubMed2001

Erythropoietin modulates angiotensin II- or noradrenaline-induced Ca(2+) mobilization in cultured rat vascular smooth-muscle cells.

BACKGROUND: It has been reported that human recombinant erythropoietin (rHuEpo) modulates the sensitivity of the cardiovascular system to angiotensin II (Ang II) or noradrenaline (NA). In the present study, we explored the effect of rHuEpo on the responsiveness of Ang II- or NA-induced cytosolic free calcium ([Ca(2+)]i) mobilization in cultured rat vascular smooth-muscle cells (VSMC). METHODS: [Ca(2+)]i concentrations in VSMC were measured by using the calcium-sensitive fluorescent dye fura-2. RESULTS: The addition of rHuEpo (250 U/ml) alone induced elevation in [Ca(2+)]i, which remained significantly elevated above basal level for at least 60 min in the presence of extracellular Ca(2+). Pre-incubation with specific protein kinase C (PKC) inhibitor calphostin C (1 micromol/l) significantly reduced the peak and the sustained elevations of [Ca(2+)]i. Pre-treatment with rHuEpo for 60 min increased both basal [Ca(2+)]i and the changes in [Ca(2+)]i by Ang II or NA in a dose-dependent manner in the presence of extracellular Ca(2+). The synergistic effects of rHuEpo with Ang II or NA were also retained when VSMC were bathed in the Ca(2+)-free medium after the pre-incubation of rHuEpo. Conversely, they were diminished in the presence of extracellular Ca(2+) combined with intracellular Ca(2+) release inhibitor 8-(NN-diethylamino)octyl-1,3,4,5-trimethoxybenzoate (TMB-8). The synergistic effects of rHuEpo were also diminished by PKC depletion or by PKC inhibitor. CONCLUSIONS: These observations suggest that rHuEpo has synergistic effects on Ang II- or NA-induced [Ca(2+)]i mobilization, particularly on intracellular Ca(2+) release, in VSMC. This may be a potential mechanism contributing to hypertension associated with rHuEpo therapy.

Angiotensin II↗
PubMed2001

Involvement of erythropoietin-induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells.

BACKGROUND/OBJECTIVE: Human recombinant erythropoietin (rHuEPO) induces cytosolic free calcium ([Ca2+]i) mobilization, an activation of mitogen-activated protein (MAP) kinase and DNA synthesis in several tissues. We explored the mechanism of rHuEPO-induced [Ca2+]i mobilization and its role in the activation of MAP kinase and DNA synthesis in vascular smooth muscle cells (VSMC). METHODS: [Ca2+]i concentrations were measured by fura-2. MAP kinase activation was analyzed using an immunocomplex kinase assay and Western blotting. DNA synthesis was measured as an incorporation of 5-bromo-2'-deoxyuridine. RESULTS: Although addition of rHuEPO significantly increased [Ca2+]i, either in the presence or absence of extracellular Ca2+, the peak level and sustained elevation of [Ca2+]i were significantly reduced in the absence of extracellular Ca2+. Pretreatment with genistein completely blocked the elevation of [Ca2+]i in both conditions. Calphostin C and staurosporine did not completely block the elevation of [Ca2+]i. Staurosporine reduced its peak level in a dose-dependent manner, whereas calphostin C reduced its peak level at concentrations over 1 nmol/l in the presence of extracellular Ca2+. Similar results to those with staurosporine were observed with nifedipine. In the absence of extracellular Ca2+, their dose-dependent effects disappeared even though rHuEPO increased [Ca2+]i. rHuEPO activated MAP kinase and DNA synthesis, both of which were significantly suppressed by the chelation of intracellular Ca2+. CONCLUSION: These findings suggest that rHuEPO increases [Ca2+]i by both Ca2+ influx and Ca2+ release from intracellular stores. Tyrosine phosphorylation is critical in the regulation of [Ca2+]i, but protein kinase C activation is important only in the regulation of Ca2+ influx. Dihydropyridine-sensitive L-type Ca2+ channels seem to be involved in rHuEPO-induced Ca2+ influx. In addition, increase of [Ca2+]i by rHuEPO stimulates MAP kinase activation and DNA synthesis in VSMC.

Animals↗
PubMed2001

Functional characterization of basolateral and luminal dopamine receptors in rabbit CCD.

Previous studies reported the existence of both D1- and D2-like receptors in the cortical collecting duct (CCD). However, especially with regard to natriuresis, it remains controversial. In the present study, rabbit CCD was perfused to characterize the receptor subtypes responsible for the tubular actions. Basolateral dopamine (DA) induced a dose-dependent depolarization of transepithelial voltage. Basolateral domperidone, a D2-like receptor antagonist, abolished depolarization, whereas SKF-81297, a D1-like receptor agonist, showed no significant change. In addition, bromocriptine, a D2-like receptor agonist, also caused depolarization, whereas SKF-81297, a D1-like receptor agonist, did not depolarize significantly. Moreover, RBI-257, a D4-specific antagonist, reversed the basolateral DA-induced depolarization. In contrast to the basolateral side, luminal DA caused depolarization via a D1-like receptor; however the change was less than that for basolateral DA. For further evaluation, 22Na+ flux (J(Na)) was measured to confirm the effect of DA on Na+ transport. Basolateral DA also caused a suppression of J(Na), and this reaction was abolished by domperidone. These results suggested that the basolateral D2-like receptor is mainly responsible for the natriuretic action of DA in rabbit CCD.

Animals↗
PubMed2001

Selective hypoaldosteronism due to combined defects of the conversion from inactive renin to active renin and the aldosterone biosynthesis from corticosterone.

A 24-year-old Japanese woman with IgA nephropathy exhibited a decreased serum aldosterone level with normal plasma renin activity after toxemia of pregnancy. Our studies revealed selective hypoaldosteronism with normal adrenoglucocorticoid functions. Levels of serum corticosterone and deoxycorticosterone were normal. Resting plasma renin activity was normal, and plasma levels of total and inactive renin were increased. Rapid ACTH administration failed to stimulate any secretion of aldosterone, whereas it adequately increased serum cortisol, deoxycorticosterone, and corticosterone concentrations. Responses of both plasma renin activity and serum aldosterone level to the furosemide-posture challenge were blunted. Angiotensin II also failed to stimulate any secretion of aldosterone despite a progressive rise in blood pressure and an appropriate increase in serum corticosterone. These results suggest that combined defects of the conversion from inactive renin to active renin and aldosterone biosynthesis are the causes of selective hypoaldosteronism in our patient.

Adrenocorticotropic Hormone↗
PubMed2001

Modulation of endothelin-1-induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cells.

BACKGROUND: It has been reported that human recombinant erythropoietin (rHuEPO) modulates the sensitivity of the cardiovascular system to vasoconstrictors. We investigated whether rHuEPO has modulative effects on the endothelin-1 (ET-1)-induced elevation of cytosolic free calcium concentration ([Ca2+]i) and mitogen-activated protein (MAP) kinase activation in vascular smooth muscle cells (VSMC). METHODS: [Ca2+]i was measured by fura-2/AM, and MAP kinase activation was analyzed by Western blotting. RESULTS: Exposure of VSMC to rHuEPO prior to stimulation with ET-1 enhanced both basal and ET-1-induced elevation of [Ca2+]i in a dose-dependent manner in the presence of extracellular Ca2+. The synergistic effect was also retained in the absence of extracellular Ca2+ after exposure to rHuEPO. However, the effect was diminished in the presence of extracellular Ca2+ combined with the intracellular Ca2+ release inhibitor TMB-8, PKC inhibitor, or PKC depletion. Exposure to rHuEPO also had a synergistic effect on the activation of MAP kinase induced by ET-1; however, this effect was diminished in the presence of the Ca2+ chelator BAPTA-AM. CONCLUSION: The results suggest that rHuEPO has synergistic effects on ET-1-induced [Ca2+]i mobilization, particularly on intracellular Ca2+ release, and MAP kinase activation in VSMC.

Animals↗