<b>AIMb>To investigate the effect of endogenous endothelin-1 (ET-1) on cardiomyocyte apoptosis induced by hypoxia and its possible mechanism.

<b>METHODSb>Cultured neonatal rat cardiomyocytes were divided into control group and ET receptor antagonist group. Control group was given DMEM only and ET receptor antagonist group was treated with ET receptor subtype A (ET(A)) receptor antagonist BQ610 and BQ123 or ET(B) receptor antagonist BQ788 and subjected to hypoxia for 24 h. The presence of apoptosis in cardiomyocytes was evaluated by TUNEL analysis and flow cytometry (FCM).

<b>RESULTSb>TUNEL analysis showed that the percentage of positive apoptotic cells in BQ610 5 micromol/L group was 13.2% +/- 3.7%, significantly lower than that in hypoxia group (24.2% +/- 2.2%, P < 0.01). FCM showed that BQ123 (0.04, 0.2 and 1.0 micromol/L) inhibited hypoxia-induced cardiomyocyte apoptosis and increased cardiomyocyte survival rate in a dose-dependent manner, while BQ788 did not show such effects.

<b>CONCLUSIONb>These findings suggest that endogenous ET-1 aggravates hypoxia-induced cardiomyocyte apoptosis and this effect is mediated through ET(A) receptor-dependent pathways.

Animals ; Animals, Newborn ; Apoptosis ; Cell Hypoxia ; Cells, Cultured ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Endothelin-1 ; physiology ; Myocytes, Cardiac ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley

<b>OBJECTIVEb>To study the expression of ET receptor and the apoptosis after intervened with ET receptor antagonist in androgen-independent prostate cancer.

<b>METHODSb>PC3, an androgen-independent prostate cancer cell line, was used. The expression of ETA and ETB receptor in PC3 was measured through RT-PCR. After intervened with selective ETA and ETB receptor antagonist, the apoptosis in PC3 was studied through flow cytometry and electron microscope.

<b>RESULTSb>Clear signal was obtained in PC3 for ETA receptor mRNA transcript, while the signal for ETB receptor mRNA transcript was very weak. The expression of ETA receptor mRNA was obviously reduced and the apoptosis of PC3 cell was observed after intervened with selective ETA receptor antagonist. There was no change after intervened with selective ETB receptor antagonist.

<b>CONCLUSIONb>ET-1 exerts its effects through the ETA receptor subtype and ETB receptor is silenced in PC3. The expression of ETA was reduced and the apoptosis was observed in PC3 when ETA receptor was blocked. It was dose-dependent.

Androgens ; physiology ; Apoptosis ; drug effects ; physiology ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Endothelin-1 ; physiology ; Humans ; In Vitro Techniques ; Male ; Neoplasms, Hormone-Dependent ; pathology ; Oligopeptides ; administration & dosage ; Peptides, Cyclic ; administration & dosage ; Piperidines ; administration & dosage ; Prostatic Neoplasms ; pathology ; physiopathology ; Receptor, Endothelin A ; metabolism ; physiology ; Receptor, Endothelin B ; metabolism ; physiology

Three-dimensional pharmacophore models were generated for AT1 and ET(A) receptors based on highly selective AT1 and ET(A) antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists (Hypo-AT(1)-7) and ETA antagonists (Hypo-ET(A)-1) were obtained through a careful validation process. All five features contained in Hypo-AT(1)-7 and Hypo-ET(A)-1 (hydrogen-bond acceptor (A), hydrophobic aliphatic (Z), negative ionizable (N), ring aromatic (R), and hydrophobic aromatic (Y)) seem to be essential for antagonists in terms of binding activity. Dual AT1 and ET(A) receptor antagonists (DARAs) can map to both Hypo-AT(1)-7 and Hypo-ET(A)-1, separately. Comparison of Hypo-AT(1)-7 and Hypo-ET(A)-1, not only AT1 and ET(A) antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ET(A) receptor antagonists.
Angiotensin II Type 1 Receptor Blockers ; chemistry ; Drug Design ; Endothelin Receptor Antagonists ; Models, Molecular ; Molecular Conformation

<b>AIMb>To determine the involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the expression of endothelin receptor type B (ETB) during culture.

<b>METHODSb>SB386023, a specific inhibitor for ERK1/2 pathway, was used to define the intracellular signaling pathway for the upregulation of ETB receptors and sarafotoxin 6c (S6c), a selective agonist for ETB receptors, induced contraction in isolated rat superior mesenteric arteries. The contraction was recorded by a sensitive in vitro myograph and the receptor mRNA was quantified by a real-time PCR. The phosphorylated ERK1/2 proteins were analyzed by phosphoELISA assay.

<b>RESULTSb>S6c induced strong contractile responses of the artery after culture for 24 h, while there was no response to S6c in fresh vessel segments. The enhanced contractile response to S6c paralleled with an increase of mRNA for ETB receptors. The phosphorylated ERK1/2 proteins significantly increased after culture for 3 h. After co-culture with SB386023 for 24 h, S6c-induced contractions significantly decreased with reduction of Emax from (217 +/- 14) % to (127 +/- 23) % (P <0.01). This response paralleled with a decreased level of ETB receptor mRNA.

<b>CONCLUSIONb>ERK1/2 pathway was involved in the up-regulation of ETB receptors on smooth muscle cells isolated from rat mesenteric arteries during culture.

Animals ; Cells, Cultured ; Male ; Mesenteric Arteries ; cytology ; Mitogen-Activated Protein Kinase 1 ; antagonists & inhibitors ; metabolism ; Mitogen-Activated Protein Kinase 3 ; antagonists & inhibitors ; metabolism ; Muscle Contraction ; drug effects ; Muscle, Smooth, Vascular ; cytology ; metabolism ; Organ Culture Techniques ; Phosphorylation ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin B ; biosynthesis ; genetics ; Signal Transduction ; Up-Regulation ; Vasoconstrictor Agents ; pharmacology ; Viper Venoms ; pharmacology

<b>OBJECTIVEb>To investigate the anti-tumor effect of the endothelin A receptor antagonist BQ123 on human prostate cancer cell line PC-3M in vitro by observing its impact on the proliferation and apoptosis of human prostate cancer cells.

<b>METHODSb>The inhibiting effect of BQ123 on the proliferation of PC-3M cells was observed by MTT assay, erosion trace test and Transwell chamber chemotaxis assay, and its induction of their apoptosis determined by Annexin V-FITC/PI staining and cytometry.

<b>RESULTSb>BQ123 exhibited increased inhibition of PC-3M cells in a time-dependent manner, with inhibition rates of 22.32%, 44.88% and 64.47% at 24 h, 48 h and 72 h, respectively (P < 0.05). The migration distances of the PC-3M cells in the BQ123 group were (103.42 +/- 75.63) microm, (243.75 +/- 121.53) microm and (422.07 +/- 36.01) microm at 12 h, 24 h and 48 h, obviously lower than (162.93 +/- 19.87) microm, (317.19 +/- 43.19) microm and (692.74 +/- 40.84) microm in the control group (P < 0.05). The number of the PC-3M cells that invaded the inferior chamber in the BQ123 group was (79.2 +/- 9.58), significantly decreased as compared with (92.6 +/- 5.94) in the control (P < 0.05). The apoptosis rate of PC-3M exposed to BQ123 was (15.03 +/- 0.93)%, significantly higher than (9.38 +/- 1.37)% in the control (P < 0.05). The ratio of PC-3M cells in different cycles showed no significant differences.

<b>CONCLUSIONb>BQ123 inhibits the proliferation of PC-3M cells and induces their apoptosis in vitro, which may give a new idea on the studies of prostate cancer therapies.

Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Endothelin A Receptor Antagonists ; Humans ; Male ; Peptides, Cyclic ; pharmacology ; Prostatic Neoplasms

Recently several kinds of new antihypertensive agents were introduced. Diuretics such as indapamide, metyrazone and eprelerone have less side effects compared to thiazide, and have an effect in renal insufficiency. Carvedilol, combined alpha- and beta- adrenergic blocker, has a vasodilating property and an effect on heart failure. The lipid soluble third generation calcium antagonists such as amlodipine, lacidipine and lercardipine are slow onset and long acting and have less side effects, which provide continued effect even if daily doses are missed. Multiple angiotensin converting inhibitors and angiotensin receptor blockers, and the specific aldosterone antagonist eprenolone to block renin-angiotensin-aldosterone system are now available. Additionally new class antihypertensive drugs such as the vasopeptidase inhibitor, the endothelin receptor blocker and the renin inhibitor have been under investigation and shown favorable clinical results, and will be available for clinical use soon.
Adrenergic Antagonists ; Aldosterone ; Amlodipine ; Angiotensin Receptor Antagonists ; Angiotensins ; Antihypertensive Agents ; Calcium ; Diuretics ; Heart Failure ; Hypertension* ; Indapamide ; Receptors, Endothelin ; Renal Insufficiency ; Renin ; Renin-Angiotensin System

Proteinuria is a cardinal manifestation of renal disease and has been proposed to promote progression of renal disease. Proteinuria develops in 9~41% of transplant recipients, and is diagnosed by routine urinalysis, urine protein to creatinine ratio, or 24-hour urine protein collection. Protein excretion of >200 mg/24 h is considered abnormal. The etiology of post-transplant proteinuria is diverse, including allograft rejection, recurrent or de novo glomerulonephritis, cyclosporine A nephrotoxicity, conversion to sirolimus, and chronic allograft nephropathy, which is the most common. Transplant renal biopsy is required to confirm the cause of proteinuria, and a combination of two or more of the transplant pathological categories can be present. High-grade proteinuria is believed to mediate progressive renal damage by conferring to proximal tubular epithelial cells with increased production of endothelin-1, chemokines such as monocyte chemoattractant protein-1 and cytokines, all of which promote interstitial fibrosis. It has been reported that proteinuria after renal transplantation affected not only graft survival but also patient survival. In proteinuric recipients, both the cardiovascular and noncardiovascular death risks seem to be significantly increased compared with nonproteinuric recipients. Low-grade (<1 g/24 h) proteinuria 1 year after transplantation is also associated with graft loss. The treatments for proteinuria are blood pressure control, and the use of angiotensin-converting enzyme inhibitor and/or angiotensin II receptor blockers therapy. Several options that are able to reduce proteinuia, including nondihydropyridine calcium channel blocker or aldosterone antagonists are also available. In conclusion, post-transplant proteinuria is a sensitive marker of graft dysfunction, correlated both to graft failure and to patient death. Appropriate management guided by proven cause and antiproteinuric treatments may improve the outcome.
Allografts ; Angiotensin Receptor Antagonists ; Biopsy ; Blood Pressure ; Calcium Channels ; Chemokine CCL2 ; Chemokines ; Creatinine ; Cyclosporine ; Cytokines ; Endothelin-1 ; Epithelial Cells ; Fibrosis ; Glomerulonephritis ; Graft Survival ; Humans ; Kidney Transplantation ; Mineralocorticoid Receptor Antagonists ; Proteinuria* ; Sirolimus ; Transplantation ; Transplants ; Urinalysis

Antihypertensive Agents ; therapeutic use ; Endothelin Receptor Antagonists ; therapeutic use ; Familial Primary Pulmonary Hypertension ; Humans ; Hypertension ; drug therapy ; Hypertension, Pulmonary ; drug therapy

<b>OBJECTIVEb>To investigate the effect of sodium ferulate (SF) on diabetic nephropathy (DN).

<b>METHODSb>Forty-eight DN patients of early stage and 54 DN patients of clinical stage were randomly divided into two groups, the conventional treatment group and the SF treatment group. Indexes, including urinary albumin excretion rate (UAER), serum endothelin (ET), blood urea nitrogen (BUN), serum creatinine (Scr) and fasting blood glucose (FBG) were observed.

<b>RESULTSb>The levels of UAER, BUN and ET were decreased in all DN patients, either early stage or clinical stage, after treated with SF for 4 weeks (P < 0.05, P < 0.01), but changed insignificantly in those treated with conventional treatment.

<b>CONCLUSIONb>SF can decrease the levels of UAER and BUN in DN patients, the mechanism may relate with the decreasing of ET production and antagonizing to the binding of ET with its receptors.

Adult ; Aged ; Coumaric Acids ; therapeutic use ; Diabetes Mellitus, Type 2 ; drug therapy ; Diabetic Nephropathies ; drug therapy ; Endothelin Receptor Antagonists ; Female ; Humans ; Male ; Middle Aged ; Phytotherapy

The relationship between the hepatic ischemia/reperfusion (I/R) injury and the balance of nitric oxide/endothelins (NO/ET) was studied. The changes of the ratio of NO/ET and the hepatic injury were observed in a rat hepatic I/R model pretreated with several tool drugs. In the acute phase of hepatic I/R injury, the ratio of plasma NO/ET was reduced from 1.58 +/- 0.20 to 0.29 +/- 0.05 (P < 0.01) and the hepatic damage deteriorated. NO donor L-Arg and ET receptor antagonist TAK-044 could alleviate the hepatic I/R injury to some degree, whereas NO synthase inhibitor L-NAME aggravated the damage. It was concluded that the hepatic I/R injury might be related with the disturbance of the NO/ET balance. Regulation of this balance might have an effect on the I/R injury.
Animals ; Arginine ; Endothelin Receptor Antagonists ; Endothelins ; blood ; Female ; Liver ; blood supply ; Male ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; blood ; Rats ; Reperfusion Injury ; blood