endothelin-1 and benazepril

To investigate the effects of different drugs on systolic blood pressure (SBP) and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats under cold stress.. A total of 40 male spontaneously hypertensive rats aged 10 weeks (160~200 g) were given adaptive feeding for 7 days at a temperature of 20±1°C and then randomly divided into control group, cold stress group, metoprolol group, amlodipine group, and benazepril group, with 8 rats in each group. SBP, body weight, and heart rate were measured once a week. After the rats were sacrificed by exsanguination, left ventricular weight (LVW) was measured, and left ventricular weight index (LVWI; mg/g) was calculated. Radioimmunoassay was used to measure the concentrations of endothelin-1 (ET-1) and angiotensin-II (Ang-II) in plasma and myocardium, and the chemical method was used to measure the concentrations of nitric oxide (NO) in plasma and myocardium. RT-PCR was used to measure the mRNA expression of endothelin-A receptor.. Compared with the cold stress group, all medication groups showed significant reductions in SBP since week 5 (P<0.05). The cold stress group showed a significant increase in LVWI compared with the control group (3.38±0.27 mg/g vs 2.89±0.19 mg/g, P<0.05). The amlodipine group showed a significant reduction in LVWI compared with the cold stress group (2.98±0.28 mg/g vs 3.38±0.27 mg/g, P<0.05). The cold stress group showed a significant reduction in plasma NO concentration compared with the control group (104.9±19.5 μmol/L vs 129.3±17.8 μmol/L, P<0.05) ; compared with the cold stress group, all the medication groups showed significant increases in blood NO concentration (P<0.05). The cold stress group showed a significant increase in myocardial ET-1 concentration compared with the control group (6.3±1.5 pg/100 mg vs 4.5±1.9 pg/100 mg, P<0.05) ; compared with the cold stress group, the amlodipine group showed a significant reduction in myocardial ET-1 concentration (4.4±1.0 pg/100 mg vs 6.3±1.5 pg/100 mg, P<0.05). The cold stress group had significantly higher mRNA expression of endothelin-A receptor than the control group (0.86±0.23 vs 0.45±0.16, P<0.01) ; compared with the cold stress group, the amlodipine group showed a significant reduction in the mRNA expression of endothelin-A receptor (0.41±0.14 vs 0.86±0.23, P<0.01).. Amlodipine can reduce the increase in SBP and inhibit LVH in spontaneously hypertensive rats under cold stress.

Topics: Angiotensin II; Animals; Benzazepines; Blood Pressure; Cold Temperature; Endothelin-1; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Rats; Rats, Inbred SHR; Stress, Physiological

The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; ATP-Binding Cassette Transporters; Benzazepines; Endothelin-1; Extracellular Matrix; Hemodynamics; Hypertension; Immunohistochemistry; KATP Channels; Kidney; Kidney Diseases; Kidney Function Tests; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the protective effects of blocking rennin-angiotensin system (RAS) on the progression of renal injury in glomerulosclerosis, a glomerulosclerosis model was made for SD rats by unilateral nephrectomy and being injected with Adriamycin into caudal vein. The rats with glomerulosclerosis were randomly divided as ten per group into those without further treatment (group D) and those treated with Benazepril (group DB), Losartan (group DL), or sham-operation (group C), respectively. After 6 weeks of administration of Benazepril or Losartan, the mRNA expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS in renal cortex were measured by RT-PCR. Besides, the expressions of TGF-beta1, ET-1 and iNOS at protein level were detected by Western blotting and the concentrations of Col IV and Fn were analyzed with immunohistochemistry respectively. Results showed that the rats in group D appeared as obvious proteinuria, hypoalbuminemia and hypercholesterolemia, which had a significant difference compared with group C (p < 0.05), and most of their mesangiums were detected with cellular proliferation and significant increasing for extracellular matrix. Renal cortex TGF-beta1, Col IV, Fn, ET-1 and iNOS in rats of group D were increased by 3.59, 2.57, 2.21, 2.58 and 3.28 times at mRNA level, and by 2.60, 1.40, 0.75, 1.83 and 2.15 times at protein level, respectively, compared with group C. When the animals were treated with Benazepril (group DB) or Losartan (group DL), however, the biochemical and pathological damages were significantly recovered, and protein expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS were also significantly diminished (p < 0.05). This study suggested that blocking RAS using Benazepril or Losartan can have protective effects on the renal injury in glomerulosclerosis by down-regulating the expressions of TGF-beta1, Col IV, Fn, ET-1 and iNOS.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Benzazepines; Collagen Type IV; DNA, Complementary; Endothelin-1; Fibronectins; Glomerulosclerosis, Focal Segmental; Kidney; Losartan; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured.. Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period.. The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently.. The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Benzazepines; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-Converting Enzymes; Hypertension; Indoles; Male; Metalloendopeptidases; Neprilysin; Nitric Oxide; Organophosphonates; Phenylalanine; Protease Inhibitors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species

To study the effect of the Compound of traditional Chinese drugs and Benazepril on gene expression of renal endothelin and its receptor of experimental diabetic nephropathy(DN). To discove the mechanism of the compound of traditional Chinese drugs in treating DN.. Streptozotocin DN model was built and influenced with the compound of traditional Chinese drugs and Benazepril. The changes of Upro, Glu, HbA1C and (PT-PCR) mRNA expression levels of ET-1, ETA-R of the renal cortex were tested, and thus the histopathological character of the kidney was analysed.. The compound of traditional Chinese drugs and Benazepril have significant difference from normal saline in the improvement of Upro, Glu, HbA1C. The compound of traditional Chinese drugs have significant difference from Benazepril in the improvement of Glu, HbA1C. The mRNA expression level of ET-1, ETA-R of the renal cortex of DN model was raised. After influenced by the compound of traditional Chinese drugs and Benazepril, the over-expression level de-creased (still higher than normal control ones). The compound of traditional Chinese drugs were more effective than Benazepril to inhibit the proliferation of the stalk region and the third cells.. ET takes part in the process of diabetic glo-Merulosclerosis. Both the compound of traditional Chinese drugs and Benazepril can influence the expression quantity from the level of gene transcription of ET and its receptor. The compound of traditional Chinese drugs can not only reduce urinary albumin of DN, but also improve blood glucose, glycosylated hemoglubin. And it can inhibit nonenzymatic glucosylation of protein as well as the proliferation of the stalk region and the third cells.

Topics: Animals; Benzazepines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drugs, Chinese Herbal; Endothelin-1; Gene Expression; Kidney Cortex; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger

Continuous intra-arterial administration of a selective endothelin-converting enzyme (ECE) inhibitor CGS 35066 at a dose of 30 mg/kg decreased the mean arterial blood pressure (MABP) in conscious unrestrained normotensive rats and spontaneously hypertensive rats (SHRs). At that dose, the magnitude of the antihypertensive effects was greater in SHRs than in normotensive rats. Additional administration of an angiotensin-converting enzyme (ACE) inhibitor benazapril (lotensin) further reduced MABP in normotensive rats and completely blocked hypertension in SHRs. However, when the selective ECE inhibitor was subsequently removed, blood pressure was less inhibited in normotenive rats whereas it remained strongly inhibited in SHRs by the ACE inhibitor alone. These results imply that simultaneous treatment with benazepril and CGS 35066 gave additive antihypertensive effects in normotensive rats but not in SHRs, when both compounds were administered at a dose of 30 mg/kg. Our results suggest that: (i) the endothelin (ET) system together with the renin-angiotensin system contribute to the maintenance of blood pressure in normal healthy rats; (ii) while an ECE inhibitor acts as an antihypertensive agent on its own, the sole efficacy of ACE inhibitor at that dose is sufficient to block MABP without the participation of the ET system in SHR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Benzazepines; Benzofurans; Blood Pressure; Drug Therapy, Combination; Endothelin-1; Endothelin-Converting Enzymes; Hypertension; Male; Metalloendopeptidases; Organophosphonates; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.. DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.. The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Catecholamines; Collagen; Diastole; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Endothelin-1; Gene Expression; Heart Failure; Heart Function Tests; Hydroxyproline; Myocardium; Myosin Heavy Chains; Organ Size; Rats; Rats, Inbred Dahl; Receptors, Angiotensin; RNA, Messenger; Sodium Chloride, Dietary; Survival Rate; Tetrazoles; Valine; Valsartan; Ventricular Remodeling

To explore the influence of angiotensin-converting enzyme inhibitors (ACEI) on plasma endothelin (ET-1), nitric oxide (NO) and renal function in renal-hypertension patients.. Sixty renal-hypertension patients (Group II) were treated with ACEI (lotensin) for 10 weeks then we measure their blood pressure (BP), plasma ET-1, NO and renal functions (BUN, Scr and proteinuria) before and after the treatment. Thirty healthy persons (Group I) acted as control.. The level of plasma ET-1 was higher and plasma NO was lower in Group II than those in Group I. After the treatment of ACEI plasma ET-1 and proteinuria were decreased (P < 0.01), and NO increased in Group II significantly (P < 0.01), while BUN and Scr decreased in abnormal-renal function patients (Group II2) (P < 0.05, P < 0.01).. The Study indicates that: ACEI is effective to renal hypertension; it decreases plasma ET-1 and increases NO in the renal hypertension patients; ACEI may play an important role in protection of renal functions and prolonging the chronic renal failure.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Urea Nitrogen; Endothelin-1; Female; Humans; Hypertension, Renal; Kidney Function Tests; Male; Middle Aged; Nitric Oxide