angiotensinogen and candesartan-cilexetil

Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.. Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague-Dawley (SD) rats. Protein levels of brain angiotensin II and mRNA levels of renin-angiotensin system components were evaluated following reperfusion (n=184 in total). Low-dose or high-dose treatments with candesartan cilexetil (1 or 10 mg/kg per day, respectively) were administered orally immediately following reperfusion once daily for 4 or 7 days (n = 119 in total). An additional group was treated with low-dose candesartan cilexetil after a 12-h delay based on the brain angiotensin II levels (n = 14).. Levels of brain angiotensin II transiently increased 4-12 h after reperfusion, which followed an increase in angiotensinogen mRNA. Candesartan cilexetil treatments significantly reduced blood pressure (BP) in rats administered the high dose and moderately in rats receiving the low dose. A low dose of candesartan cilexetil reduced the infarct size, cerebral edema, and neurological deficits, whereas the high-dose treatments showed limited reductions. Furthermore, oxidative stress following reperfusion was reduced with the low-dose treatments. The therapeutic time window was open for at least 12 h after reperfusion when brain angiotensin II levels had peaked.. Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Brain Edema; Brain Ischemia; Hypotension; Ischemia; Rats; Rats, Sprague-Dawley; Tetrazoles; Time Factors

Controlling hypertension by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), mechanisms that inhibit later pathway steps in the renin-angiotensin system (RAS), have clinically afforded protection against cardiac and renal disease.. In order to determine if blocking the RAS rate-limiting step of angiotensin II generation via renin inhibition could afford similar end organ protection in a human-relevant preclinical model, this study investigated the cardiac and renal effects of a nonpeptide, piperidine renin inhibitor (RI; 100 mg/kg/day PO) in double transgenic mice (dTGM) which express both human renin and angiotensinogen genes. RI was compared to the ARB, candesartan (3 mg/kg/day PO), and to the ACEI, enalapril (60 mg/kg/day PO) in a 4-week dosing paradigm. These doses of RI, ACEI and ARB were previously found to normalize mean blood pressure (MBP) to 110 + 3, 109 + 7 and 107 + 6 mmHg, respectively, after 1 day of treatment.. In the dTGM, PRA, plasma aldosterone, GFR, microalbuminuria and left ventricular free wall thickness (LVH) were higher than in the wild type C57BL/6 mice. Microalbuminuria and LVH were significantly reduced by 93% and 9% for the RI, 83% and 13% for enalapril and 73% and 6% for candesartan, respectively. PRA and aldosterone were reduced by the RI 56% and 23%, respectively. These results suggest that the RI provides protection against cardiac and renal disease, similar to ARB and ACEI.

Topics: Administration, Oral; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiotonic Agents; Drug Administration Schedule; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Piperidines; Quinolines; Renin; Renin-Angiotensin System; Tetrazoles; Time Factors; Ultrasonography

The present study was designed to clarify the role of angiotensin II (Ang II) in modulating renal tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) production and to investigate the effect of one dose of Ang II inhibitor on cytokines production following lipopolysaccharide (LPS) to cause endotoxemia. Two studies were performed: 1) Ang II was infused intravenously at a rate of 0.2 microg/kg per minute for 4 h in rats and then kidneys were collected to assay TNF-alpha and IL-6 mRNA levels; 2) Four-week-old Wistar rats pre-treated with angiotensin-converting enzyme inhibitor, enalapril, or type I Ang II-receptor antagonist, TCV-116, were injected with LPS (0.1, 0.5, 1.0 mg, i.p.), and then 2 or 4 h later, kidneys were collected to assay TNF-alpha, IL-6, renin and angiotensinogen mRNA levels. After a 4-h intravenous infusion of Ang II, renal TNF-alpha or IL-6 mRNA level significantly increased 1.9-fold or 2.1-fold (each P<0.05) to the control level, respectively. LPS stimulated TNF-alpha, IL-6 and angiotensinogen mRNA levels in the kidney but in rats given enalapril or TCV-116, LPS-induced IL-6 and TNF-alpha mRNA levels were completely suppressed (each P<0.05). This suggests that a single dose of renin-angiotensin system inhibitor suppressed renal IL-6 and TNF-alpha production and may prevent cytokine-induced renal damage during endotoxemia.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blotting, Northern; Cytokines; Enalapril; Endotoxins; Gene Expression Regulation; Interleukin-6; Kidney; Lipopolysaccharides; Male; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Tumor Necrosis Factor-alpha

The effects of chronic treatment with an angiotensin II receptor antagonist, candesartan cilexetil (TCV-116, 0.1, 1, 10 mg/kg), and an angiotensin converting enzyme inhibitor, enalapril maleate (enalapril, 10 mg/kg), on the development of end-organ damage were examined in stroke-prone spontaneously hypertensive rats (SHRSP). The control SHRSP developed severe hypertension with stroke signs and increased urinary protein excretion. TCV-116 (0.1 mg/kg) reduced the stroke incidence and urinary protein excretion without affecting the blood pressure. TCV-116 (1 and 10 mg/kg) and enalapril reduced blood pressure, the stroke incidence, the urinary indices and left ventricular weight. Circulating renin-angiotensin system (RAS) and renal renin mRNA expression were significantly accelerated or tended to be accelerated in the control SHRSP with end-organ damages. A low dose of TCV-116 tended to reduce the RAS indices in plasma by improving the damages, whereas a high dose (10 mg/kg) increased them by the reflexes with blocking RAS. The present results indicate that chronic All blockade reduces the increase in blood pressure, end-organ damages and RAS related to the damages in SHRSP.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiomegaly; Cerebrovascular Disorders; Enalapril; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Renin; RNA, Messenger; Tetrazoles

Activity of the renin-angiotensin system in the nephrotic syndrome was investigated in rats with acute nephritis induced by anti-glomerular basement membrane (GBM) antibody. Injection of anti-GBM antibody resulted in a transient 2-fold elevation of both plasma renin and angiotensinogen with a peak at 12 h. Angiotensinogen mRNA levels in the liver also rapidly and transiently increased 4-fold at 3 h. The manifestation of acute nephritis, indicated by proteinuria, hypoalbuminemia, hypercholesterolemia and an increase in serum creatinine, following injection of anti-GBM antibody, was inhibited by a single administration of the selective angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg, p.o.) 2 h before an injection with the antibody, but not by successive administration of this drug for 1 week from 3 d after the injection of antibody. These results suggested that the enhanced generation of angiotensin II by elevated levels of both renin and its substrate in the early phase of anti-GBM nephritis promotes the evolution of acute nephritis via angiotensin II type 1 receptor.

Topics: Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Antibodies; Basement Membrane; Benzimidazoles; Biphenyl Compounds; Glomerular Mesangium; Glomerulonephritis; Liver; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles