aliskiren and Body-Weight

The current investigation, designed to investigate the role of rutin in two-kidney one-clip (2K1C) induced renovascular dysfunction associated with hypertension in rat.. The renovascular hypertension was developed by the application of vascular clip on left renal artery in rats; the right kidney was kept as such throughout the experimental protocol. The rutin (200 and 300 mg/kg; p.o.) and aliskiren (50mg/kg; p.o.) were administered for 9 consecutive days. The battery of pathophysiological tests i.e., systolic pressure, diastolic pressure and heart rate were performed to assess the anti-hypertensive effect of rutin. In addition, changes of kidney weight/body weight (KW/BW) ratio along with plasma renin content and renal tissue biomarkers i.e., thiobarbituric acid reactive substance (TBAR) and reduced glutathione (GSH) levels were estimated.. The administration of rutin significantly (P<0.05) attenuated the 2K1C of left kidney induced elevated systolic and diastolic pressure in a dose dependent manner. In addition, it also reduces the ratio of KW/BW along with a decrease in plasma renin content, tissue TBARS and increase the GSH levels. There were no significant changes observed in heart rate. Similar results were observed in aliskiren treated group.. The anti-hypertensive effect of rutin may be a useful herbal medicine for the management of hypertension due to its potential free radical scavenging, inhibition of lipid peroxidation and plasma renin inhibitory action.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Fumarates; Glutathione; Heart Rate; Hypertension, Renovascular; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Rutin; Thiobarbituric Acid Reactive Substances

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR).. Four groups of 12-week-old male offspring were sacrificed: control, CR, CR+aliskiren, and CR+losartan group. The CR group included offspring from 50% food-restricted maternal rats. The CR+aliskiren and CR+losartan groups were produced by treating CR offspring with oral aliskiren 10 mg/kg/day or losartan 20 mg/kg/day between 2-4 weeks of age, respectively.. Blood pressure increased in CR rats, which was prevented by aliskiren or losartan. CR increased plasma ADMA levels, which aliskiren prevented. Renal renin and prorenin receptor (PRR) expression increased in CR rats treated with aliskiren, whereas both were reduced by losartan. Both aliskiren and losartan decreased renal mRNA expression of angiotensinogen, angiotensin II type 2 receptor, and Mas in CR rats. However, aliskiren increased angiotensin II type 2 receptor and Mas protein levels in CR kidneys.. Early aliskiren therapy prevents CR-induced hypertension via ADMA reduction, decreases angiotensinogen expression, and increases renal angiotensin II type 2 receptor and Mas protein.

Topics: Amides; Angiotensin-Converting Enzyme 2; Animals; Animals, Newborn; Arginine; Blood Pressure; Blotting, Western; Body Weight; Caloric Restriction; Female; Fumarates; Gene Expression Regulation; Histone Deacetylases; Hypertension; Losartan; Male; Peptidyl-Dipeptidase A; Rats, Sprague-Dawley

Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.

Topics: Amides; Angiotensin II Type 2 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiotonic Agents; Drug Therapy, Combination; Female; Fumarates; Imidazoles; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrazoles; Valine; Valsartan

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population.. In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In-life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In-life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed.. With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64.. All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Female; Fumarates; Hypertension; Kidney; Lymphocyte Count; Male; Maternal Exposure; Postpartum Period; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Toxicokinetics

In the present study, we investigated the ameliorative potential of aliskiren in dextran sulfate sodium (DSS) induced colitis in mice. Aliskiren (3 and 10mg/kg, i.p.) was administered for 10 days from the day of DSS administration. The severity of colitis in mice was assessed using body weight loss, colon and spleen weight, hematological parameters, food intake, stool consistency, rectal bleeding and colon shortening. Colonic malondialdehyde (MDA), myeloperoxidase (MPO) and renin mRNA levels were also estimated. Furthermore, TNF-α and IL-6 in plasma and colon were analyzed. The results showed that aliskiren (10mg/kg, i.p.) significantly improved the severity of colitis by, decrease in weight loss, improvement in food intake and stool consistency, decrease in rectal bleeding, decrease in relative colon and spleen weight and improvement in colonic shortening. Aliskiren (10mg/kg, i.p.) improved blood hemoglobin, red blood cells (RBC) and hematocrit. Colonic malondialdehyde (MDA), MPO and histolopathological score were significantly diminished by aliskiren (10mg/kg, i.p.). Furthermore, aliskiren (10mg/kg, i.p.) significantly diminished the elevated levels of TNF-α, IL-6 and renin mRNA in inflammed colon. These results indicate involvement of renin in colitis and inhibition of renin by aliskiren ameliorates colitis.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Eating; Erythrocytes; Female; Fumarates; Gene Expression Regulation; Hematocrit; Hemoglobins; Malondialdehyde; Mice; Organ Size; Peroxidase; Renin; RNA, Messenger; Spleen

Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; DNA Fragmentation; Extracellular Matrix; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Hemodynamics; Humans; Inflammation; Insulin; Insulin Resistance; Liver; Mice; Muscles; Rats; Rats, Wistar; ROC Curve

Doxorubicin (DXR) is one of the most effective and widely used anthracycline antibiotics. However, its clinical application is hampered by toxic effects in many organs. Nephrotoxicity is one of the major side effects of anthracycline antibiotics. This study was designed to investigate the possible protective effects of aliskiren (a direct renin inhibitor) in DXR-induced nephrotoxicity in rats.. Wistar albino rats were intraperitoneally (ip) injected with DXR and renin activity, albumin, total protein, urea, creatinine levels in plasma and ultrastructural changes in podocytes were assessed.. Rats subjected to DXR administration had significant (p<0.01) increases in systolic blood pressure, plasma renin activity, plasma concentration of urea, creatinine and tissue malondialdehyde and significant (p<0.01) reductions in plasma concentrations of albumin, total protein and antioxidant defense (reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)) in renal tissues. Furthermore, DXR-induced nephrotoxicity has also been characterized by broadening of podocyte foot processes, enlargement of glomerular basement membrane width and reduction in slit pore diameter. The above effects of DXR were significantly (p<0.01) prevented by aliskiren treatment.. These findings revealed that the blockade of renin activity by aliskiren is a promising approach in the treatment of DXR-induced nephrotoxicity.

Topics: Amides; Animals; Antioxidants; Benzimidazoles; Benzoates; Blood Pressure; Body Weight; Creatinine; Doxorubicin; Fumarates; Kidney Diseases; Lipid Peroxidation; Organ Size; Oxidative Stress; Podocytes; Rats; Rats, Wistar; Renin; Serum Albumin; Systole; Telmisartan; Urea

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Topics: Amides; Animals; Biological Transport; Blood Pressure; Body Weight; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Fumarates; Glucose; Insulin; Insulin Resistance; Muscle, Skeletal; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Renin; Signal Transduction

Topics: Amides; Animals; Bile Ducts; Blood Pressure; Body Weight; Fumarates; Hemodynamics; Hypertension, Portal; Ligation; Liver Cirrhosis, Experimental; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers, Tumor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Fumarates; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Male; Mesangial Cells; Mice; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

1. Aliskiren is a renin inhibitor with an IC(50) of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin-converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen-2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen-2)27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague-Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren-induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.

Topics: Aldosterone; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Female; Fumarates; Heart; Kallikreins; Kidney; Lung; Mice; Myocytes, Cardiac; Perindopril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tissue Kallikreins

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.. Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.. All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.. Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fumarates; Glucose Intolerance; Hydralazine; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Organ Size; Pancreas; Renin

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Clinical Trials as Topic; Female; Fumarates; Humans; Hypertension; Male; Renin; Sex Characteristics

Blockade of the renin-angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy.. Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg(-1) day(-1) by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg(-1) day(-1) in drinking water), over a 16 week period.. Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril.. These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.

Topics: Aldosterone; Amides; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Fumarates; Kidney; Organ Size; Rats; Rats, Inbred Strains; Renin