angiotensin-i and Body-Weight

Combined hormonal oral contraceptives (OCs) may lead to a mild rise in blood pressure and body weight. In rare instances, large increments in blood pressure are measured. We investigated the effect of a combination of ethinyl estradiol (EE) plus a progestogen with antimineralocorticoid, i.e. natriuretic, properties [Drospirenone (DRSP)] on body weight, blood pressure, the renin-aldosterone system, atrial natriuretic factor, plasma lipids, and glucose tolerance. It is anticipated that this will lead to the development of an OC that does not raise body weight or blood pressure. Four groups of 20 women each received 30 micrograms EE plus 3 mg DRSP (group A), 20 micrograms EE plus 3 mg DRSP (group B), 15 micrograms EE plus 3 mg DRSP (group C), and, as a control OC, 30 micrograms EE plus 150 micrograms levonorgestrel (Microgynon, Schering; group D) for 6 months. During the OC-free control cycles before and after treatment and throughout treatment, the target parameters were measured. Between the pretreatment cycle and the sixth treatment cycle, mean body weight fell by 0.8 to 1.7 kg in groups A, B, and C (P < 0.05 vs. D), whereas it rose by 0.7 kg in group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in groups A, B, and C (significant for A and C vs. D) and increased by 1-2 mm Hg in group D. Renin substrate rose equally in all groups (P < 0.05), whereas PRA and plasma aldosterone rose significantly only in the DRSP groups, presumably due to sodium loss. In the DRSP groups, high density lipoprotein cholesterol rose (P < 0.05), in contrast to group D. Low density lipoprotein cholesterol fell slightly (P > 0.05), whereas triglyceride levels showed a stronger increase in the DRSP groups (P < 0.05) than in group D. All groups attained good cycle control; group A had the best. Side-effects were minimal. To our knowledge, this is the first report on a combined OC that leads to a small decrease in body weight and blood pressure. It may be especially beneficial for women susceptible for a gain in weight and a rise in blood pressure.. The potential of a new oral contraceptive (OC) containing drospirenone (DRSP) to avert the moderate increases in body weight and blood pressure often associated with use of existing combined OCs was investigated in a study of four groups of 20 German women each. Group A received 30 mcg of ethinyl estradiol (EE) and 3 mg of DRSP, Group B was administered 20 mcg of EE and 3 mg of DRSP, Group C received 15 mcg of EE and 3 mg of DRSP, and Group D was given a standard OC containing 30 mcg of EE and 150 mcg of levonorgestrel. Between the pretreatment cycle and the last (sixth) treatment cycle, mean body weight fell by 0.8-1.7 kg in Groups A, B, and C, but rose by 0.7 kg in Group D. Systolic and diastolic blood pressures fell by 1-4 mm Hg in Groups A, B, and C and rose by 1-2 mm Hg in Group D. Renin substrate rose equally in all four groups, while plasma renin activity, plasma aldosterone, and high density lipoprotein cholesterol rose significantly only in the three DRSP groups and serum triglyceride levels were significantly higher in Group D than in the three DRSP groups. Glucose tolerance increases were similar in all four groups. Finally, all groups--but especially Group A--experienced good cycle control and there were no serious side effects. These findings suggest that a combined OC containing DRSP may be especially beneficial for women who have a tendency to gain weight or experience a rise in blood pressure while taking OCs.

Topics: Adolescent; Adult; Aldosterone; Androstenes; Angiotensin I; Blood Pressure; Body Weight; Contraceptives, Oral, Combined; Ethinyl Estradiol; Female; Glucose Tolerance Test; Humans; Lipids; Mineralocorticoids; Renin; Renin-Angiotensin System

The angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin-angiotensin system (RAS). We recently found that ACE2 knockout (ACE2KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of ACE2 on physiological aging. Male wild-type, ACE2KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. ACE2KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in ACE2KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in ACE2KO mice than that in wild-type and MasKO mice, and increased with A1-7 in ACE2KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene

Topics: Adipose Tissue; Aging; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Body Weight; Bone Resorption; Cyclin-Dependent Kinase Inhibitor p16; Forelimb; Gene Deletion; Hand Strength; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle Weakness; Muscles; Organ Size; PAX3 Transcription Factor; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Time Factors

Alzheimer's disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. However, the interaction between angiotensin II and angiotensin 1-7 in AD remains to be defined. The present study was undertaken to examine the interaction between these peptides in AD. 5XFAD mice, a useful model of AD, were separated into three groups: 1) saline-infused, 2) angiotensin II-infused, and 3) angiotensin II-infused and angiotensin 1-7-co-infused. These peptides were systemically given to 5XFAD mice via osmotic minipump for 4 weeks. Systemic angiotensin II infusion for 4 weeks induced significant hypertension in both wild-type and 5XFAD mice. Angiotensin II induced cognitive abnormality in 5XFAD mice as estimated by the Morris water maze test and the nest building test, and this effect was associated with cerebral blood flow reduction, cortical arterial amyloid-β deposition, hippocampal inflammation, and neuron loss in 5XFAD mice. In addition, angiotensin II infusion led to gastrocnemius muscle atrophy in 5XFAD mice. Co-infusion of angiotensin 1-7 prevented the above mentioned detrimental effects of angiotensin II in the brain and gastrocnemius muscle in 5XFAD mice, without significant influence on blood pressure. The left ventricular hypertrophic response to angiotensin II was attenuated in 5XFAD mice compared with wild-type mice, which was not significantly altered by co-administration of angiotensin 1-7. Our results show that angiotensin 1-7 counteracts angiotensin II-induced cognitive impairment, brain injury, and skeletal muscle injury in AD mice.

Topics: Alzheimer Disease; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Cerebrovascular Circulation; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Muscle, Skeletal; Peptide Fragments; Rotarod Performance Test

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Pressure; Body Weight; Cardiotonic Agents; Diastole; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Kidney; Kidney Function Tests; Male; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Rats, Wistar; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sitagliptin Phosphate; Up-Regulation; Ventricular Remodeling

We investigate the effects of aerobic exercise training (AET) on the thermogenic response, substrate metabolism and renin angiotensin system (RAS) in the subcutaneous white adipose tissue (SC-WAT) of mice fed cafeteria diet (CAF). Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n = 10), CHOW-TR (chow diet, trained; n = 10), CAF-SED (CAF, sedentary; n = 10) and CAF-TR (CAF, trained; n = 10). AET consisted in running sessions of 60 min at 60% of maximal speed, five days per week for eight weeks. The CAF-SED group showed higher body weight and adiposity, glucose intolerance and insulin resistance (IR), while AET prevented such damages in CAF-TR group. AET reduced the p-AKT/t-AKT ratio and increased ATGL expression in CHOW-TR and CAF-TR groups and increased t-HSL and p-HSL/t-HSL ratio in CAF-TR. AET prevented adipocyte hypertrophy in CAF-TR group and increased UCP-1 protein expression only in CHOW-TR. Serum ACE2 increased in CHOW-TR and CAF-TR groups, and Ang (1-7) increased in the CHOW-TR group. In the SC-WAT, CAF-TR group increased the expression of AT1, AT2 and Mas receptors, whereas CHOW-TR increased Ang (1-7) and Ang (1-7)/Ang II ratio in SC-WAT. No changes were observed in ACE and Ang II. Positive correlations were observed between UCP-1 and kITT (r = 0.6), between UCP-1 and Ang (1-7) concentration (r = 0.6), and between UCP-1 and Ang (1-7)/Ang II ratio (r = 0.7). In conclusion, the AET prevented obesity and IR, reduced insulin signaling proteins and increased lipolysis signaling proteins in the SC-WAT. In addition, the CAF diet precludes the AET-induced thermogenic response and the partial modulation of the RAS suggests that the protective effect of AET against obesity and IR could not be associated with SC-WAT RAS.

Topics: Adipose Tissue, White; Adiposity; Angiotensin I; Angiotensin II; Animals; Biomarkers; Body Weight; Feeding Behavior; Glucose; Insulin Resistance; Male; Mice, Inbred C57BL; Obesity; Peptide Fragments; Peptides; Physical Conditioning, Animal; Renin-Angiotensin System; RNA, Messenger; Subcutaneous Fat; Thermogenesis; Uncoupling Protein 1

The renin-angiotensin system is a key regulator of metabolism with beneficial effects of the angiotensin 1-7 (Ang 1-7) peptide. We hypothesized that the antiobesity effect of Ang 1-7 was related to the stimulation of brown adipose tissue (BAT). We administered Ang 1-7 (0.54 mg kg

Topics: Adipocytes, Brown; Adipose Tissue, Brown; Angiotensin I; Animals; Body Weight; Cell Proliferation; Diet, High-Fat; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Thermogenesis

This study aimed to study the impact of a combination of maternal and post-weaning high-fat diets and whether resveratrol was beneficial. Sprague-Dawley dams were fed either chow or a high-fat diet, before mating, during pregnancy, and into lactation. At weaning, their offspring were randomly fed chow or a high-fat diet. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal high-fat/postnatal chow diet), CH (maternal chow/postnatal high-fat diet), and HH (maternal/postnatal high-fat diet). A fifth group consisted of HH plus resveratrol. The 4 month-old offspring of HH group had higher body weight, higher levels of plasma triglycerides, leptin, angiotensin I and angiotensin II and abnormal intraperitoneal glucose tolerance test results, which fulfilled the features of metabolic syndrome. The dysregulation of the renin-angiotensin system was seen in multiple organs. Sirtuin 1 expression/abundance was reduced by a maternal/postnatal high-fat diet, in all the organs examined. Resveratrol ameliorated most of the features of metabolic syndrome and molecular alterations. The administration of a high-fat diet in both periods showed interactive metabolic effects in the plasma and many organs. Our results suggest that a maternal high-fat diet sensitizes offspring to the adverse effects of subsequent high-fat intake on multiple organs.

Topics: Adipose Tissue; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Diet, High-Fat; Female; Glucose Tolerance Test; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Obesity; Pregnancy; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Resveratrol; Sirtuin 1; Triglycerides

Radiofrequency ablation of renal sympathetic nerve (RDN) shows effective BP reduction in hypertensive patients while the specific mechanisms remain unclear.. We hypothesized that abnormal levels of norepinephrine (NE) and changes in NE-related enzymes and angiotensinconverting enzyme 2 (ACE2), angiotensin (Ang)-(1-7) and Mas receptor mediate the anti-hypertensive effects of RDN.. Mean values of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were assessed at baseline and follow-up. Plasma and renal norepinephrine (NE) concentrations were determined using highperformance liquid chromatography with electrochemical detection, and levels of NE-related enzyme and ACE2-Ang(1-7)- Mas were measured using real time PCR, Western blot and immunohistochemistry or Elisa in a hypertensive canine model fed with high-fat diet and treated with RDN. The parameters were also determined in a sham group treated with renal arteriography and a control group fed with normal diet.. RDN decreased SBP, DBP, MAP, plasma and renal NE. Compared with the sham group, renal tyrosine hydroxylase (TH) expression was lower and renalase expression was higher in the RDN group. Compared with the control group, renal TH and catechol-o-methyl transferase (COMT) were higher and renalase was lower in the sham group. Moreover, renal ACE2, Ang-(1-7) and Mas levels of the RDN group were higher than those of the sham group, which were lower than those of the control group.. RDN shows anti-hypertensive effect with reduced NE and activation of ACE2-Ang(1-7)-Mas, indicating that it may contribute to the anti-hypertensive effect of RDN.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blotting, Western; Body Weight; Catechol O-Methyltransferase; Catheter Ablation; Chromatography, High Pressure Liquid; Diet, High-Fat; Dogs; Hypertension; Immunohistochemistry; Kidney; Models, Animal; Monoamine Oxidase; Norepinephrine Plasma Membrane Transport Proteins; Peptide Fragments; Peptidyl-Dipeptidase A; Random Allocation; Reference Values; Renal Artery; Reproducibility of Results; Sympathectomy; Treatment Outcome; Tyrosine 3-Monooxygenase

The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.

Topics: Albuminuria; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Body Weight; Cytochrome P-450 CYP1A1; Diminazene; Enzyme Activators; Gene Expression Regulation; Hypertension, Malignant; Kidney; Mice; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Rats; Rats, Transgenic; Renin; Renin-Angiotensin System; Sodium

Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1-7). Increased concentration of renal Ang-(1-7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.

Topics: Angiotensin I; Animals; Blood Glucose; Body Weight; Bradykinin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Dosage; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Kidney; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Spectrometry, Fluorescence

What is the central question of this study? Activation of angiotensin-converting enzyme 2, resulting in production of angiotensin-(1-7) and stimulation of its receptor, Mas, exerts beneficial actions in a number cardiovascular diseases, including ischaemic stroke. A potential beneficial role for angiotensin-(1-7) in haemorrhagic stroke has not previously been reported. What is the main finding and its importance? Central administration of angiotensin-(1-7) into stroke-prone spontaneously hypertensive rats, a model of haemorrhagic stroke, increases lifespan and improves the neurological status of these rats, as well as decreasing microglial numbers in the striatum (implying attenuation of cerebral inflammation). These actions of angiotensin-(1-7) have not previously been reported and identify this peptide as a potential new therapeutic target in haemorrhagic stroke. Angiotensin-(1-7) [Ang-(1-7)] exerts cerebroprotective effects in ischaemic stroke, and this action is associated with a blunting of intracerebral inflammatory processes and microglial activation. Given that intracerebral inflammation and microglial activation play key roles in the mechanism of injury and brain damage in both ischaemic and haemorrhagic stroke, we have investigated the potential beneficial actions of Ang-(1-7) in stroke-prone spontaneously hypertensive rats (spSHRs), an established animal model of hypertension-induced haemorrhagic stroke. Angiotensin-(1-7) was administered by continuous infusion via the intracerebroventricular route for 6 weeks into spSHRs fed a high-sodium (4%) diet, starting at 49 days of age. This treatment resulted in a significant increase in survival of the spSHRs. Median survival was 108 days in control, artificial cerebrospinal fluid-infused spSHRs and 154 days in Ang-(1-7)-treated spSHRs. This effect was partly reversed by intracerebroventricular infusion of the Mas receptor blocker, A779. This Ang-(1-7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site. Importantly, infusions of Ang-(1-7) had no effect on kidney pathology, heart pathology, body weight, serum corticosterone levels or blood pressure. This study is the first to demonstrate the cerebroprotective actions of Ang-(1-7), including increased survival time, in spSHRs. As such, these data reveal a potential therapeutic target

Topics: Angiotensin I; Animals; Blood Pressure; Body Weight; Corpus Striatum; Corticosterone; Heart; Hypertension; Infusions, Intraventricular; Kidney; Male; Microglia; Peptide Fragments; Rats; Rats, Inbred SHR; Stroke

We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), Sprague-Dawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose. Compared with control rats, FF rats had increased mean arterial pressure and cardiac sympathetic tone with impaired baroreflex sensitivity. FF rats also presented increased circulating triglycerides, leptin, insulin, and glucose with impaired glucose tolerance. Furthermore, relative weights of liver and retroperitoneal adipose tissue were increased in FF rats. Glycogen content was reduced in liver, but increased in muscle. In contrast, fructose-fed rats subjected to chronic intracerebroventricular infusion of Ang-(1-7) presented reduced cardiac sympathetic tone with normalized mean arterial pressure, baroreflex sensitivity, glucose and insulin levels, and improved glucose tolerance. Relative weight of liver, and hepatic and muscle glycogen contents were also normalized in FF+A7 rats. In addition, FF+A7 rats had reduced mRNA expression for neuronal nitric oxide synthase and NR1 subunit of N-methyl-d-aspartate receptor in hypothalamus and dorsomedial medulla. Ang-(1-7) infusion did not alter fructose-induced hyperleptinemia and increased relative weight of retroperitoneal adipose tissue. There were no differences in body weights, neither in liver mRNA expression of phosphoenolpyruvate carboxykinase or glucose-6-phosphatase among the groups. These data indicate that chronic increase in Ang-(1-7) levels in the brain may have a beneficial role in fructose-fed rats by ameliorating cardiovascular and metabolic disorders.

Topics: Angiotensin I; Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Brain; Dietary Carbohydrates; Disease Models, Animal; Fructose; Glycogen; Infusions, Intraventricular; Insulin; Metabolic Syndrome; Peptide Fragments; Rats; Rats, Sprague-Dawley; Risk Factors

Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Glucose; Body Weight; Cytochrome P-450 CYP4A; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Erectile Dysfunction; Male; Penis; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; rho-Associated Kinases; Streptozocin

To test the hypothesis that chronic infusion of angiotensin-(1-7) [Ang-(1-7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1-7) may stabilize mature plaque by targeting macrophages.. In vivo, the effects of Ang-(1-7) on atherogenesis and plaque stability were observed in ApoE(-/-) mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1-7) on vascular smooth muscle cells' proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1-7) dose-dependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells' proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1-7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1-7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques.. Ang-(1-7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE(-/-) mice, thus providing a novel and promising approach to the treatment of atherosclerosis.

Topics: Angiotensin I; Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Pressure; Body Weight; Cell Movement; Cell Proliferation; Collagen; Dose-Response Relationship, Drug; Lipids; Macrophages; Matrix Metalloproteinases; Mice; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Peptide Fragments; Receptor, Angiotensin, Type 2; RNA, Messenger; Vasodilator Agents

Antenatal corticosteroid exposure reduces renal function and alters the intrarenal renin-angiotensin system to favor angiotensin activation of angiotensin type 1 receptor (AT1R) mediated responses in ovine offspring. This study aimed to assess whether antenatal steroid exposure would affect renal responses to the direct intrarenal infusion of angiotensin-(1-7) in rams and the angiotensin receptors involved in mediating responses to the peptide. Adult, uninephrectomized rams exposed to either betamethasone or vehicle before birth received intrarenal angiotensin-(1-7) infusions (1 ng/kg/min) alone or in combination with antagonists to angiotensin receptors for 3 h. Basal sodium excretion (UNa) was significantly lower and mean arterial pressure was significantly higher in betamethasone- compared to the vehicle-treated sheep. Angiotensin-(1-7) decreased UNa more in betamethasone- than in vehicle-treated sheep. Candesartan reversed the response to angiotensin-(1-7) but D-Ala(7)-angiotensin-(1-7) did not. Angiotensin-(1-7) infusion decreased effective renal plasma flow in both groups to a similar extent and the response was reversed by candesartan, but was not blocked by D-Ala(7)-angiotensin-(1-7). Glomerular filtration rate increased significantly in both groups after 3 h infusion of angiotensin-(1-7) plus candesartan. These results suggest that antenatal exposure to a clinically relevant dose of betamethasone impairs renal function in rams. Moreover, angiotensin-(1-7) appears capable of activating the AT1R in uninephrectomized rams.

Topics: Aging; Angiotensin I; Animals; Betamethasone; Blood Pressure; Body Weight; Female; Glomerular Filtration Rate; Kidney; Male; Nephrectomy; Organ Size; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Regional Blood Flow; Sheep; Sodium

The transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] via its Mas receptor can prevent the development of hyperglycaemia-induced cardiovascular complications. Here, we investigated whether Ang-(1-7) can inhibit hyperglycaemia-induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro.. Streptozotocin-induced diabetic rats were chronically treated with Ang-(1-7) or AG1478, a selective EGF receptor inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in primary cultures of vascular smooth muscle cells (VSMCs).. Diabetes significantly enhanced phosphorylation of EGF receptor at tyrosine residues Y992, Y1068, Y1086, Y1148, as well as ERK1/2 and p38 MAPK in the mesenteric vasculature bed whereas these changes were significantly attenuated upon Ang-(1-7) or AG1478 treatment. In VSMCs grown in conditions of high glucose (25 mM), an Src-dependent elevation in EGF receptor phosphorylation was observed. Ang-(1-7) inhibited both Ang II- and glucose-induced transactivation of EGF receptor. The inhibition of high glucose-mediated Src-dependant transactivation of EGF receptor by Ang-(1-7) could be prevented by a selective Mas receptor antagonist, D-Pro7-Ang-(1-7).. These results show for the first time that Ang-(1-7) inhibits EGF receptor transactivation via a Mas receptor/Src-dependent pathway and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular dysfunction.

Topics: Angiotensin I; Angiotensin II; Animals; Body Weight; Diabetes Mellitus; ErbB Receptors; Glucose; Hyperglycemia; Male; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Quinazolines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; src-Family Kinases; Transcriptional Activation; Tyrphostins

It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg(-1) per day losartan, an angiotensin receptor blocker, or with 20 mg kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Imidazolidines; Kidney; Losartan; Male; Myocardium; Organ Size; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System

We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cerebral Cortex; Cognition Disorders; Cranial Irradiation; Dose Fractionation, Radiation; Doublecortin Protein; Male; Radiation Injuries, Experimental; Ramipril; Rats; Rats, Inbred F344

Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Appetite; Appetitive Behavior; Body Weight; Captopril; Drug Combinations; Drug Evaluation, Preclinical; Furosemide; Immunohistochemistry; Male; Paraventricular Hypothalamic Nucleus; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sodium; Sodium Chloride, Dietary; Subfornical Organ; Supraoptic Nucleus; Taste

High Na(+) intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na(+) overload-programmed alterations in Na(+) transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney.. Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na(+)+K(+))ATPase expression and activity. Ouabain-insensitive Na(+)-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT(2) receptor expression decreased while AT(1) expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na(+)+K(+))ATPase, partially recovered the response of Na(+)-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na(+) or not. In addition, treatment with enalapril per se reduced AT(2) receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na(+)-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS.. Maternal Na(+) overload programmed alterations in renal Na(+) transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril was beneficial predominantly through its influence on Na(+) pumping activities in adult offspring. However, side effects including down-regulation of PKA, PKC and AT(2) receptors and increased TBARS could impair renal function in later life.

Topics: Adenosine Triphosphatases; Aging; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Transport; Blood Pressure; Body Weight; Cation Transport Proteins; Creatinine; Cyclic AMP-Dependent Protein Kinases; Enalapril; Female; Gene Expression Regulation; Kidney Tubules, Proximal; Lipid Peroxidation; Macrophages; Male; Parturition; Pregnancy; Protein Kinase C; Rats; Receptors, Angiotensin; Renin-Angiotensin System; Signal Transduction; Sodium; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances; Water; Weaning

Excessive sympathetic activity contributes to the pathogenesis and progression of hypertension. Enhanced cardiac sympathetic afferent reflex (CSAR) is involved in sympathetic activation. This study was designed to determine the roles of angiotensin (Ang)-(1-7) in paraventricular nucleus (PVN) in modulating sympathetic activity and CSAR and its signal pathway in renovascular hypertension.. Renovascular hypertension was induced with two-kidney, one-clip method. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic-denervated and cervical-vagotomized rats with anesthesia. CSAR was evaluated with the RSNA and MAP responses to epicardial application of capsaicin. PVN microinjection of Ang-(1-7) and cAMP analogue db-cAMP caused greater increases in RSNA and MAP, and enhancement in CSAR in hypertensive rats than in sham-operated rats, while Mas receptor antagonist A-779 produced opposite effects. There was no significant difference in the angiotensin-converting enzyme 2 (ACE2) activity and Ang-(1-7) level in the PVN between sham-operated rats and hypertensive rats, but the Mas receptor protein expression in the PVN was increased in hypertensive rats. The effects of Ang-(1-7) were abolished by A-779, adenylyl cyclase inhibitor SQ22536 or protein kinase A (PKA) inhibitor Rp-cAMP. SQ22536 or Rp-cAMP reduced RSNA and MAP in hypertensive rats, and attenuated the CSAR in both sham-operated and hypertensive rats.. Ang-(1-7) in the PVN increases RSNA and MAP and enhances the CSAR, which is mediated by Mas receptors. Endogenous Ang-(1-7) and Mas receptors contribute to the enhanced sympathetic outflow and CSAR in renovascular hypertension. A cAMP-PKA pathway is involved in the effects of Ang-(1-7) in the PVN.

Topics: Adenine; Afferent Pathways; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Body Weight; Bucladesine; Cyclic AMP; Heart; Hypertension, Renovascular; Kidney; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Reflex; Sympathetic Nervous System; Thionucleotides

The enhanced cardiac sympathetic afferent reflex (CSAR) is involved in the sympathetic activation that contributes to the pathogenesis and progression of hypertension. Activation of AT(1) receptors by angiotension (Ang) II in the paraventricular nucleus (PVN) augments the enhanced CSAR and sympathetic outflow in hypertension. The present study is designed to determine whether Ang-(1-7) in PVN plays the similar roles as Ang II and the interaction between Ang-(1-7) and Ang II on CSAR in renovascular hypertension.. The two-kidney, one-clip (2K1C) method was used to induce renovascular hypertension. The CSAR was evaluated by the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to epicardial application of capsaicin in sinoaortic-denervated and cervical-vagotomized rats with urethane and α-chloralose anesthesia. Either Ang II or Ang-(1-7) in PVN caused greater increases in RSNA and MAP, and enhancement in CSAR in 2K1C rats than in sham-operated (Sham) rats. Mas receptor antagonist A-779 and AT(1) receptor antagonist losartan induced opposite effects to Ang-(1-7) or Ang II respectively in 2K1C rats, but losartan had no effects in Sham rats. Losartan but not the A-779 abolished the effects of Ang II, while A-779 but not the losartan blocked the effects of Ang-(1-7). PVN pretreatment with Ang-(1-7) dose-dependently augmented the RSNA, MAP, and CSAR responses to the Ang II in 2K1C rats. Ang II level, AT(1) receptor and Mas receptor protein expression in PVN increased in 2K1C rats compared with Sham rats but Ang-(1-7) level did not.. Ang-(1-7) in PVN is as effective as Ang II in enhancing the CSAR and increasing sympathetic outflow and both endogenous Ang-(1-7) and Ang II in PVN contribute to the enhanced CSAR and sympathetic outflow in renovascular hypertension. Ang-(1-7) in PVN potentiates the effects of Ang II in renovascular hypertension.

Topics: Afferent Pathways; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Heart; Heart Rate; Hypertension, Renovascular; Kidney; Losartan; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Reflex; Sympathetic Nervous System; Systole

The contribution of the intrarenal renin-angiotensin system to the development of hypertension is incompletely understood. Here, we used targeted homologous recombination to generate mice that express angiotensin-converting enzyme (ACE) in the kidney tubules but not in other tissues. Mice homozygous for this genetic modification (ACE 9/9 mice) had low BP levels, impaired ability to concentrate urine, and variable medullary thinning. In accord with the ACE distribution, these mice also had reduced circulating angiotensin II and high plasma renin concentration but maintained normal kidney angiotensin II levels. In response to chronic angiotensin I infusions, ACE 9/9 mice displayed increased kidney angiotensin II, enhanced rate of urinary angiotensin II excretion, and development of hypertension. These findings suggest that intrarenal ACE-derived angiotensin II formation, even in the absence of systemic ACE, increases kidney angiotensin II levels and promotes the development of hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Female; Hypertension; Infusions, Subcutaneous; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1

ANG-(1-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A(y)/Ta mice. KK-A(y)/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-Ala(7)-ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG II+ANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-β1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Immunohistochemistry; Mesangial Cells; Mice; NADPH Oxidases; Peptide Fragments; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric

This study evaluated the effect of angiotensin (Ang)-(1-7) on vascular remodelling in a rat autologous jugular vein graft model in which rats underwent autologous jugular vein graft transplantation (Ang-[1-7] and control groups) or sham surgery (sham group). The animals received continuous jugular infusion of Ang-(1-7) at 25 μg/kg per h (Ang-[1-7] group) or normal saline (control and sham groups) starting 3 days after surgery. Ang-(1-7) infusion reduced venous graft hyperplasia, vascular remodelling, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, p38 mitogen-activated protein kinase (MAPK) activation and levels of proliferating cell nuclear antigen and α-smooth muscle actin compared with control animals. The vascular tissue Ang II level was higher in Ang-(1-7) and control rats than in sham animals. These findings suggest that Ang-(1-7) acts by inhibiting the activation of ERK1/2 and p38 MAPK in vascular tissue. The use of exogenous Ang-(1-7) could improve the outcome of vein grafting through the attenuation of vascular remodelling.

Topics: Actins; Angiotensin I; Angiotensin II; Animals; Blood Vessel Prosthesis; Body Weight; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hemodynamics; Infusions, Intravenous; Jugular Veins; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Transplantation, Autologous

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.

Topics: Adrenergic beta-Agonists; Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Appetite; Blood Pressure; Body Weight; Captopril; Dehydration; Diuretics, Osmotic; Drinking; Female; Heart Rate; Injections, Intraventricular; Isoproterenol; Kidney; Lactation; Male; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Chloride; Sodium, Dietary; Thirst; Time Factors; Water-Electrolyte Balance

Obesity and diabetes remain among the world's most pervasive health problems. Although the importance of angiotensin II for metabolic regulation is well documented, the role of the angiotensin-(1-7)/Mas axis in this process is poorly understood. The aim of this study was to evaluate the effect of increased angiotensin-(1-7) plasma levels in lipid and glucose metabolism using transgenic rats that express an angiotensin-(1-7)-releasing fusion protein, TGR(A1-7)3292 (TGR).. The increased angiotensin-(1-7) levels in TGR induced enhanced glucose tolerance, insulin sensitivity, and insulin-stimulated glucose uptake. In addition, TGR presented decreased triglycerides and cholesterol levels, as well as a significant decrease in abdominal fat mass, despite normal food intake. These alterations were accompanied by a marked decrease of angiotensinogen expression and increased Akt in adipose tissue. Furthermore, augmented plasma levels and expression in adipose tissue was observed for adiponectin. Accordingly, angiotensin-(1-7) stimulation increased adiponectin production by primary adipocyte culture, which was blocked by the Mas antagonist A779. Circulating insulin and muscle glycogen content were not altered in TGR.. These results show that increased circulating angiotensin-(1-7) levels lead to prominent changes in glucose and lipid metabolism.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Angiotensin I; Angiotensin II; Animals; Biomarkers; Blood Glucose; Body Weight; Cells, Cultured; Cholesterol; Insulin; Leptin; Lipid Metabolism; Male; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, G-Protein-Coupled; Time Factors; Triglycerides; Up-Regulation

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the (5/6) nephrectomy ((5/6) Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or (5/6) Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG-(1-7) for 4 wk. In (5/6) Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In (5/6) Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. (5/6) Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in (5/6) Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with (5/6) Nx alone, an effect reversed by losartan. Treatment of (5/6) Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after (5/6) Nx. Inhibition of ACE2 in (5/6) Nx mice increases albuminuria via an AT(1) receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after (5/6) Nx. We propose that endogenous ACE2 is renoprotective in CKD.

Topics: Albuminuria; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Chronic Disease; Disease Models, Animal; Glomerular Filtration Rate; Hematocrit; Imidazoles; Infusion Pumps; Injections, Subcutaneous; Inulin; Kidney; Kidney Diseases; Leucine; Losartan; Male; Mice; Nephrectomy; Organ Size; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Time Factors

We investigated changes in salt preference, food and water intake, renin activity and salt excretion in adult offspring from ewes that were fed a high-salt diet (14% NaCl, high-salt offsrping) or grazed saltbush (saltbush offspring) from day 60 of pregnancy until day 21 of lactation. High-salt offspring were compared to offspring born to ewes consuming a control diet (2% NaCl) and saltbush offspring were compared to offspring from ewes which grazed a control diet of dry pasture. All offspring were weaned at 3 months of age and grazed the same clover-based pasture until testing started at 8 months of age. The preference for a low-salt diet (0.5% NaCl) when offered with an alternative (7% NaCl) did not differ between the offspring groups. High-salt offspring and saltbush offspring had a lower food intake (14% and 27% respectively) and lower water intake (35% and 20% respectively) than their control offspring. Both high-salt offspring and saltbush offspring had lower basal renin activity than their respective controls. After consuming salt, the renin activity of the saltbush offspring continued to be lower than controls whereas the renin activity of the high-salt offspring became similar to controls. In general, the saltbush offspring excreted an oral salt load more rapidly, though this depended on the extent of the salt load. This important adaptation of offspring born to ewes that consumed saltbush during pregnancy may improve their ability to cope with high-salt diets such as saltbush when they consume it themselves. However, the high-salt offspring did not possess such beneficial adaptations.

Topics: Angiotensin I; Animals; Animals, Newborn; Body Weight; Dose-Response Relationship, Drug; Drinking; Eating; Female; Food Preferences; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Renin; Salts; Sheep; Sodium Chloride, Dietary; Time Factors

The effect of NaCl plus 3% chitosan on the systolic blood pressure of spontaneously hypertensive rats (SHR) were evaluated and compared with NaCl plus KCl (NaCl, 49.36% + KCl 49.36%) and chitosan or NaCl treatment alone. In SHR, administration of NaCl plus chitosan (44 mM Na/day) for two months significantly decreased the systolic blood pressure greater than of NaCl plus KCl and NaCl alone. NaCl plus chitosan resulted, though not statistically significant, in decreased urinary Na(+) excretion and decreased blood urea nitrogen levels. Urinary creatinine of NaCl plus chitosan was slightly decreased compared to 3 treated groups. Serum electrolytes levels, however, remained unchanged. The combination of NaCl and chitosan may be superior to the conventional use of NaCl plus KCl or NaCl alone in the prevention of hypertension. Even though these supplementary diets have demonstrated potential anti-hypertensive effects in the experimental animal model, further research is needed before any recommendations can be made.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Blood Urea Nitrogen; Body Weight; Chitosan; Chlorides; Creatinine; Heart; Histocytochemistry; Hypertension; Kidney; Male; Potassium; Potassium Chloride; Random Allocation; Rats; Rats, Inbred SHR; Sodium; Sodium Chloride, Dietary; Systole

Increasing evidence suggests that the renin-angiotensin-system contributes to the etiology of obesity. To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril ( approximately 40 mg/kg . d). Rats given captopril weighed less than controls when fed a high-fat diet (369.3 +/- 8.0 vs. 441.7 +/- 8.5 g after 35 d; P < 0.001) or low-fat chow (320.1 +/- 4.9 vs. 339.8 +/- 5.1 g after 21 d; P < 0.0001). This difference was attributable to reductions in adipose mass gained on high-fat (23.8 +/- 2.0 vs. 65.12 +/- 8.4 g after 35 d; P < 0.0001) and low-fat diets (12.2 +/- 0.7 vs. 17.3 +/- 1.3 g after 21 d; P < 0.001). Rats given captopril ate significantly less [3110.3 +/- 57.8 vs. 3592.4 +/- 88.8 kcal (cumulative 35 d high fat diet intake); P < 0.001] despite increased in neuropeptide-Y mRNA expression in the arcuate nucleus of the hypothalamus and had improved glucose tolerance compared with free-fed controls. Comparisons with pair-fed controls indicated that decreases in diet-induced weight gain and adiposity and improved glucose tolerance were due, primarily, to decreased food intake. To determine whether captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for 2 d. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that angiotensin-converting enzyme inhibition protects against the development of diet-induced obesity and glucose intolerance.

Topics: Adipose Tissue; Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Captopril; Dietary Fats; Eating; Energy Metabolism; Glucose; Injections, Intraventricular; Injections, Subcutaneous; Male; Neuropeptide Y; Obesity; Peptidyl-Dipeptidase A; Rats; Rats, Long-Evans; Renin; RNA, Messenger

We examined the influence of chronic treatment with angiotensin-(1-7) [Ang-(1-7)] on renox (renal NADPH oxidase, NOX-4) and the development of renal dysfunction in streptozotocin-treated spontaneously hypertensive rats (diabetic SHR).. Mean arterial pressure, urinary protein and vascular responsiveness of the isolated renal artery to vasoactive agonists were studied in vehicle- or Ang-(1-7)-treated SHR and diabetic SHR.. Ang-(1-7) decreased the elevated levels of renal NADPH oxidase (NOX) activity and attenuated the activation of NOX-4 gene expression in the diabetic SHR kidney. Ang-(1-7) treatment increased sodium excretion but did not affect mean arterial pressure in diabetic SHR. There was a significant increase in urinary protein (266 +/- 22 mg/24 h) in the diabetic compared to control SHR (112 +/- 13 mg/24 h) and treatment of diabetic SHR with Ang-(1-7) reduced the degree of proteinuria (185 +/- 23 mg/24 h, p < 0.05). Ang-(1-7) treatment also attenuated the diabetes-induced increase in renal vascular responsiveness to endothelin-1, norepinephrine, and angiotensin II in SHR, but significantly increased the vasodilation of the renal artery of SHR and diabetic SHR to the vasodilator agonists.. These results suggest that treatment with Ang-(1-7) constitutes a potential therapeutic strategy to alleviate NOX-mediated oxidative stress and to reduce renal dysfunction in diabetic hypertensive rats.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Activation; Gene Expression Regulation, Enzymologic; Hyperglycemia; Hypertension, Renal; Male; NADPH Oxidase 4; NADPH Oxidases; Peptide Fragments; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vasoconstriction; Vasodilation

17beta-Oestradiol (E2)-mediated inhibition of angiotensin-converting enzyme (ACE) protects the E2-replete kidney from the progression of hypertensive renal disease. Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, counters the actions of ACE by catalysing the conversion of angiotensin II (Ang II) to angiotensin(1-7) [Ang(1-7)]. We investigated E2 regulation of ACE2 in the renal wrap (RW) model of hypertension in rats. After 6 weeks on a high-sodium diet (4% NaCl), the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA expression (36%) in the ovariectomized RW rat (RW-OVX); E2 replacement prevented these effects. The RW-OVX rats exhibited greater renal injury, including 1.7-fold more tubulointerstitial fibrosis and 1.6-fold more glomerulosclerosis than E2-replete females (RW-Intact and RW-OVX+E2). Angiotensin(1-7) infusion prevented these exacerbating effects of ovariectomy on renal pathology; no differences in indicators of renal injury were observed between RW-OVX-Ang(1-7) and RW-Intact rats. These renal protective effects of Ang(1-7) infusion were not attributable to increased ACE2 activity or to changes in heart rate or body weight, since these parameters were unchanged by Ang(1-7) infusion. Furthermore, Ang(1-7) infusion did not attenuate renal injury by reducing mean arterial pressure (MAP), since infusion of the peptide did not lower MAP but rather caused a slight increase during a 6 week chronic treatment for Ang(1-7). These results suggest that E2-mediated upregulation of renal ACE2 and the consequent increased Ang(1-7) production contribute to E2-mediated protection from hypertensive renal disease. These findings have implications for E2-deficient women with hypertensive renal disease and suggest that therapeutics targeted towards increasing ACE2 activity and Ang(1-7) levels will be renal protective.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Body Weight; Estradiol; Female; Heart Rate; Hypertension, Renovascular; Kidney; Kidney Glomerulus; Ovariectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Up-Regulation

Renin in collecting duct cells is upregulated in chronic angiotensin II-infused rats via angiotensin II type 1 receptors. To determine whether stimulation of collecting duct renin is a blood pressure-dependent effect; changes in collecting duct renin and associated parameters were assessed in both kidneys of 2-kidney, 1-clip Goldblatt hypertensive (2K1C) rats. Renal medullary tissues were used to avoid the contribution of renin from juxtaglomerular cells. Systolic blood pressure increased to 184+/-9 mm Hg in 2K1C rats (n=19) compared with sham rats (121+/-6 mm Hg; n=12). Although renin immunoreactivity markedly decreased in juxtaglomerular cells of nonclipped kidneys (NCK: 0.2+/-0.0 versus 1.0+/-0.0 relative ratio) and was augmented in clipped kidneys (CK: 1.7+/-1.0 versus 1.0+/-0.0 relative ratio), its immunoreactivity increased in cortical and medullary collecting ducts of both kidneys of 2K1C rats (CK: 2.8+/-1.0 cortex; 2.1+/-1.0 medulla; NCK: 4.6+/-2.0 cortex, 3.2+/-1.0 medulla versus 1.0+/-0.0 in sham kidneys). Renal medullary tissues of 2K1C rats showed greater levels of renin protein (CK: 1.4+/-0.2; NCK: 1.5+/-0.3), renin mRNA (CK: 5.8+/-2.0; NCK: 4.9+/-2.0), angiotensin I (CK: 120+/-18 pg/g; NCK: 129+/-13 pg/g versus sham: 67+/-6 pg/g), angiotensin II (CK: 150+/-32 pg/g; NCK: 123+/-21 pg/g versus sham: 91+/-12 pg/g; P<0.05), and renin activity (CK: 8.6 microg of angiotensin I per microgram of protein; NCK: 8.3 microg of angiotensin I per microgram of protein; sham: 3.4 microg of angiotensin I per microgram of protein) than sham rats. These data indicate that enhanced collecting duct renin in 2K1C rats occurs independently of blood pressure. Upregulation of distal tubular renin helps to explain how sustained intrarenal angiotensin II formation occurs even during juxtaglomerular renin suppression, thus allowing maintained effects on tubular sodium reabsorption that contribute to the hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Hypertension, Renovascular; Immunohistochemistry; Juxtaglomerular Apparatus; Kidney Cortex; Kidney Medulla; Kidney Tubules, Collecting; Male; Rats; Rats, Sprague-Dawley; Renal Artery; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Surgical Instruments; Up-Regulation; Vasoconstrictor Agents

We recently demonstrated that renin-angiotensin system (RAS) overactivity during late gestation in rats is associated with increased kidney and urine levels of ANG-(1-7) and enhanced kidney immunostaining of ANG-(1-7) and angiotensin-converting enzyme 2 (ACE2). To understand the temporal-spatial changes in normal and hypertensive pregnancies, the renal distribution of ANG-(1-7) and ACE2 in association with kidney angiotensin peptides and ACE2 activity was examined in virgin, normal pregnant (NP; gestational days 5, 15, and 19) and reduced uterine perfusion pressure (RUPP at day 19) pregnant Sprague-Dawley rats. ANG-(1-7) and ACE2 immunocytochemical staining increased 1.8- and 1.9-fold and 1.7- and 1.8-fold, respectively, at days 15 and 19 of NP, compared with virgin rats. ANG-(1-7) and ANG II concentrations were increased in the kidney at 19 days of gestation. ACE2 activity measured using a fluorescent substrate was increased 1.9- and 1.9-fold in the cortex and 1.9- and 1.8-fold in the medulla at days 15 and 19 of NP. In the RUPP animals, ANG-(1-7) immunostaining and concentration were significantly decreased compared with 19-day NP rats. ACE2 activity was unchanged in the cortex and medulla of RUPP rats. In conclusion, during NP, the concurrent changes of ACE2 and ANG-(1-7) suggest that ACE2 plays an important role in regulating the renal levels of ANG-(1-7) at mid to late gestation. However, the decrease in renal ANG-(1-7) content in the absence of a concomitant decrease in ACE2 implicates the participation of other ANG-(1-7) forming or degrading enzymes during hypertensive pregnancy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Body Weight; Estradiol; Female; Fluorescent Antibody Technique; Hypertension, Pregnancy-Induced; Immunohistochemistry; Kidney; Peptide Fragments; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Proteinuria; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renin; Urodynamics; Uterus

The present study investigated the hypoglycemic action of des-aspartate-angiotensin I (DAA-I), a metabolite of angiotensin I, in two animal models of type 2 diabetes. The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT(1) receptor and exerts responses opposing those of angiotensin II and on recent reports that curtailment of angiotensin II formation by angiotensin converting enzyme inhibitors and blockade of the AT(1) receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. Diabetic KKAy mice and GK rats were administered orally (by gavage) one of the following doses of DAA-I: 400, 600, or 800 nmol/kg.d for 4 and 6 wk, respectively. Control diabetic animals were similarly administered water. Blood glucose of each animal was determined fortnightly by oral glucose tolerance test and blood insulin on the last day of treatment. Animals were killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged animals. Orally administered DAA-I had no effect on blood insulin level but exerted dose-dependent hypoglycemic action in KKAy mice and GK rats after 4 and 6 wk of treatment, respectively. At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. These findings show that DAA-I is not an insulin secretagogue and exerts hypoglycemic action by attenuating insulin resistance, the first such demonstration indicating that the nonapeptide is involved in glycemic regulation.

Topics: Angiotensin I; Animals; Blood Glucose; Blotting, Western; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glucose Transporter Type 4; Hypoglycemic Agents; Immunoprecipitation; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Phosphodiesterase I; Random Allocation; Rats; Rats, Wistar

Recent evidence suggests that the intrarenal renin-angiotensin system (RAS) may play an important role in the development of glomerular changes associated with diabetic nephropathy. In this study, the glomerular RAS was examined in male Sprague-Dawley rats made diabetic with streptozotocin (STZ), and the findings compared with those obtained in control nondiabetic rats. In diabetic rat glomerular extracts, angiotensinogen and angiotensin II (ANG II) levels were increased significantly by 2.2- and 1.9-fold, respectively, compared with nondiabetic controls. No significant differences in ANG I and angiotensin-converting enzyme (ACE) levels were observed between these groups. The HPLC analysis of the glomerular extracts demonstrated that exogenous ANG I was converted into various ANG peptides including ANG II, ANG1-9, and ANG1-7. A significant increase in formation of ANG II from exogenous ANG I was observed in STZ rats compared with control rats. Preincubation of glomerular extracts with captopril resulted in a 20-30% decrease in ANG II conversion from exogenous ANG I in diabetic and control rats. The possible role of ANG1-9 in formation of ANG II was examined by HPLC. Exogenous ANG1-9 in glomerular extracts was converted into ANG II, this conversion being significantly higher in STZ rats than in control rats. These findings provide new information that ANG1-9 is produced in rat glomerular extracts, can be converted to ANG II, and that this conversion is also stimulated in diabetic rat glomeruli. Thus this study demonstrates that in diabetic rats, glomerular ANG II levels are increased due to an increase in angiotensinogen and an increase in the formation of ANG II.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Glucose; Body Weight; Captopril; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney Glomerulus; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley

Vascular smooth muscle cells in spontaneously hypertensive rats (SHR) express angiotensin II-forming chymase (rat vascular chymase [RVCH]), which may contribute to blood pressure regulation. In this study, we studied whether chymase-dependent angiotensin II formation contributes to the regulation of blood pressure in SHR. The systolic blood pressure in 16-week-old Wistar-Kyoto (WKY) rats was 113 +/- 9 mmHg, compared to 172 +/- 3 mmHg in SHR. Using synthetic substrates for measuring angiotensin-converting enzyme (ACE) and chymase activities, it was found that both ACE and chymase activities in extracts from SHR aortas were significantly higher than in those from WKY rat aortas. Using angiotensin I as a substrate, angiotensin II formation in SHR was found to be significantly higher than that in WKY rats, and its formation was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. RVCH mRNA expression could not be detected in aorta extracts from either WKY rats or SHR. In carotid arteries isolated from WKY rats and SHR, angiotensin I-induced vasoconstriction was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. Angiotensin I-induced pressor responses in both WKY rats and SHR were also completely inhibited by an ACE inhibitor, but they were not affected by a chymase inhibitor. In SHR, an ACE inhibitor and an angiotensin II receptor blocker showed equipotent hypotensive effects, but a chymase inhibitor did not have a hypotensive effect. These results indicated that chymase-dependent angiotensin II did not regulate blood pressure in SHR in the present study.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Chymases; Gene Expression Regulation, Enzymologic; Hypertension; Male; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Serine Endopeptidases; Vasoconstriction

Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whether Ang (1-7) contributes to the anti-proteinuric effects of ACE-I treatment. Therefore, we evaluated whether Ang (1-7) infusion reduces proteinuria in a rat model of adriamycin-induced renal disease. In addition, the effect of a selective Ang (1-7) blocker, [D-Ala7]-Ang (1-7) (A779), was investigated in rats treated with the ACE-I, lisinopril (LIS). Six weeks after induction of proteinuria, therapy was started in four different groups: control, Ang (1-7), LIS, and LIS+A779. After two weeks, the rats were sacrificed. Six weeks after injection of adriamycin, the rats had developed proteinuria of 323+/-40 mg/24 hours. The proteinuria remained stable in the control group and in the Ang (1-7) group, but was reduced in both LIS and LIS+A779-treated groups. Similarly, blood pressure (BP) was unchanged in the control and the Ang (1-7) groups, but reduced in both the LIS and the LIS+A779 groups. Plasma levels of Ang (1-7) were increased in the Ang (1-7) and in both LIS-treated groups. We conclude that systemic Ang (1-7) plays no major role in the anti-proteinuric and BPlowering effects of ACE-I in this rat model of adriamycin-induced nephrosis.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Body Weight; Creatine; Creatinine; Doxorubicin; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar

Aldosterone participates in the pathophysiology of several models of progressive chronic renal disease. Because of the causal connection between transforming growth factor-beta(1) (TGF-beta) and scarring in many such models, we hypothesized that aldosterone could evoke TGF-beta in the kidney. Aldosterone infusion for 3 days in otherwise normal rats caused a more than twofold increase in TGF-beta excretion without changes in systolic pressure or evidence of kidney damage. Concurrent treatment with amiloride did not alter this effect, indicating that aldosterone's stimulation of TGF-beta was independent of its regulation of sodium or potassium transport. However, concurrent treatment with spironolactone did block the increase in TGF-beta, indicating that the effect depends on the mineralocorticoid receptor. Renal mRNA for serum glucocorticoid kinase rose, but no change in TGF-beta message occurred, suggesting posttranscriptional enhancement of renal TGF-beta. In summary, aldosterone provokes renal TGF-beta, and this action may contribute to aldosterone's fibrotic propensity.

Topics: Aldosterone; Angiotensin I; Animals; Blood Pressure; Body Weight; Drug Implants; Gene Expression Regulation; Kidney; Male; Nuclease Protection Assays; Rats; Rats, Sprague-Dawley; Renin; Stimulation, Chemical; Transforming Growth Factor beta; Water-Electrolyte Balance

We investigated the hypothesis that thromboxane A2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng x kg(-1) x min(-1) sc for 14 days) using TP-R knockout (TP -/-) and wild-type (+/+) mice. TP -/- had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF2alpha) and nitric oxide (NOx). Infusion of ANG II into TP +/+ increased ROS and thromboxane B2 (TxB2) and increased RVR and FF. ANG II infusion into TP -/- mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP -/- : +6 +/- 2 vs. TP +/+: +15 +/- 3 mmHg) and failed to increase FF, ROS, or TxB2 but increased NOx and paradoxically decreased RVR (-2.1 +/- 1.7 vs. +2.6 +/- 0.8 mmHg x ml(-1) x min(-1) x g(-1)). Blockade of AT1 receptor of TP -/- mice infused with ANG II reduced MAP (-8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP -/- mice have a basal increase in RVR and FF associated with ROS.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Body Weight; Dinoprost; Electrolytes; Epoprostenol; Female; Heart Rate; Hematocrit; Hypertension, Renal; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitrites; Organ Size; Receptor, Angiotensin, Type 1; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Specific Pathogen-Free Organisms; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Urine; Vascular Resistance; Vasoconstrictor Agents

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Stroke-prone spontaneously hypertensive rats (SHRSP) maintained on Stroke-Prone Rodent Diet and 1% NaCl drinking water (starting at 8 wk of age) rapidly develop stroke and malignant nephrosclerosis that can be prevented, despite continued hypertension, by drugs targeting angiotensin II and aldosterone actions. This study evaluated estrogen's effects in the SHRSP model. Female SHRSP that were sham operated (SHAM), ovariectomized (OVX) at 4 wk of age, or OVX and treated with estradiol benzoate (E2,30 microg x kg-1 x wk-1) were studied. In a survival protocol, OVX rats lived significantly longer (15.1 +/- 0.3 wk) compared with SHAM (13.6 +/- 0.2 wk) or OVX+E2 rats (12.4 +/- 0.2 wk). In a protocol in which animals were matched for age, at 11.5 wk, terminal systolic blood pressure and urine protein excretion were elevated in SHAM and OVX+E2 rats compared with OVX rats; blood urea nitrogen, renal microvascular and glomerular lesions, and plasma renin concentration were elevated in OVX+E2 relative to SHAM or OVX rats. In a survival protocol using intact female SHRSP, treatment with an antiestrogen (tamoxifen, 7 mg.kg-1.wk-1) prolonged survival by >2 wk compared with controls (P < 0.01). The data indicate that estrogen promotes microangiopathy in the kidney and stroke in saline-drinking SHRSP.

Topics: Angiotensin I; Animals; Blood Pressure; Body Weight; Capillaries; Estradiol; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Female; Kidney; Neovascularization, Pathologic; Organ Size; Ovariectomy; Rats; Rats, Inbred SHR; Receptors, Estrogen; Renin; Sodium Chloride; Stimulation, Chemical; Stroke; Survival Analysis; Tamoxifen

The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart.. We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis.. Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.

Topics: Age Factors; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Body Weight; Cardiomegaly; Collagen; Hemodynamics; Losartan; Mice; Mice, Transgenic; Myocardium; Organ Size; Organ Specificity; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Angiotensin II (Ang II)-dependent hypertension is associated with augmented intrarenal concentrations of Ang II; however, the distribution of the increased intrarenal Ang II has not been fully established.. To determine the changes in renal interstitial fluid Ang II concentrations in Ang II-induced hypertension and the consequences of treatment with an angiotensin II type 1 (AT1) receptor blocker.. Rats were selected to receive vehicle (5% acetic acid subcutaneously; n = 6), Ang II (80 ng/min subcutaneously, via osmotic minipump; n = 7) or Ang II plus an AT1 receptor antagonist, candesartan cilexetil (10 mg/kg per day, in drinking water; n = 6) for 13-14 days, at which time, experiments were performed on anesthetized rats. Microdialysis probes were implanted in the renal cortex and were perfused at 2 microl/min. The effluent dialysate concentrations of Ang I and Ang II were measured by radioimmunoassay and reported values were corrected for the equilibrium rates at this perfusion rate.. Ang II-infused rats developed greater mean arterial pressures (155 +/- 7 mmHg) than vehicle-infused rats (108 +/- 3 mmHg). Ang II-infused rats showed greater plasma (181 +/- 30 fmol/ml) and kidney (330 +/- 38 fmol/g) Ang II concentrations than vehicle-infused rats (98 +/- 14 fmol/ml and 157 +/- 22 fmol/g, respectively). Renal interstitial fluid Ang II concentrations were much greater than plasma concentrations, averaging 5.74 +/- 0.26 pmol/ml in Ang II-infused rats - significantly greater than those in vehicle-infused rats (2.86 +/- 0.23 pmol/ml). Candesartan treatment prevented the hypertension (87 +/- 3 mmHg) and led to increased plasma Ang II concentrations (441 +/- 27 fmol/ml), but prevented increases in kidney (120 +/- 15 fmol/g) and renal interstitial fluid (2.15 +/- 0.12 pmol/ml) Ang II concentrations.. These data indicate that Ang II-infused rats develop increased renal interstitial fluid concentrations of Ang II, which may contribute to the increased vascular resistance and reduced sodium excretion. Furthermore, the augmentation of renal interstitial fluid Ang II is the result of an AT1 receptor-mediated process and can be dissociated from the plasma concentrations.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Body Weight; Extracellular Fluid; Hypertension, Renal; Kidney; Male; Microdialysis; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles; Vasoconstrictor Agents

In the present study we investigated the possible role of angiotensin-(1-7) [Ang-(1-7)] in modulating renal functional responses to intrarenal (i.e.) infusion of angiotensin II (ANG II) in normotensive anesthetized rats. ANG II (6 ng/min, n = 14) decreased glomerular filtration rate (GFR), renal plasma flow (RPF), absolute and fractional sodium excretion by -24 +/- 5, -25 +/- 6, -44 +/- 6 and -28 +/- 7%, respectively (p < 0.05). i.r. infusion of Ang-(1-7) (50 ng/min, n = 13) did not significantly alter GFR (+6 +/- 4%) but reduced RPF by -19 +/- 7% (p < 0.05). Ang-(1-7) increased absolute and fractional sodium excretion by +36 +/- 6 and +37 +/- 8%, respectively (p < 0.05). Infusion of Ang-(1-7) did not prevent the decreases in GFR and RPF but completely blunted the decreases in absolute (-2 +/- 2%) and fractional sodium excretion (-4 +/- 4%) induced by ANG II (n = 11). Blockade of the Ang-(1-7) receptor by [7-D-Ala]-Ang-(1-7) (5 microg/min, n = 11) significantly decreased GFR, RPF, absolute and fractional sodium excretion by -28 +/- 7, -20 +/- 5, -32 +/- 7 and -24 +/- 4%, respectively (p < 0.05), suggesting that the action of endogenous ANG II is unopposed by compensatory effect of endogenous Ang-(1-7). i.r. infusion of Ang-(1-7) (n = 10) did not alter the effect of Ang-(1-7) receptor blockade on RPF (-21 +/- 6%) but blunted its effects on GFR (+4 +/- 3%) and absolute (+7 +/- 5%) and fractional (+6 +/- 4%) urinary sodium excretion probably by displacing the receptor blocker. While exogenous ANG II during blockade of the Ang-(1-7) receptor and the AT(2) receptor (by PD 123319; 1 microg/min i.r., n = 9) resulted in the same decreases in absolute and fractional sodium excretion (-39 +/- 8 and -38 +/- 6%, respectively, p < 0.05) as did ANG II in the absence of Ang-(1-7) receptor blockade. These results suggest that in normotensive rats high i.r. Ang-(1-7) concentration attenuates the tubular, i.e. sodium reabsorptive effect, but not the vascular effect of exogenous i.r. ANG II. Results obtained during blockade of Ang-(1-7) and of AT(2) receptors imply that AT(2) receptors play a role in tubular sodium reabsorption in the presence of high ANG II concentration.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Glomerular Filtration Rate; Imidazoles; In Vitro Techniques; Kidney; Kidney Function Tests; Male; Organ Size; Peptide Fragments; Pyridines; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Renal Circulation; Sodium; Urodynamics

Chronic infusion of angiotensin-(1-7) [Ang-(1-7)] lowers blood pressure in salt-induced and spontaneously hypertensive (SHR) rats. In the present study, we have examined the acute effect of Ang-(1-7) in salt-induced hypertension using Dahl salt-sensitive rats placed on low (0.3%) or high (8.0% NaCl) salt diets for 2 weeks. Rats fed a high salt diet showed a greater rise in BP than those fed a low salt diet. Ang-(1-7) (24 microg/kg) reduced mean arterial pressure (MAP), enhanced the release of prostacyclin and nitric oxide, and suppressed thromboxane A(2) levels. A-779 (48 microg/kg, i.v), a selective Ang-(1-7) antagonist, partially blocked these effects of Ang-(1-7). The Ang-(1-7)-induced depressor response observed in these animals was related to an increase in vasodilatory prostanoids, a decrease in the constrictor prostanoid thromboxane A(2), and an increase in nitric oxide levels in both plasma and isolated aortic rings.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Cyclic GMP; Dinoprostone; Epoprostenol; Hypertension; Male; Nitric Oxide; Peptide Fragments; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Salts; Thromboxane A2; Thromboxane B2; Time Factors

We hypothesized that angiotensin II type-1 (AT(1)) receptor blocker (AT(1)RB) would prevent adverse left ventricular (LV) remodeling and LV dysfunction when started at the outset of mitral regurgitation (MR).. Little is known regarding the efficacy of AT(1)RB treatment of MR.. Mitral regurgitation was induced by chordal disruption in adult mongrel dogs. Six normal dogs (NLs) were compared to six untreated MR dogs (MR) and seven dogs treated with the receptor blocker irbesartan (MR+AT(1)RB) started 24 h after induction of MR (60 mg/kg p.o. b.i.d.) and continued for three months.. Treatment with AT(1)RB decreased systemic vascular resistance but did not significantly improve cardiac output, LV end-diastolic dimension (LVEDD) or LVEDD/wall thickness compared to untreated MR dogs. Resting isolated cardiomyocyte length increased in MR versus NLs and was further increased in AT(1)RB dogs. Left ventricular end-systolic dimension increased to a greater extent from baseline in AT(1)RB dogs versus untreated MR dogs (29 +/- 9% vs. 12 +/- 6%, p < 0.05), despite a significantly lower LV peak systolic pressure in AT(1)RB dogs. Plasma-angiotensin (ANG) II was elevated greater than threefold in both MR and MR+AT(1)RB versus NLs. In contrast, intracardiac ANG II was increased greater than twofold in MR dogs versus NLs, but was normalized by AT(1)RB.. The use of AT(1)RB decreased systemic vascular resistance and attenuated local expression of the renin-angiotensin system but did not prevent adverse LV chamber and cardiomyocyte remodeling. These results suggest that blockade of the AT(1) receptor does not improve LV remodeling and function in the early myocardial adaptive phase of MR.

Topics: Alabama; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chymases; Disease Models, Animal; Dogs; Female; Heart Ventricles; Hemodynamics; Male; Mitral Valve Insufficiency; Receptor, Angiotensin, Type 1; Renin; Serine Endopeptidases; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

1. Inhibition of the renin-angiotensin system (RAS) improves symptoms and prognosis in heart failure. The experimental basis for these benefits remains unclear. We examined the effects of inhibition of ACE or blockade of angiotensin II type 1 (AT1) receptor on the haemodynamics, cardiac G-proteins, and collagen synthesis of rats with coronary artery ligation (CAL), a model in which chronic heart failure (CHF) is induced. 2. Rats were orally treated with the ACE inhibitor trandolapril (3 mg kg(-1) day(-1)) or the AT1 receptor blocker L-158809 (1 mg kg(-1) day(-1)) from the 2nd to 8th week after CAL. CAL resulted in decreases in the left ventricular systolic pressure and its positive and negative dP/dt, an increase in the left ventricular end-diastolic pressure, and the rightward shift of the left ventricular pressure-volume curve. Long-term treatment with either drug improved these signs of CHF to a similar degree. 3. Cardiac Gsalpha and Gqalpha protein levels decreased, whereas the level of Gialpha protein increased in the animals with CHF. Long-term treatment with trandolapril or L-158809 attenuated the increase in the level of cardiac Gialpha protein of the animals with CHF without affecting Gsalpha and Gqalpha protein levels. Cardiac collagen content of the failing heart increased, whose increase was blocked by treatment with either drug. 4. Exogenous angiotensin I stimulated collagen synthesis in cultured cardiac fibroblasts, whose stimulation was attenuated by either drug. 5. These results suggest that blockade of the RAS, at either the receptor level or the synthetic enzyme level, may attenuate the cardiac fibrosis that occurs after CAL and thus affect the remodelling of the failing heart.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Dose-Response Relationship, Drug; Fibroblasts; GTP-Binding Proteins; Heart; Heart Failure; Heart Septum; Heart Ventricles; Hemodynamics; Imidazoles; Indoles; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles

To prevent the action of angiotensin II by blockade with either an angiotensin converting enzyme inhibitor (ACE I) or an angiotensin receptor antagonist (ARA) is difficult due to the physiological compensations. Combined therapy with both drugs may enable complete blockade, and in rats in high doses this has produced a syndrome that results in death.. To determine the effect of combined blockade using losartan (10 mg/kg per day) and perindopril (6 mg/kg per day) on blood pressure, cardiac growth, renal function and behaviour, and to determine how this is influenced by different salt intakes in normotensive Sprague Dawley rats.. Rats were fed an 0.2 or 4% NaCl diet and received the above drugs intraperitoneally. Blood pressure was measured by telemetry. Cardiac weight was measured after 10 days of therapy. Renal function was assessed by plasma creatinine and electrolytes, plasma renin and angiotensinogen concentrations were measured.. On 0.2% NaCl intake, combined blockade lowered blood pressure progressively; at day 7, rats on 0.2% NaCl developed a syndrome of listlessness and failure to eat which led to loss of weight and death. Cardiac size was dramatically reduced. Plasma creatinine was elevated to 50% above normal. There was a polyuria. The syndrome was reversed by adding NaCl to the drinking water or prevented in rats on a 4% NaCl intake. In rats on 0.2% NaCl plasma renin rose dramatically with medication and angiotensinogen became depleted. Haematocrit in all groups of rats did not differ.. Combined blockade of the renin-angiotensin system can cause death in rats on a reduced NaCl intake. This was prevented by a high salt intake. The syndrome may result from depletion of angiotensinogen and the failure to synthesize sufficient angiotensin II that may be critical for normal cardiac growth and function and critical for survival.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Blood; Blood Pressure; Body Weight; Diet, Sodium-Restricted; Drug Synergism; Eating; Heart; Losartan; Organ Size; Perindopril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

Angiotensin-converting enzyme (ACE) inhibitors have proven an effective means to control hypertension and manage cardiac hypertrophy. It is presently unknown if newer specific angiotensin II subtype 1 receptor (AT1R) antagonists are as effective or more effective in treating these conditions compared with ACE inhibitors. There is evidence that these classes of drugs may affect cardiac hypertrophy by different mechanisms. This study compared the effect of irbesartan, an AT1R antagonist, with that of captopril, an ACE inhibitor, on expression of early genetic markers of cardiac hypertrophy in lean male SHHF/Mcc-fa(cp) rats. SHHF/Mcc-fa(cp) rats (n = 10/group) were given captopril (100 mg/kg/day), irbesartan (50 mg/kg/day), or placebo for 16 weeks. Irbesartan and captopril significantly reduced systolic pressure and produced similar rightward shifts in the angiotensin I dose-response curve. Renal renin gene expression was increased 8.6-fold by irbesartan and 17.7-fold by captopril. The only effect on echocardiographic findings was a similar decrease in aortic peak velocity, an index of systolic function, by both treatments. Early markers of cardiac hypertrophy were significantly attenuated by both drugs. Both drugs produced marked and equivalent reductions in left ventricular atrial natriuretic peptide (ANP) messenger RNA (mRNA) levels compared with controls. This decrease in ANP gene expression was accompanied by a decrease in plasma ANP concentration in the treatment groups. The shift from V1 to V3 myosin isozymes was similarly decreased in both treatment groups, compared with controls. These data suggest that captopril and irbesartan are similarly effective in controlling expression of genes associated with ventricular hypertrophy in heart failure-prone SHHF/Mcc-fa(cp) rat.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Body Weight; Captopril; Cardiomegaly; Dose-Response Relationship, Drug; Echocardiography; Gene Expression; Heart Failure; Irbesartan; Isoenzymes; Male; Myosin Heavy Chains; Organ Size; Rats; Rats, Inbred Strains; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; RNA, Messenger; Systole; Tetrazoles

Urinary excretion rates of angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)] were determined in normotensive Sprague Dawley (SD), spontaneously hypertensive (SHR), and mRen-2 transgenic hypertensive animals before and following blockade of Ang II synthesis or activity for two weeks. This study was performed to determine for the first time whether inhibition of Ang II alters the excretion of angiotensin peptides in the urine. Rats were given either tap water or water medicated with lisinopril, losartan or both agents in combination. Blood pressure was monitored at regular intervals during the experiment by the tail-cuff method, and once again at the end of the study with a catheter implant into a carotid artery. Metabolic studies and 24 h urinary excretion variables and angiotensin peptides were determined before and during the procedures. While all three treatments normalized the blood pressure of hypertensive animals, therapy with either lisinopril or the combination of lisinopril and losartan had a greater antihypertensive effect in both SHR and [mRen-2]27 transgenic hypertensive rats. In the urine, the concentration of the angiotensins (normalized by 24-h creatinine excretion) was several-fold higher in the untreated hypertensive animals than in normotensive SD rats. In SD rats, lisinopril or lisinopril and losartan produced a sustained rise in urinary levels of Ang-(1-7) without changes in the excretion of Ang I and Ang II. In contrast, Ang I and Ang-(1-7) were significantly elevated in SHR medicated with lisinopril alone or in combination with losartan. Only losartan, however, augmented urinary levels of Ang II in the SHR. The antihypertensive effects of the three separate regimens had no effect on the urinary excretion of angiotensin peptides in [mRen-2]27 transgenic hypertensive rats. These data show that Ang I and Ang-(1-7) are excreted in large amounts in the urine of SD, SHR and [mRen-2]27 hypertensive rats. The unchanged Ang-(1-7) excretion in transgenic hypertensive (Tg+) rats after inhibition of the renin-angiotensin system agrees with the previous finding of a reduced plasma clearance of the peptide in this model of hypertension. The data suggest that this form of hypertension may be associated with increased activity of an endogenous converting enzyme inhibitor.

Topics: Administration, Oral; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Pressure; Body Weight; Drinking; Electrolytes; Hemodynamics; Hypertension; Lisinopril; Losartan; Male; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

The water-seeking behavior (WR) of toads (Bufo viridis) was investigated. Fully hydrated toads that are allowed free choice of wet or dry filter paper voluntarily and spontaneously select to sit on water-soaked paper at a regular frequency during trials. Dehydration of bladder-emptied toads by 14% elicits WR in all animals. Injection of aldosterone or angiotensin-I reduced the dehydration threshold to 7% weight loss. WR frequency increased when plasma osmolality was elevated by injection of NaCl or other solutes (both ionic and non-ionic). Only urea, to which cell membranes are highly permeable, was the exception that did not produce this response. The increase in WR frequency induced by elevated plasma osmolality was augmented by injection of aldosterone or angiotensin-I. In vivo water uptake, measured in a water bath, was increased by an NaCl or oxytocin injection, but not by aldosterone. It is concluded that elevated plasma osmolality induces an increase in WR frequency that is separate and prior to the water uptake process. Different hormones are involved in each step.

Topics: Aldosterone; Angiotensin I; Animals; Behavior, Animal; Body Weight; Bufonidae; Dehydration; Female; Male; Osmolar Concentration; Osmosis; Oxytocin; Skin Absorption; Sodium Chloride; Urea; Urinary Bladder; Water

The effect of cold exposure on the systemic renin-angiotensin system and on regulation of the angiotensin II (Ang II) receptor was examined in target organs for Ang II with cardiovascular relevance (left ventricle, kidney, lung) and metabolic relevance [interscapular brown adipose tissue (ISBAT), liver] to the functional consequences of cold exposure. In time course studies, the effects were examined of 4 hr or 1, 3 and 7 days of exposure to cold (4 degrees C) on plasma Ang II concentration and Ang II receptor binding characteristics in rat liver. Plasma Ang II concentration increased 10-fold after 4 hr of cold exposure, returned to control levels at days 1 and 3 of cold exposure, and was again increased (2-fold) at 7 days of cold exposure. The affinity of [125I]Sar1, Ile8-Ang II binding in membranes prepared from rat liver was not altered in cold-exposed rats. The density (Bmax) of binding sites in liver from cold-exposed rats was increased by day 1 and remained elevated over time-matched controls. Alterations in Ang II receptor density did not parallel plasma Ang II concentration in their time course, suggesting that cold-induced regulation of the Ang II receptor was not substrate mediated. In rats from the 7-day time point of cold exposure, Ang II receptor binding characteristics were examined in ISBAT and lung. Increases in Ang II receptor density were evident in ISBAT but not lung. To determine whether cold-induced increases in food intake contributed to elevations in plasma Ang II concentration and/or Ang II receptor density, a group of cold-exposed rats (7 days) were pair-fed to food intake levels of control rats. Pair-feeding of cold-exposed rats eliminated increases in plasma Ang II and norepinephrine concentration but did not prevent increases in Ang II receptor density in liver, ISBAT, kidney and left ventricle. Moreover, increases in Ang II receptor density were augmented in kidney and left ventricle from cold-exposed rats that were pair-fed. Results from these studies demonstrate that cold exposure resulted in an increase in plasma Ang II concentration through mechanisms related to increased food intake. Elevations in food intake in cold-exposed rats contributed to tissue-specific increases in Ang II receptor density. Moreover, cold-induced increases in Ang II receptor density were not related to plasma Ang II concentration.

Topics: Adipose Tissue; Angiotensin I; Angiotensin II; Animals; Body Weight; Cold Temperature; Drinking; Eating; Iodine Radioisotopes; Leptin; Liver; Male; Norepinephrine; Proteins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Time Factors

To investigate the role of the renin-angiotensin system in the regulation of adrenal growth in deoxycorticosterone (DOC)-salt hypertensive rats, and the adrenal gene expression of angiotensin AT1 and AT2 receptors, three groups of uninephrectomized rats + DOC pellet + 0.9% NaCl were given water (DOC), losartan (DOC-L), or ramipril (DOC-R) by gavage. Controls had sham surgery and water gavage. Tail-cuff systolic and mean intra-arterial blood pressures were significantly higher in the three DOC groups than in controls and not different among the groups. Adrenal weight of DOC was slightly but not significantly greater than that of controls, while those of DOC-L and DOC-R were greater than that of controls (P < .01). Northern blots showed that AT1 and AT2 gene expression was significantly reduced in DOC (by 33% and 60%), while that of AT1 (but not AT2) was significantly reduced further (versus control and DOC) in DOC-L and DOC-R. There were negative correlations between adrenal weight and AT1 (r = -.80, P < .0001) or AT2 (r = -.60, P < .005). We conclude that DOC-salt hypertension downregulates adrenal AT1 and AT2 gene expression by different mechanisms. Removal of the effects of angiotensin by losartan or ramipril downregulates AT1 further and promotes adrenal growth, indicating the presence of an AT1-mediated growth-inhibitory action of angiotensin II on the adrenal gland. These observations constitute an additional example of a growth-inhibitory role for the AT1 receptor, opposite to its more common growth-promoting actions in other organs and tissues.

Topics: Adrenal Glands; Angiotensin I; Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Hypertension; Male; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger

To characterize the effects of estrogen, estrogen combined with progestin, and no treatment in ovariectomized cynomolgus monkeys during long-term reproductive hormone replacement.. Forty-five surgically postmenopausal cynomolgus monkeys fed a lipid-lowering diet were administered a conjugated equine estrogen (Premarin, 7.2 micrograms/day for the first 8 months, then 166 micrograms/day for the remaining 22 months), alone or in combination with 650 micrograms/day medroxyprogesterone acetate (Cycrin) for 30 months, or left with no hormone replacement therapy. Animals were anesthetized with ketamine-pentobarbital, and samples were taken for measurements of plasma renin activity, angiotensin converting enzyme activity, and angiotensin peptides, angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)].. Chronic replacement therapy with estrogen resulted in a significant elevation of the plasma renin activity [11.7 +/- 2.0 ng/ml per h control versus 22.8 +/- 4.6 ng/ml per h with estrogen (P < 0.05) versus 32.8 +/- 4.9 ng/ml per h with combination therapy (P < 0.01)], whereas estrogen or combination therapy caused a significant reduction in angiotensin converting enzyme activity [229 +/- 8 nmol/ml per min control versus 189 +/- 10 nmol/ml per min with estrogen (P < 0.05) versus 196 +/- 11 nmol/ml per min with combination therapy (P < 0.05)]. Both of these changes in angiotensin processing enzymes observed during replacement therapy resulted in significant increases in plasma Ang I levels [46.7 +/- 12.5 pg/ml control versus 175.5 +/- 65.9 pg/ml with estrogen (P < 0.05) and 561.7 +/- 373.6 pg/ml with combination therapy (P < 0.05)]. Plasma Ang II and Ang-(1-7) levels were not significantly changed. The mean blood pressure did not change with either treatment.. These studies reveal that, although chronic estrogen replacement activates renin activity and Ang I, it causes a shift in the processing of angiotensin peptides such that the concurrent reduction in angiotensin converting enzyme activity leads to unchanged plasma Ang II levels. Thus, the potentially harmful effects of estrogen-induced hyperreninemia are balanced by its actions interfering with the formation of the vasoactive product Ang II.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Drug Interactions; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Macaca fascicularis; Medroxyprogesterone Acetate; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Imidazoles; Kidney; Kidney Function Tests; Kidney Glomerulus; Losartan; Organ Size; Proteinuria; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Tetrazoles; Tissue Embedding

Age-related changes in plasma aldosterone and corticosterone concentrations as well as in plasma renin activity in response to 10 days of sodium deprivation were studied in old as compared to adult male Long-Evans rats. Chronic sodium deprivation greatly increased plasma concentrations of aldosterone both in old and in adult animals. However, this effect was significantly higher (+85.2%) in old (+3,574 pmol/l) as compared to adult (+1,820 pmol/l) rats. Concomitantly, adrenal weights were statistically increased in sodium-deprived old rats (+25%) whereas they were unchanged in adult animals; plasma corticosterone concentration was unchanged by sodium restriction in the two age groups. Because a putative modest decline with age of the metabolic clearance rate of aldosterone could not account totally for such an important increase in plasma concentration, it is assumed that it is, in its most part, due to an increased production. Furthermore, although plasma renin activity of senescent rats, fed either a normal or a sodium-deprived diet, was lower as compared to adult rats, the absolute and percent increases of this activity in response to sodium deprivation were, respectively, similar and higher in old as compared to adult rats and so could partially contribute to the higher aldosterone response.

Topics: Aging; Aldosterone; Angiotensin I; Animals; Body Weight; Corticosterone; Diet, Sodium-Restricted; Male; Radioimmunoassay; Rats; Renin; Sodium

The ingestion of water and 0.3 M NaCl solution and the secretion of key hormones were studied in groups of intact and bilaterally renal-denervated rats after extracellular fluid depletion. Hypovolemia with mild hypotension was produced by subcutaneous injections of the diuretic furosemide (10 mg/kg) followed by injections of the angiotensin-converting enzyme inhibitor captopril (5 mg/kg s.c.). Denervated rats drank significantly less of a concentrated saline solution in response to depletion than intact control rats did, but drank similar amounts of water. Denervated rats finished testing in significantly greater negative water and sodium balance compared with controls. Renal denervation did not impair the secretion of renin and aldosterone or the formation of angiotensin I. The diminished sodium intake of denervated rats is not attributable to reduced water and sodium excretion in response to the hypovolemic protocol. These results indicate that the integrity of the renal nerves is important for the normal elaboration of salt appetite in response to hypovolemia/hypotension.

Topics: Aldosterone; Angiotensin I; Animals; Appetite; Blood Proteins; Body Fluids; Body Weight; Denervation; Diuresis; Drinking; Hematocrit; Kidney; Male; Nervous System Physiological Phenomena; Rats; Rats, Sprague-Dawley; Renin; Sodium; Sodium Chloride

The renin-angiotensin system has been implicated in the hypertrophic adaptation of the heart to exogenous pathological loads, such as hypertension and aortic stenosis; however, the role of this hormonal system in the cardiac adaptations to physiological loads, such as chronic exercise conditioning, has not been established. We therefore studied the effect of angiotensin receptor 1 (AT1) blockade on the chronic cardiac responses of rats subjected to an 8-wk swimming program. Compared with matched sedentary controls, untreated swimmers increased their left ventricular weights by 13%, and swimmers treated with the AT1 antagonist L-158809 increased their left ventricular weights by 11% (both P < 0.05 vs. sedentary controls). The incorporation of labeled amino acids into the heart at the time of death was unchanged in all groups, and therefore the increase in heart weight in both swim-conditioned groups appeared to reflect a decrease in the rate of protein degradation in the heart. Hearts from both swim-conditioned groups manifested an increase in the V1-predominant myosin isoform pattern but not an increase in atrial natriuretic factor mRNA expression or protein kinase C translocation. The fact that these patterns of adaptation are preserved in exercised conditioned animals treated with an AT1 antagonist suggests that the chronic hypertrophic response of the heart to physiological loads is not influenced by the renin-angiotensin system.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Northern; Body Weight; Cardiomegaly; Contractile Proteins; Female; Heart Rate; Imidazoles; Myocardial Contraction; Organ Size; Physical Conditioning, Animal; Protein Kinase C; Rats; Rats, Wistar; RNA, Messenger; Tetrazoles

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Electrolytes; Enalapril; Female; Lactation; Male; Menstrual Cycle; Papio; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

The objective of the present study was to determine the relationship between plasma renin levels, and the development of hypertension and cardiac hypertrophy in TGR (mREN2)27 hypertensive rats. Systolic blood pressure and left ventricular mass index (LVMI) were measured in transgenic heterozygote and normotensive Sprague Dawley control rats at 25, 35, 45, 55, 65, and 75 days of age together with determinations of plasma active renin and prorenin, and renal and adrenal tissue renin, which were assayed at pH 6.5, 7.4, and 8.5. The systolic blood pressure and the LVMI of the transgenic rats were significantly increased compared to control rats by 55 and 65 days of age, respectively. Plasma active renin of the transgenic rats, measured at physiological pH, was significantly higher from 55 days of age, increasing in parallel with blood pressure and remaining significantly higher than controls at all age groups tested. Assays of both plasma and adrenal renin at various pHs showed a profile of angiotensin I generation that matched mouse renin more closely than that of rat renin. The ratio of angiotensin I (Ang I) generation at pH 8.5 and pH 6.5 was 0.5 for normal rat plasma but was between 3 and 5 for mouse plasma. Plasma prorenin and adrenal tissue renin from transgenic rats exhibited a pH profile consistent with the major portion being mouse renin. However, the low level of kidney renin observed in the transgenic rats exhibited a pH ratio (8.5/6.5) identical to that of normal rat renin (0.5), suggesting that residual renin within the kidney was predominantly of rat origin. These data indicate that plasma renin levels closely parallel the development of high blood pressure and LVMI and show that interpretation of the renin status of this strain is critically dependent on the assay conditions used. Under the conditions used in this study it was found that the TGR(mRen2)27 rat is a high mouse plasma renin model of hypertension.

Topics: Adrenal Glands; Aging; Angiotensin I; Animals; Animals, Genetically Modified; Blood Pressure; Body Weight; Echocardiography; Hydrogen-Ion Concentration; Hypertension; Hypertrophy, Left Ventricular; Kidney; Mice; Organ Size; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Renin

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Biphenyl Compounds; Blood Pressure; Body Weight; Cardiomegaly; Enalapril; Heart Ventricles; Imidazoles; Losartan; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Ventricular Function

Simultaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg) results in short-latency thirst and sodium appetite (i.e., the rapid ingestion of water and NaCl solution). To elucidate potential mechanisms for mediating this behavior, changes in plasma levels of key hormones involved in fluid intake and balance were characterized in rats subjected to this treatment protocol. Rats treated jointly with furosemide and low-dose captopril had exaggerated increases in plasma renin activity and angiotensin I but equivalent increases in plasma aldosterone compared with rats treated with either agent alone. Treatment with furosemide plus low-dose captopril increased plasma vasopressin but not plasma oxytocin. The administration of a higher dose of captopril (100 mg/kg) with furosemide, a combination of drugs that does not stimulate fluid intake (29), further increased plasma renin activity and angiotensin I but prevented the rise in plasma vasopressin. The results support the hypothesis that thirst and salt appetite generated by this protocol depend on angiotensin II formed within brain circumventricular organs rather than the systemic circulation.

Topics: Aldosterone; Angiotensin I; Animals; Appetite; Body Weight; Captopril; Diuresis; Dose-Response Relationship, Drug; Drug Interactions; Electrolytes; Furosemide; Male; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Sodium, Dietary

The aim of the study was to compare, in a rat model of congestive heart failure, the effect of captopril, a selective angiotensin-converting enzyme (ACE; EC 3.4.15.1) inhibitor, to that of alatriopril, a mixed inhibitor of ACE and atriopeptidase (EC 3.4.24.11), an enzyme implicated in the degradation of atrial natriuretic factor (ANF). Myocardial infarction was induced by ligation of the left coronary artery. Groups of rats received orally twice daily captopril (10 mg/kg), alatriopril (100 mg/kg) or vehicle. Treatments were started 18 to 20 h after ligation and continued for 4 weeks. Hypertrophic and hormonal changes reflecting congestive heart failure were assessed in rats with large infarcts by measuring the relative weight of cardiac tissues as well as by assaying ANF in heart and plasma and by measuring renin activity in plasma. Both treatments significantly reduced cardiac hypertrophy, but alatriopril showed a greater efficacy than captopril--the increase in relative heart weight reaching 38% with captopril and only 22% with alatriopril (P < .05). The hypertrophy of right ventricle was reduced by 47% with alatriopril and by 35% with captopril (N.S.), whereas the corresponding reductions for atria were 47% vs. 21% (P < .05). Both treatments prevented the ligation-induced increase of ANF level in the right ventricle. In contrast, plasma ANF level was significantly reduced after captopril but not after alatriopril treatment, a difference that probably reflects the protection of endogenous ANF in circulation resulting from atriopeptidase inhibition. Plasma renin was increased by 36-fold after captopril but only by 1.6-fold after alatriopril, a difference that presumably reflects the inhibition of renal renin secretion by endogenous ANF after alatriopril. These data suggest that enhancement of ANF levels in circulation via atriopeptidase inhibition magnifies the capacity of ACE inhibitors to prevent cardiac hypertrophy, and they show the potential therapeutic value of mixed ACE-atriopeptidase inhibitors in congestive heart failure.

Topics: Alanine; Amino Acid Sequence; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Bradykinin; Captopril; Cardiomegaly; Dioxoles; Disease Models, Animal; Heart Failure; Hormones; Male; Molecular Sequence Data; Myocardial Infarction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin

In experiments designed to analyze cardiovascular structure in response to antihypertensive therapy with an ACE inhibitor, we decided to start very early in life with the aim to prevent blood pressure increases and the development of vascular structural changes. In these treated groups of rats we unexpectedly observed that after they were weaned, their water consumption and urine volume, respectively, increased substantially. The present study was designed to determine if inhibition of the renin-angiotensin system produced similar effects in different strains of rats, and focused on characterizing the abnormal fluid balance occurring as a consequence to neonatal treatment with ACE inhibitors or angiotensin II blockers. Three-day-old Wistar Kyoto (WKY), Wistar (WR) and spontaneously hypertensive rats (SHR) were given either saline, enalapril, captopril, losartan and the AT2 blocker, PD123319, in the same amount of volume for 20 days. Treatment was stopped and rats were examined with regard to renal morphology at 4, 14 and 30 weeks of age. In addition, water consumption, urine volume, urine electrolytes and osmolality were analyzed at 14 weeks of age, that is, 10 weeks off treatment. Early treatment with the ACE inhibitors, enalapril and captopril, and the AT1 blocker, losartan, but not the AT2 blocker, PD 123319, in the SHR and in the normotensive strains WKY and WR produced persistent, irreversible histopathological renal abnormalities in adult life, long after the rats had been taken off treatment. These abnormalities consisted of mainly cortical tubulointerstitial inflammation, various degrees of papillary atrophy and pelvic dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Blood Pressure; Body Fluids; Body Weight; Electrolytes; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Renin-Angiotensin System

We investigated the effects of leukotriene (LT) D4 and its novel potent and selective antagonist L-660,711 on isolated rat hearts with chronic myocardial infarction. The left coronary artery was ligated permanently or for 30 or 60 min and followed by reperfusion. Hearts were isolated and perfused in the Langendorff mode 4 days, 4 wk, or 8 wk after the operation. Dose-response curves for LTD4 (12-240 ng/min) on coronary flow were shifted to the left in rats with permanent coronary occlusion for 8 wk or with coronary occlusion for 30 or 60 min and reperfusion for 4 wk. In contrast, dose-response curves were unchanged in rats 4 days after myocardial infarction. L-660,711 shifted dose-response curves for LTD4 on coronary flow to the right in all groups. The negative inotropic and chronotropic effects of LTD4 could be markedly attenuated by L-660,711 in all groups. Our findings suggest that the effect of LTD4 is enhanced in rat hearts with chronic myocardial infarction. L-660,711 effectively antagonized the vasoconstrictor effect of exogenous LTD4.

Topics: Angiotensin I; Angiotensin II; Animals; Body Weight; Bronchodilator Agents; Coronary Circulation; Heart; Heart Rate; In Vitro Techniques; Leukotriene D4; Male; Myocardial Infarction; Organ Size; Propionates; Quinolines; Rats; Rats, Wistar; Time Factors; Ventricular Function, Left

The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT1) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the renin-angiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753, 10 mg/kg/day; benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat. Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT1 receptor.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Benzazepines; Biphenyl Compounds; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Hemodynamics; Imidazoles; Losartan; Male; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Time Factors

We examined the effect of angiotensin I (AI), without the effect of angiotensin II (AII) converted from AI, on the weight of the adrenal glands, adrenal corticosterone (B) and adrenal aldosterone under conditions where the renin-angiotensin system was suppressed, since a reduction in the size of the adrenal glands is often observed in DOCA/salt hypertensive rats. Sixty male Wistar rats fed on a 1% NaCl solution were divided into 6 groups as follows: a) Salt group: received sesame oil and vehicle, b) Salt + C group: received sesame oil and MK422 (0.14 mg/day), an angiotensin converting enzyme inhibitor (CEI), c) DOCA group: received DOCA (30 mg/week) and vehicle, d) DOCA + A group: received DOCA and AI (0.5 mg/kg/day), e) DOCA + A + C group: received DOCA and AI with MK422, and f) DOCA + C group: received DOCA and MK422. After 4 weeks, the rats were sacrificed to sample their blood and remove their adrenal glands. There was no significant difference in adrenal B among the groups apart from the DOCA + C group. Adrenal aldosterone was lower in the groups of DOCA/salt hypertensive rats than in the Salt group and Salt + C group. Furthermore, the DOCA + A + C group and DOCA + C group had lower adrenal aldosterone levels than the DOCA group and DOCA + A group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Glands; Aldosterone; Angiotensin I; Animals; Blood Pressure; Body Weight; Corticosterone; Desoxycorticosterone; Hypertension; Male; Organ Size; Rats; Rats, Inbred Strains; Renin; Sodium Chloride

1. To learn how pulmonary vascular injury alters the ability of the lung to metabolize vasoactive autacoids, lung vascular lesions were produced in rats by a single subcutaneous injection of monocrotaline (90 mg kg-1), and the blood pressure responses to angiotensin I (AI), angiotensin II (AII), bradykinin, prostaglandin E2 (PGE2) and substance P were examined. Vasoactive agents were given intravenously or intra-arterially. 2. On histological examination of the lung at 3 weeks after monocrotaline treatment, degeneration or necrotization of endothelial cells was evident. 3. The conversion of AI to AII was only slightly depressed by monocrotaline treatment. On the other hand, the depressor response to intravenously injected bradykinin was enhanced in monocrotaline-treated rats. When the rats were pretreated with indomethacin the depressor response to intravenous bradykinin was the same for both control and monocrotaline-treated groups which suggests that endogenous prostaglandins are involved in the enhancement of the response to bradykinin. 4. In monocrotaline-treated rats the depressor response to intravenous PGE2 was significantly enhanced depending on the period following the treatment, while that to the intra-arterial injection did not differ from control. 5. The data suggest that monocrotaline-induced lung injury impairs the metabolism of PGE2 during pulmonary circulation but has little effect on the conversion of AI to AII and the degradation of bradykinin in rats.

Topics: Angiotensin I; Angiotensin II; Animals; Autacoids; Blood Pressure; Body Weight; Bradykinin; Dinoprostone; Injections, Subcutaneous; Lung; Lung Diseases; Male; Monocrotaline; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; Substance P; Time Factors

This study evaluated the effect of hyperoxia on the pharmacokinetic function of the lung. Hyperoxia is known to disrupt the activities of the pulmonary prostaglandin dehydrogenase/reductase and angiotensin converting enzymes. This would be predicted to alter the activation/deactivation of prostaglandins or angiotensin. The ability of these enzyme systems to act upon these compounds was evaluated by measuring the changes in the peripheral vascular responses to exogenous prostaglandin and angiotensin. Two groups of conscious, chronically catheterized rabbits, one exposed to ambient air and the other to greater than 98% oxygen, were given bolus injections of angiotensin I, angiotensin II, prostaglandin E2, sodium nitroprusside, and phenylephrine before and during up to 88 h of air or oxygen exposure. The hyperoxic animals' responsiveness to angiotensin I and angiotensin II decreased by 47% and 55%, respectively, after 72 h of oxygen exposure. The hyperoxic animals demonstrated a 54% increase in the vasodilatory response to arterial prostaglandin E2. Normoxic rabbits demonstrated no changes in response to any of the compounds tested. These data indicate that chronic hyperoxia influences either the synthesis/degradation and/or vascular receptors to both angiotensin I and II and prostaglandins.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Dinoprostone; Female; Heart Rate; Hemodynamics; Lung; Male; Nitroprusside; Organ Size; Oxygen; Prostaglandins E; Rabbits; Time Factors

Systemic and pulmonary vascular reactivity to graded doses of angiotensin I (ANG I), angiotensin II (ANG II), and, as a control, phenylephrine were examined in 14- or 28-day hypoxia-exposed and air control rats. Hypoxic rats exhibited pulmonary hypertension that was reversible on return to room air, but systemic arterial pressure was not altered by hypoxia. Systemic pressor responses to ANG I and ANG II were significantly less in the hypoxic rats than in the control rats at 14 and 28 days but returned to control levels in hypoxic animals that were then returned to room air, demonstrating reversibility of the hypoxia-induced changes in vascular reactivity. Pulmonary pressor responses to ANG I were significantly less at 14 days, whereas responses to ANG II were significantly greater at 28 days, in hypoxic rats than in controls. There were no significant differences in systemic and pulmonary pressor responses to phenylephrine between the hypoxic and air control animals. The altered systemic and pulmonary pressor responsiveness to ANG I and ANG II in hypoxic rats is probably related to mechanisms specific to the renin-angiotensin system, such as inhibition of intrapulmonary angiotensin-converting enzyme activity and down regulation of ANG II receptors in the systemic circulation. Further study is needed to elucidate these mechanisms.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Hypoxia; Male; Peptidyl-Dipeptidase A; Phenylephrine; Pulmonary Artery; Rats; Rats, Inbred Strains

This study examined the role of the renal nerves in both the maintenance and developmental phases of hypertension produced by sodium restriction in one-kidney rats. Results indicate that mild hypertension is sustained through 6 wk after unilateral nephrectomy in rats fed a sodium-deficient diet, with the greatest increase in systolic blood pressure occurring within the first 2 wk. Six weeks after nephrectomy, renal denervation was performed in the sodium-restricted, hypertensive rats, and the blood pressure returned to normotensive levels. Plasma renin activity (PRA) was elevated fourfold after 6 wk of sodium restriction and was unchanged by renal denervation. In another series of experiments that examined the development of hypertension in this experimental model, contralateral renal denervation was performed at the time of nephrectomy, and this prevented the subsequent development of hypertension. PRA was significantly attenuated in these low-sodium, renal-denervated rats that failed to become hypertensive when compared with PRA in hypertensive low-sodium, sham-denervated rats. Kidney norepinephrine content was reduced by 96% after renal denervation in both phases of the hypertension. These data demonstrate that intact renal nerves are necessary for both the development and maintenance of mild hypertension after sodium restriction in one-kidney rats. The pressor contribution of the renal nerves to the hypertension in this experimental model appears to be related, at least in part, to the activation of the renin-angiotensin pressor mechanism.

Topics: Angiotensin I; Animals; Body Weight; Denervation; Diet, Sodium-Restricted; Heart Rate; Hypertension, Renal; Kidney; Male; Nephrectomy; Norepinephrine; Potassium; Rats; Rats, Inbred Strains; Renin

The separate role of mineralocorticoid and glucocorticoid hormone action in maintaining arterial pressure was studied in normotensive rats. Four groups were prepared: adrenalectomized (ADX) rats given 6 micrograms aldosterone/24 h (ALDO; n = 9) or 10 micrograms dexamethasone/24 h (DEX; n = 9) by intraperitoneal Alzet pumps, shamoperated controls (control; n = 10) and ADX rats with no hormone replacement (ADX; n = 9). All groups were given 1% NaCl + 2.5% glucose drinking solution. Measurements of plasma corticosterone and aldosterone and urinary aldosterone excretion confirmed the adequacy of the experimental groups. Forty-eight hours after ADX or sham, base-line intra-arterial mean arterial pressure (MAP) in conscious undisturbed rats was similar in the four groups. Captopril (1 mg/kg iv) produced a similar reduction in MAP in ALDO (-11 +/- 2 mmHg) and DEX (-12 +/- 1 mmHg) groups, despite a lower plasma renin activity (PRA) in ALDO (2.0 +/- 0.7 and 6.0 +/- 1.5 ng X ml-1 X h-1, respectively; P less than 0.05). dP (Me)TyrAVP (50 micrograms/kg iv) caused a greater decrease in MAP in ALDO (-15 +/- 3 mmHg) than in DEX (-8 +/- 1 mmHg; P less than 0.05). Combined blockade with both antagonists resulted in a greater MAP reduction in ALDO (-29 +/- 4 mmHg) than in DEX (-15 +/- 4 mmHg; P less than 0.05). These results indicate that glucocorticoid hormone action maintains arterial pressure in ADX rats by mechanisms similar to normal rats and largely independent of the renin-angiotensin system and vasopressin. In contrast, mineralocorticoid replacement alone in ADX rats requires increased participation of both peptide systems for maintenance of arterial pressure.

Topics: Adrenalectomy; Aldosterone; Angiotensin I; Animals; Blood Pressure; Body Weight; Captopril; Corticosterone; Dexamethasone; Electrolytes; Male; Rats; Rats, Inbred Strains; Renin

We performed a longitudinal study for 20 weeks on spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR) to determine the relationship between peptide metabolism and the age-dependent increase in blood pressure. In both SHR and WKR, the plasma level of aminopeptidase A (AP-A) clearly showed an age-dependent decrease. The plasma level of aminopeptidase B paralleled that of AP-A in WKR, but such an age-dependency was not observed in SHR, thus showing a dissociation between the two aminopeptidases. With age in both strains, the level of angiotensin-converting enzyme tended to decrease, while that of kallikrein activity tended to increase. In addition to these findings, a multivariate study testing the relationship of blood pressure to these enzyme activities, as well as to plasma levels of angiotensin I and renin activity, suggested abnormalities in the networks of proteolytic enzymes and in the peptide metabolism surrounding the renin-angiotensin system in SHR. These abnormalities may play some important roles in pathophysiological mechanisms of hypertension in SHR.

Topics: Aging; Aminopeptidases; Angiotensin I; Animals; Blood Pressure; Body Weight; Glutamyl Aminopeptidase; Hypertension; Male; Peptide Hydrolases; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin

Hyperoxia has been shown to disrupt certain membrane bound enzyme systems within the pulmonary endothelium which are responsible for the metabolism of several endogenous vasoactive compounds. This study was to evaluate whether the potential disruption of the prostaglandin dehydrogenase/reductase and angiotensin converting enzymes, as a consequence of hyperoxia, would alter the activation/deactivation of prostaglandins or the angiotensins (I and II) and thereby alter their peripheral cardiovascular actions. Two groups of anesthetized dogs, one group ventilated with ambient air and the other with 100% oxygen, were given bolus injections of angiotensin I, angiotensin II, prostaglandin E2, sodium nitroprusside, and phenylephrine before and during 8 h of exposure to air or oxygen. The hyperoxic animals demonstrated a significant increase in mean arterial pressure responsiveness to both angiotensin I and angiotensin II. The responsiveness to the drugs increased by 41% for angiotensin I and 43% for angiotensin II. The ambient air control dogs showed no significant changes for any compounds tested. These data indicate that with 8 h of hyperoxia the renin-angiotensin system's ability to influence cardiovascular function is augmented, whereas, the hemodynamic effects of prostaglandins are unaltered.

Topics: Angiotensin I; Angiotensin II; Angiotensins; Animals; Blood Pressure; Body Weight; Dinoprostone; Dogs; Female; Heart Rate; Hemodynamics; Hyperbaric Oxygenation; Male; Organ Size; Prostaglandins E; Regional Blood Flow; Renin-Angiotensin System; Vascular Resistance

Acute administration of the angiotensin I converting enzyme inhibitor, captopril (2 X 10(-4) M), was shown in an earlier study to attenuate the contractile responses of aortic rings of rats to alpha-adrenergic agonists in vitro. The objective of the present study was to determine the effect of chronic treatment with captopril on reactivity of aortic rings from both normotensive and renal hypertensive rats when captopril was no longer present. Four groups of rats were used: (1) normotensive, untreated; (2) normotensive, captopril-treated (48 mg/kg b.w. per day for five weeks); (3) hypertensive (bilateral renal encapsulation for five weeks), untreated and (4) hypertensive, captopril-treated. Renal encapsulation was associated with a significant increase in systolic blood pressure, which was prevented by concomitant treatment with captopril. At the end of the five weeks treatment aortic rings, 4 mm in length, were washed for 2 h to remove the captopril, following which contractile responses to various vasoactive agents were studied in vitro. Chronic treatment with captopril attenuated significantly contractile responses to both norepinephrine (10(-9) to 10(-5) M) and phenylephrine (10(-8) to 10(-4) M) but had no effect on isoproterenol-induced relaxation of KCl-depolarized tissue in the presence of 10(-5) M phentolamine. Contractile responses to angiotension I (10(-10) to 10(-7) M) did not differ statistically among the four groups. Following addition of captopril (2 X 10(-4) m) to the bath for 30 min, contractile responses to angiotensin I were attenuated in all four groups of rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Agonists; Angiotensin I; Angiotensin II; Animals; Aorta, Thoracic; Body Weight; Captopril; Female; Hypertension, Renal; Isoproterenol; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Organ Size; Phenylephrine; Potassium Chloride; Proline; Rats; Rats, Inbred Strains

The object of this study was to determine if chronic thoracic vena caval constriction affected mechanisms regulating water balance, independent of known changes in sodium metabolism in the dog. Fluid and electrolyte balances were determined for 5 days before and 14 days after constriction of the vena cava (n = 5) and in a separate population of time controls (n = 4). Cardiac output was reduced and heart rate was increased in response to chronic caval constriction although blood pressure was maintained at control levels. Water intake and plasma arginine vasopressin (AVP) increased from 31 +/- 4 ml/kg and 1.3 +/- 0.2 pg/ml during the control period to 81 +/- 6 ml/kg and 3.4 +/- 0.6 pg/ml during the period of caval constriction. The caval dogs developed a positive water balance, which preceded the development of a positive sodium balance. This led to a significant fall in plasma osmolality from a control mean of 296 +/- 1 to 284 +/- 4 mosmol/kg during caval constriction and dilutional hyponatremia. Plasma and blood volume increased significantly in response to constriction and were accompanied by formation of 123 +/- 10 ml/kg of ascitic fluid. These results show that water intake and plasma levels of AVP were increased in spite of a fall in plasma osmolality and an increase in vascular volume. These responses cannot be secondary to sodium retention because water was retained in excess of sodium hence hyponatremia. Therefore, chronic caval constriction causes a profound primary disturbance in mechanisms regulating water balance, which may contribute to the formation of edema fluid.

Topics: Adrenocorticotropic Hormone; Aldosterone; Angiotensin I; Animals; Arginine Vasopressin; Blood Pressure; Body Weight; Cardiac Output; Dogs; Drinking; Female; Male; Potassium; Sodium; Vena Cava, Superior; Water-Electrolyte Balance

Topics: 3-Mercaptopropionic Acid; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Catecholamines; Hypertension; Male; Rats; Sulfhydryl Compounds; Thiazoles; Thiazolidines

Topics: Angiotensin I; Animals; Blood Pressure; Body Weight; Bradykinin; Captopril; Drinking; Female; Hypertension, Renal; Organ Size; Proline; Rats

Changes in angiotensin-converting enzyme were measured in the lungs of fetal rabbits isolated and perfused in situ at varying ages from 22 days gestation to 7 days of age under controlled conditions of flow, pH, and temperature. Enzyme activity was assessed by infusing bradykinin or angiotensin I in Krebs-Henseleit solution and measuring residual peptide in the effluent by radioimmunoassay. The levels of substrate studied were below those required for enzyme saturation. Lungs of 22 day gestation fetuses removed only one-third of either peptide. The activity at term and in neonatal life resulted in more than 80% peptide removal. The time of the greatest rise in the percent substrate cleared occurs earlier than the time of the greatest increase in lung and body weight. The lower percentage of substrate cleared in early gestation appears to result in part from a limited surface area for enzyme activity in the primitive fetal pulmonary microvascular bed, since morphological studies with fluorescein-tagged anticonverting enzyme antibody demonstrated the presence of enzyme in the lung as early as 17 days of gestation. Electron micrographs of the pulmonary endothelial cell surface reveal that the degree of surface infolding and hence surface area increases with gestation. The higher percentage of substrate cleared in later gestation closely parallels the structural and ultrastructural development of the vascular bed. The presence of converting enzyme in the placenta by the second third of gestation and the large size of the placenta suggest that this organ may be a major locus of converting enzyme activity in the fetus.

Topics: Angiotensin I; Animals; Body Weight; Bradykinin; Endothelium; Female; Fetus; Gestational Age; Lung; Microcirculation; Peptidyl-Dipeptidase A; Perfusion; Placenta; Pregnancy; Rabbits