angiotensin-i and Hypertension--Renal

The role of the renin-angiotensin system in the pathogenesis of one-clip, two-kidney hypertension has been studied in man, dog and rat. Particular attention has been paid to peripheral plasma concentrations of angiotensin II in different circumstances; angiotensin II infusion has been combined with radioimmunoassay to construct angiotensin II/blood pressure dose-response curves. The effect of converting enzyme inhibitors has been studied, precautions being taken to avoid obtaining falsely high values for plasma angiotensin II because of cross-reaction with angiotensin I in these circumstances. The initial phase of one-clip, two-kidney hypertension is attributable to the direct pressor effect of the immediate rise in plasma angiotensin II. Subsequently, plasma angiotensin II is relatively lower, although blood pressure remains high. This upward resetting of the plasma angiotensin II/blood pressure relationship can be mimicked by infusing angiotensin II chronically at low dose. After reconstruction of a stenosed renal artery, or excision of a post-stenotic kidney, the angiotensin II/blood pressure relationship returns slowly to normal. In this second phase of one-clip, two-kidney hypertension, the long-term administration of saralasin, or of converting enzyme inhibitor, can also return arterial pressure to normal; brief administration of these drugs is less effective or ineffective. The results are compatible with, although they do not conclusively establish, an important slow pressor action of the renin-angiotensin system in the second phase of one-clip, two-kidney hypertension. This provides a rational basis for the use of captopril clinically in this condition.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Dogs; Female; Furosemide; Humans; Hypertension, Renal; Male; Middle Aged; Potassium; Proline; Radioimmunoassay; Rats; Renal Artery Obstruction; Renin; Saralasin; Sodium

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding, Competitive; Blood Pressure; Chemical Phenomena; Chemistry; Humans; Hypertension; Hypertension, Renal; Peptidyl-Dipeptidase A; Renin; Sodium

Topics: Adenoma; Adrenal Cortex Neoplasms; Aldosterone; Angiotensin I; Angiotensin II; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Kidney Neoplasms; Pregnancy; Pregnancy Complications, Cardiovascular; Renal Artery Obstruction; Renal Dialysis; Renin; Sodium

Studies implicate that angiotensin 1-7 (Ang1-7) imparts protective effects in the kidney. However, its relevance in hypertensive kidney disease is not fully understood. The purpose of this study was to explore the role of Ang1-7 on renal damage/remodeling during hypertension and its potential underlying molecular-cellular mechanisms.. Hypertension was induced in adult Sprague-Dawley rats by infusion of aldosterone (ALDO; 0.75 μg/hour) for 4 weeks with or without co-treatment of Ang1-7 (1 mg/kg/day). Untreated rats served as controls. Systolic blood pressure was monitored by tail-cuff technique. Renal fibrosis was evaluated by picrosirius red staining and renal collagen volume fraction was quantitated using imaging analyzing system. The expression of profibrotic factors [transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-D (PDGF-D), fibroblast growth factor-1 (FGF-1), vascular endothelial growth factor-D (VEGF-D), and tissue inhibitors of metalloproteinases (TIMPs)] and free radical producing enzymes (inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in the kidney were examined by reverse transcription-polymerase chain reaction and western blot. Renal oxidative stress was assessed by malondialdehyde (MDA) measurement.. Chronic ALDO infusion caused hypertension and hypertensive renal disease represented as glomerular damage/sclerosis. Ang1-7 co-treatment did not affect blood pressure in ALDO-treated rats, but significantly attenuated the glomerular damage/fibrosis. ALDO treatment significantly elevated renal expression of profibrogenic factors, including TGF-β1, TIMP-1/TIMP-2, FGF-1, PDGF-D, and VEGF-D, whereas Ang1-7 co-treatment significantly reduced renal TGF-β1, TIMP-1/TIMP-2, and FGF-1, but not PDGF-D and VEGF-D. Furthermore, ALDO infusion elevated NADPH oxidase (gp91phox) and MDA in the kidney, which was attenuated by Ang1-7 co-treatment.. Ang1-7 plays a protective role in the hypertensive kidney disease independent of blood pressure. The beneficial effects of Ang1-7 are likely mediated via suppressing TGF-β/FGF-1 pathways and oxidative stress.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Hypertension, Renal; Kidney; Lymphokines; Male; Nephritis; Oxidative Stress; Peptide Fragments; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; RNA; Tissue Inhibitor of Metalloproteinases; Vascular Endothelial Growth Factor D

Topics: Angiotensin I; Humans; Hypertension, Renal; Peptide Fragments; Sympathetic Nervous System

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Captopril; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Gene Expression Regulation; Hypertension, Renal; Kidney Cortex; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Random Allocation; Rats, Wistar; Renin; RNA, Messenger

Apolipoprotein E-deficient (apoE(-/-)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)-(1-7) treatment ameliorates endothelial dysfunction in apoE(-/-) mice. However, the mechanism of Ang-(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang-(1-7) function, we used apoE(-/-) and wild-type mice fed on Western diet that were treated via osmotic minipumps either with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(-/-) compared with wild-type mice. This apoE(-/-)-specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC(20)), causing renal vasoconstriction. Here, we provide evidence that chronic Ang-(1-7) treatment attenuated the renal pressor response to Ang II in apoE(-/-) mice to wild-type levels. Ang-(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogen-activated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogen-activated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(-/-) but not in apoE(-/-) mice treated with Ang-(1-7). Moreover, Ang-(1-7) treatment had no effect in Mas(-/-)/apoE(-/-) double-knockout mice confirming the specificity of Ang-(1-7) action through the Mas-receptor. In summary, Ang-(1-7) modulates vascular function via Mas-receptor activation that attenuates pressor response to Ang II in apoE(-/-) mice by reducing reactive oxygen species-mediated p38 mitogen-activated protein kinase activity.

Topics: Angiotensin I; Angiotensin II; Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Female; Hypertension, Renal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrazoles; Receptors, G-Protein-Coupled; Renal Circulation; Vascular Resistance

Angiotensin-(1-7) [ANG-(1-7)] plays a counterregulatory role to angiotensin II in the renin-angiotensin system. In trained spontaneous hypertensive rats, Mas expression and protein are upregulated in ventricular tissue. Therefore, we examined the role of ANG-(1-7) on cardiac hemodynamics, cardiac functions, and cardiac remodeling in trained two-kidney one-clip hypertensive (2K1C) rats. For this purpose, rats were divided into sedentary and trained groups. Each group consists of sham and 2K1C rats with and without ANG-(1-7) infusion. Swimming training was performed for 1 h/day, 5 days/wk for 4 wk following 1 wk of swimming training for acclimatization. 2K1C rats showed moderate hypertension and left ventricular hypertrophy without changing left ventricular function. Chronic infusion of ANG-(1-7) attenuated hypertension and cardiac hypertrophy only in trained 2K1C rats but not in sedentary 2K1C rats. Chronic ANG-(1-7) treatment significantly attenuated increases in myocyte diameter and cardiac fibrosis induced by hypertension in only trained 2K1C rats. The Mas receptor, ANG II type 2 receptor protein, and endothelial nitric oxide synthase phosphorylation in ventricles were upregulated in trained 2K1C rats. In conclusion, chronic infusion of ANG-(1-7) attenuates hypertension in trained 2K1C rats.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Heart Ventricles; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney; Male; Nitric Oxide Synthase Type III; Peptide Fragments; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Surgical Instruments; Swimming

High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT(1)R) vs. AT(2)-ACE2-angiotensinogen (Ang) (1-7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT(1A/B)R, ACE, AT(2)R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT(1B)R increased, renin decreased, and ACE2, AT(2)R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT(2)R, and MasR, and no changes in renin and AT(1)R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT(2)R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT(1)R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

Topics: Actins; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Chromatography, High Pressure Liquid; Hypertension, Renal; Kidney; Kidney Cortex; Male; Mass Spectrometry; Obesity; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Zucker; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin; Sodium, Dietary; Spectrometry, Mass, Electrospray Ionization

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

The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a backcross of the hypertensive (mRen2)27 transgenic rat with normotensive Lewis rats, provides a new model by which primary hypertension can be studied without the genetic variability found in the original strain. The purpose of this study was to characterize the Lew.Tg(mRen2) rats by dually investigating the effects of type 1 angiotensin II (ANG II) receptor (AT(1)) blockade and angiotensin-converting enzyme (ACE) activity inhibition on the ANG-(1-7)/ACE2 axis of the renin-angiotensin system in this new hypertensive model. The control of blood pressure elicited by 12-day administration of either lisinopril (mean difference change = 92 +/- 2, P < 0.05) or losartan (mean difference change = 69 +/- 2, P < 0.05) was associated with 54% and 33% increases in cardiac ACE2 mRNA and 54% and 43% increases in cardiac ACE mRNA, respectively. Lisinopril induced a 3.1-fold (P < 0.05) increase in renal cortical expression of ACE2, whereas losartan increased ACE2 mRNA 3.5-fold (P < 0.05). Both treatment regimens increased renal ACE mRNA 2.6-fold (P < 0.05). The two therapies augmented ACE2 protein activity, as well as increased cardiac and renal AT(1) receptor mRNAs. ACE inhibition reduced plasma ANG II levels (81%, P < 0.05) and increased plasma ANG-(1-7) (265%, P < 0.05), whereas losartan had no effect on the peptides. In contrast with what had been shown in normotensive rats, ACE inhibition decreased renal ANG II excretion and transiently decreased ANG-(1-7) excretion, whereas losartan treatment was associated with a consistent decrease in ANG-(1-7) urinary excretion rates. In response to the treatments, the expression of both renal cortical renin and angiotensinogen mRNAs was significantly augmented. The paradoxical effects of blockade of ANG II synthesis and activity on urinary excretion rates of the peptides and plasma angiotensins levels suggest that, in Lew.Tg(mRen2) congenic rats, a failure of compensatory ACE2 and ANG-(1-7)-dependent vasodepressor mechanisms may contribute both to the development and progression of hypertension driven by increased formation of endogenous ANG II.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Congenic; Animals, Genetically Modified; Crosses, Genetic; Hypertension, Renal; Kinetics; Lisinopril; Losartan; Male; Models, Genetic; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Renin; Renin-Angiotensin System; RNA, Messenger; Time Factors

Although angiotensin II (Ang II) is involved in the progression of renal diseases, infusion of Ang II was reported to surprisingly ameliorate the early phase of anti-Thy-1.1 nephritis. Considering the known proangiogenic effect of Ang II and that angiogenic glomerular capillary repair is required for the recovery of damaged glomeruli in rat anti-Thy-1.1 nephritis, we hypothesized that Ang II infusion starting prior to the initiation of nephritis may induce the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), resulting in the increased glomerular capillary area in the early phase.. Ang II was infused (170 ng/min) in rats, and 5 days later, nephritis was induced by the administration of monoclonal 1-22-3 antibodies. Ang II type 1 or type 2 receptor antagonist (AT(1)R or AT(2)R, respectively) (losartan or PD123319, respectively) was coadministered.. Ang II infusion affected on neither the deposition of Ig nor mesangiolysis in the initial phase, and resulted in the aggravation of creatinine clearance at day 14 and 35 after initiating anti-Thy-1.1 nephritis. Histologic alterations were ameliorated accompanied by reduced loss in rat endothelial cell antigen (RECA)-1(+) endothelial area in Ang II-infused nephritic rats on day 6 and 14 as compared to control nephritic group, and nephritic alterations were mostly resolved on day 35 in both groups. At the early stage (day 6), glomerular expression of VEGF and receptors flk-1 and flt-1 as well as Ang-1, and receptor Tie2 were increased, and glomerular monocyte infiltration and the expression of angiopoietin-2 (Ang-2), a natural antagonist of Ang-1, were reduced. Both Ang II receptors were involved in the regulation of angiogenic factors and receptors.. These results demonstrate that infusion of exogenous Ang II starting prior to the induction of nephritis activates VEGF and Ang-1 signaling regulated via both Ang II receptors, potentially leading to the accelerated recovery of injured glomerular endothelial cells in the early phase of anti-Thy-1.1 nephritis. Increased expression of VEGF and Ang-1 on podocytes further suggests the crucial association of endothelial cells and podocytes in maintaining proper glomerular capillary structures.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Capillaries; Glomerulonephritis; Hypertension, Renal; Immunohistochemistry; Isoantibodies; Kidney Glomerulus; Macrophages; Male; Monocytes; Neovascularization, Physiologic; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, TIE-2; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vasoconstrictor Agents

Angiotensin-converting enzyme (ACE)2, a homologue of ACE, which is insensitive to ACE inhibitors and forms angiotensin-(1-7) [Ang-(1-7)] from angiotensin II (Ang II) with high efficiency was investigated in response to chronic blockade with lisinopril, losartan, and both drugs combined.. Thirty-six adult Lewis rats were assigned to receive these medications in their drinking water for 2 weeks while their arterial pressure, water intake, and urine volume were recorded throughout the study. Measures of renal excretory variables included assessing excretion rates of angiotensin I (Ang I), Ang II and Ang-(1-7) while blood collected at the completion of the study was used for measures of plasma angiotensin concentrations. Samples from renal cortex were assayed for renin, angiotensinogen (Aogen), neprilysin, angiotensin types 1 and 2 (AT(1) and AT(2)) and mas receptor mRNAs by semiquantitative reverse transcriptase (RT) real-time polymerase chain reaction (PCR). ACE2 activity was determined as the rate of Ang II conversion into Ang-(1-7).. Comparable blood pressure reductions were obtained in rats medicated with either lisinopril or losartan, whereas both drugs produced a greater decrease in arterial pressure. Polyuria was recorded in all three forms of treatment associated with reduced osmolality but no changes in creatinine excretion. Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1-7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1-7) but increased plasma Ang II without changing urinary Ang II excretion. Combination therapy mimicked the effects obtained with lisinopril on plasma and urinary Ang I and Ang-(1-7) levels. Renal cortex Aogen mRNA increased in rats medicated with either lisinopril or the combination, whereas all three treatments produced a robust increase in renal renin mRNA. In contrast, ACE, ACE2, neprilysin, AT(1), and mas receptor mRNAs remained unchanged with all three treatments. Renal cortex ACE2 activity was significantly augmented in rats medicated with lisinopril or losartan but not changed in those given the combination.. Our data revealed a role for ACE2 in Ang-(1-7) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. The data further indicate that increased levels of Ang-(1-7) in the urine of animals after ACE inhibition or AT(1) receptor blockade reflect an intrarenal formation of the heptapeptide.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Carboxypeptidases; Gene Expression Regulation, Enzymologic; Hypertension, Renal; Kidney; Lisinopril; Losartan; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Receptors, Angiotensin; Renin-Angiotensin System

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

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

It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)-evoked release of NO and prostacyclin.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Epoprostenol; Fibrinolytic Agents; Hypertension, Renal; Imidazoles; Infusions, Intravenous; Losartan; Male; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Pyridines; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Venous Thrombosis

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.

Topics: Angiotensin I; Angiotensin II; Animals; Chronic Disease; Chymases; Cilazapril; Dogs; Hemodynamics; Hypertension, Renal; Imidazoles; Ischemia; Kidney; Male; Oligopeptides; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Renal Circulation; Renin-Angiotensin System; Serine Endopeptidases; Tetrazoles

Three children with renal hypertension are described. Two had histories of neuroblastoma treated by surgical resection and chemotherapy. They both presented later with unilateral atrophic kidney and marked hypertension. Only the child with severe cardiac failure demonstrated high plasma brain natriuretic peptide (BNP) concentrations. The remaining patient had a history of chronic nephritis treated with continuous ambulatory peritoneal dialysis. She also had chronic hypertension and severe cardiac failure. This child demonstrated high plasma BNP levels. The endogenous secretion of BNP is not triggered by hypertension alone, even though exogenous BNP has the pharmacological effect of reducing renin activity.

Topics: Adolescent; Angiotensin I; Angiotensin II; Atrophy; Blood Pressure; Child; Child, Preschool; Female; Heart Failure; Humans; Hypertension, Renal; Kidney; Male; Natriuretic Peptide, Brain; Neuroblastoma; Renin; Ventricular Function, Left

-This study was designed to investigate distribution and regulation of the renal AT1A and AT2 subtype receptors in rats with either systemic angiotensin II (Ang II)-induced hypertension or acute phase renal hypertension (2-kidney, 1-clip [2K1C] or 2-kidney, 1-figure-of-8-wrap [2K1W]). In normal rat kidneys, positive immunostaining for the AT1A receptor was observed in the intrarenal vasculature, glomeruli, proximal and distal tubules, and collecting ducts. The AT2 receptor was localized mainly to the glomeruli. The AT1A but not AT2 receptor protein expression was significantly reduced in rats with 10-day systemic Ang II-induced hypertension. In both 7-day 2K1C and 3-day 2K1W rats, the AT1A receptor was significantly reduced in ischemic and contralateral kidneys compared with sham-operated control rats. Reduction in AT2 receptor expression was observed only in the ischemic kidneys in 2K1C and 2K1W renal hypertensive rats. These results demonstrate that the AT1A receptor is widely distributed in the glomerulus and all other nephron segments of the rat kidney. Renal AT1A but not AT2 receptor protein is downregulated in rats with Ang II-induced hypertension. In renal hypertensive rats, the AT1A receptor is bilaterally downregulated and the AT2 receptor is downregulated only in the ischemic kidney.

Topics: Acute Disease; Angiotensin I; Angiotensin II; Animals; Blotting, Western; Down-Regulation; Female; Gene Expression Regulation; Hypertension; Hypertension, Renal; Immunohistochemistry; Kidney; Kidney Glomerulus; Kidney Tubules; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin

The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo. KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 >10 microM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 noncompetitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20-85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg(-1)) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1-74 mg kg(-1)). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (>24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg(-1), respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (>8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2 h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mm Hg, 1.04 and 7.96 mg kg(-1), respectively). These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Aorta; Dogs; Furosemide; Hypertension, Renal; Imidazoles; Losartan; Male; Oligopeptides; Pressoreceptors; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Recombinant Proteins; Tetrazoles; Vasoconstriction

We tested the hypothesis that changes in angiotensin-converting enzyme (ACE) gene expression can regulate the rate of local vascular angiotensin II (Ang II) production. We perfused isolated rat hindlimbs with an artificial medium and infused renin and Ang I via the perfusate. Ang I and II were measured by radioimmunoassay. We then increased ACE gene expression and ACE levels in the rat aorta by producing two-kidney, one clip (2K1C) hypertension for 4 weeks. Gene expression was measured by RNAse protection assay, and ACE activity in the vessel wall was measured by the Cushman-Cheung assay. Angiotensin I infusion at 1, 10, 100, and 1000 pmol/mL led to 371 +/- 14 (+/-SEM), 3611 +/- 202, 44,828 +/- 1425, and 431,503 +/- 16,439 fmol/mL Ang II released, respectively, from the hindlimbs (r = .98, P < .001). Thus, the conversion rate did not change across four orders of magnitude, and the system was not saturable under these conditions. In 2K1C hindlimbs, Ang I infusion (0.5 pmol/mL) resulted in increased Ang II generation (157 +/- 16 versus 123 +/- 23 fmol/mL, P = .014 at minute 10) compared with controls. ACE gene expression and ACE activity were increased in 2K1C hindlimbs compared with controls (36 +/- 4 versus 17 +/- 1 mU/mg protein, P < .001). Ang II degradation in the two groups did not differ. To investigate the conversion of locally generated Ang I, we infused porcine renin (0.5 milliunits per mL) into 2K1C and control hindlimbs. Despite markedly higher Ang I release in sham-operated than in 2K1C rats (71 +/- 8 versus 37 +/- 6 pmol/mL, P = .008 at minute 12), Ang II was only moderately increased (36 +/- 3 versus 25 +/- 6 pmol/mL, P = .12 at minute 12). This difference between 2K1C rats and controls reflected a higher rate of conversion in 2K1C rats. Thus, Ang I conversion in the rat hindlimb is linear over a wide range of substrate concentrations and occurs at a fixed relationship. Nevertheless, increased ACE gene expression and ACE activity in the vessel wall lead to an increase in the conversion of Ang I to Ang II. We conclude that local ACE gene expression and ACE activity can influence the local rate of Ang II production.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Gene Expression; Hindlimb; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Perfusion; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

The antihypertensive effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl¿ valine, CAS 137862-53-4, CGP 48933), an angiotensin II type 1 receptor antagonist, were examined in hypertensive rats and dogs. In normotensive rats and deoxycorticosterone acetate (DOCA)/salt hypertensive rats, valsartan had no effect on blood pressure. Single oral administrations of valsartan at doses of 3-30 mg/kg reduced blood pressure dose-dependently in renal (2 kidney 1 clip, 2K1C) hypertensive and spontaneously hypertensive rats (SHR). Repeated oral administrations of valsartan to these hypertensive rats controlled blood pressure throughout a treatment period of 4 weeks, and showed no rebound phenomenon following drug withdrawal. This drug at 30 mg/kg p.o. decreased blood pressure in renal (2K1C) hypertensive dogs by single and repeated administrations. The extent and duration of the hypotensive action of valsartan were similar to those of enalapril. Valsartan would thus appear as useful as enalapril.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Dogs; Enalapril; Heart Rate; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Valine; Valsartan

To compare the effects of an angiotensin-converting enzyme inhibitor on circulating and tissue renin-angiotensin system, we measured different renin-angiotensin system parameters during the first day of treatment (Day 1) as well as after two weeks of treatment (Day 14). Ramipril was given orally once daily to adult male spontaneously hypertensive rats. Renin activity, angiotensin-converting enzyme activity and levels of angiotensin I and angiotensin II in the plasma, renal cortex and renal medullar were assessed at Day 1 and Day 14 of the treatment. In the plasma, both renin activity and angiotensin I increased 10 to 15 fold one to four hours after acute as well as at Day 14 of ramipril treatment and then returned to basal values within 24 hours. Plasma angiotensin II levels were not significantly decreased at Day 1 or Day 14. The decrease in the angiotensin II/angiotensin I ratio suggested a sustained inhibition of plasma angiotensin-converting enzyme at Day 14. In the renal cortex and medulla, a clearly different pattern was observed: in ramipril treated rats, renin activity in the renal cortex and medulla did not change at Day 1 but at Day 14 we observed a slight and sustained increase in renin activity. Despite very high basal levels of renin activity, angiotensin I levels in the renal cortex were comparable to those in the plasma. The angiotensin I level increased only one-fold one hour after ramipril intake at Day 1 and Day 14. This suggests that angiotensinogen may have a limiting role in the synthesis of angiotensin I in the kidney. Angiotensin II levels were slightly higher in the renal cortex and medulla than in the plasma suggesting local synthesis of the peptide. In the kidney, angiotensin II levels decreased one and four hours after the acute or prolonged ramipril treatment and the angiotensin II/angiotensin I ratio was reduced at the same time. Our results show that the responses of the plasma and kidney components of the renin-angiotensin system to angiotensin-converting enzyme inhibition are different in the plasma and the kidney suggesting that the circulating and tissue renin-angiotensin system are at least in part independent.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dose-Response Relationship, Drug; Hypertension, Renal; In Vitro Techniques; Kidney; Male; Ramipril; Rats; Rats, Inbred SHR; Renin; Time Factors

Previous studies have shown that uninephrectomized rats infused chronically with low doses of angiotensin II (Ang II) develop progressive hypertension that is prevented by coadministration of losartan in the drinking water. The present study was performed to contrast the effects of chronic and acute losartan treatment in reversing the Ang II-mediated actions on arterial pressure and renal function. Ang II was infused subcutaneously via osmotic minipumps (40 ng/min) for 13 days in two groups (N = 10 and N = 6); one group also received losartan in the drinking water (30 mg/kg.day) throughout this period. Untreated rats (N = 6) and rats (N = 6) receiving only losartan served as control groups. Ang II-infused rats had higher mean arterial pressures (153 +/- 7 versus 107 +/- 3 mm Hg) and lower GFR (0.7 +/- 0.04 versus 0.98 +/- 0.06 mL/min.g) than Ang II-infused rats receiving losartan chronically. The Ang II-infused rats responded to acute doses of losartan (10 mg/kg) with progressive reductions in arterial pressure and significant increases in cortical blood flow (34 +/- 12% increase), renal plasma flow, GFR, and sodium excretion; however, the increases in renal blood flow and GFR were not sustained as systemic arterial pressure decreased. Because Ang II-infused rats receiving losartan chronically still exhibited decreases in RBF in response to a bolus dose of Ang II, further studies evaluated the effects of acute losartan treatment in rats treated chronically with losartan. Although arterial pressure decreased only slightly, demonstrating adequate systemic vascular blockade, there were still substantial and sustained increases in renal plasma flow, cortical blood flow (20 +/- 4% increase), GFR, and sodium excretion. In summary, the modest responses to acute losartan in Ang II-infused rats indicate that chronic Ang II infusions lead to alterations in renal function that are only partially reversible by acute losartan treatment. In contrast, chronic treatment with losartan prevents the Ang II-induced decrease in GFR. The renal responses to acute losartan in the Ang II-infused rats treated chronically with losartan suggest that substantive intrarenal actions of Ang II can be maintained even when the systemic vascular AT1 receptors are effectively blocked.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Glomerular Filtration Rate; Hypertension, Renal; Losartan; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.

Topics: Administration, Oral; Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Enalapril; Enzyme Activation; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Artery; Surgical Instruments; Tetrazoles; Vasoconstrictor Agents

To assess in conscious two-kidney, one clip renal hypertensive rats whether angiotensin converting enzyme (ACE) inhibition with lisinopril, angiotensin II receptor blockade with losartan or vasodilation with sodium nitroprusside have similar effects on intra-arterial mean blood pressure, heart rate and splanchnic nerve activity.. A bolus dose of lisinopril or losartan (both 10 mg/kg, intravenously) induced within 2 h an equal reduction in mean blood pressure, whereas sodium nitroprusside infused during the same period (at 10 micrograms/min) lowered mean blood pressure, but less strongly. The heart rate was accelerated significantly more during sodium nitroprusside infusion than during lisinopril or losartan treatment. Splanchnic nerve activity increased significantly only in those rats given sodium nitroprusside. No change in the parameters studied was observed in vehicle-treated rats. The doses of lisinopril and losartan were repeated after 12 and 24 h. Before administration of the last dose, the mean blood pressure was still low. Administration of lisinopril or losartan again 24 h after the initial dose had no further effect on the mean blood pressure, heart rate or splanchnic nerve activity.. These results obtained in rats with a renin-dependent form of hypertension show that blockade of the renin-angiotensin system for 24 h produces an equivalent blood pressure reduction irrespective of whether it is due to ACE inhibition or angiotensin II antagonism. The results also indicate that there is less reflex activation of sympathetic nerve activity when blood pressure is lowered with a blocker of the renin-angiotensin system rather than with a direct vasodilator such as sodium nitroprusside.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Heart Rate; Hypertension, Renal; Imidazoles; Lisinopril; Losartan; Male; Nitroprusside; Rats; Rats, Wistar; Renin-Angiotensin System; Splanchnic Nerves; Sympathetic Nervous System; Tetrazoles

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9, 46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Angiotensin I; Animals; Aspartic Acid Endopeptidases; Blood Pressure; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; Hypertension; Hypertension, Renal; Male; Metalloendopeptidases; Molecular Sequence Data; Neprilysin; Peptides, Cyclic; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Topics: Angiotensin I; Angiotensin II; Animals; Captopril; Chromatography, High Pressure Liquid; Diet, Sodium-Restricted; Hypertension, Renal; Male; Nephrectomy; Rats; Rats, Inbred Strains; Renin; Time Factors

The possible role of the vascular angiotensin converting enzyme (ACE) in the development of two-kidney, one clip (2-K, 1C) hypertensive dogs was studied in different blood vessels. Vascular ACE activity per mg protein differed in a variety of blood vessels; the activity appeared to vary inversely with the outer diameter of arteries. The systemic blood pressure in mongrel dogs increased after partial occlusion of the left renal artery, and the hypertension lasted for 8 months. Plasma renin activity (PRA) was raised only for the first 4 weeks after the operation and then returned to the original level in the chronic stage of hypertension. Plasma ACE activity did not alter during the experimental period. In contrast, ACE activities in the jejunal, pulmonary and renal arteries, aorta, lung and cerebral cortex, significantly increased in the chronic hypertensive stage (8 months after occlusion). The production of angiotensin II (ANG II) from ANG I was significantly greater in isolated arteries from 8-month hypertensive dogs than in those from normotensive dogs when assessed by the contractile responses to ANG I and ANG II. These results indicate that acceleration by increased vascular ACE activity of the production of ANG II in the vascular wall may contribute to the maintenance of hypertension in the chronic stage of 2-K, 1C hypertensive dogs having normal PRA and plasma ACE activity.

Topics: 3-Mercaptopropionic Acid; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Dogs; Dose-Response Relationship, Drug; Hypertension, Renal; Male; Muscle Contraction; Peptidyl-Dipeptidase A; Renin; Thiazolidines

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.

Topics: 3-Mercaptopropionic Acid; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Dogs; Female; Hypertension, Renal; Male; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Sulfhydryl Compounds; Thiazolidines

We have investigated the relationship between the acute blood pressure lowering effect of captopril and renin status. Differences in renin status were induced by unilateral artery clipping combined with unilateral or bilateral nephrectomy in rats. The blood pressure lowering effect of captopril correlated very closely with plasma or aortic renin across a very wide range of renin levels.

Topics: Anesthesia; Angiotensin I; Angiotensin II; Animals; Aorta, Thoracic; Blood Pressure; Captopril; Hypertension; Hypertension, Renal; Kidney Cortex; Male; Nephrectomy; Rats; Rats, Inbred Strains; Renal Artery; Renin; Renin-Angiotensin System; Urethane

The possible role of vascular angiotensin converting enzyme (ACE) is examined in vitro and in vivo. In helically cut strips of arteries isolated from dogs, contractions induced by angiotensin (ANG) I are suppressed by ACE inhibitor or ANG II antagonist. This indicates that vascular ACE contributes to the local formation of ANG II. In two-kidney, one-clip hypertensive rats, plasma-renin activity (PRA) rises rapidly with the elevation of blood pressure, then decreases gradually, despite sustained high blood pressure. Renin activity in the aorta also increases with the development of hypertension and then decreases in parallel with PRA. ACE activity in plasma does not change before or after the unilateral occlusion of the renal artery until after 16 weeks, whereas the enzyme activity in the aorta significantly increases. The conversion rate calculated from the pressor responses, and from the constricting effects of ANG I and ANG II, both in situ and in helically cut strips obtained from chronic hypertensive rats with increased vascular ACE activities, are significantly higher than those obtained from normotensive rats. Vascular ACE, which can effectively produce ANG II from ANG I locally, appears to play an important role in the maintenance of chronic hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Arteries; Blood Pressure; Hypertension, Renal; Peptidyl-Dipeptidase A; Rats

A patient with secondary (sporadic type) hypokalemic periodic paralysis with relative hypertension had reninism with a high concentration of plasma angiotensin I (ANG-I) but no hyperaldosteronism or high angiotensin II value. Angiotensin-converting enzyme (ACE) activity was usually normal. Results of other hormonal analyses were also normal. However, the glomerular filtration rate and filtration fraction of the kidneys were greatly elevated. Despite severe hypokalemia, the patient's potassium clearance was high. No evidence of distinct hyperplasia of the juxtaglomerular cells was obtained. These results suggest that decreased affinity of ACE to the substrate ANG-I (so-called ACE dysfunction syndrome) produced the reninism and high concentration of plasma ANG-I, and that the latter induced an increase in the glomerular filtration rate of the kidneys with sequential occurrence of secondary hypokalemic periodic paralysis.

Topics: Adolescent; Angiotensin I; Angiotensin II; Glomerular Filtration Rate; Humans; Hypertension, Renal; Hypokalemia; Male; Paralyses, Familial Periodic; Peptidyl-Dipeptidase A; Renin

Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Dose-Response Relationship, Drug; Hypertension, Renal; Indoles; Male; Oligopeptides; Perindopril; Pressoreceptors; Rats; Rats, Inbred Strains; Teprotide

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

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

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Bradykinin; Brain Ischemia; Carboxypeptidases; Dose-Response Relationship, Drug; Hypertension, Renal; Hypertension, Renovascular; Lung; Lysine Carboxypeptidase; Peptidyl-Dipeptidase A; Rabbits

The angiotensin converting-enzyme inhibitor captopril was used as long-term preoperative treatment in a series of hypertensive patients with unilateral renal arterial disease. There were immediate and sustained falls in plasma angiotensin II and aldosterone concentrations, with converse increases in circulating renin and angiotensin I. In patients with sodium and potassium deficiency and secondary aldosterone excess before treatment captopril corrected the sodium and potassium deficits; in these cases the initial hypotensive response was profound but the later effect was less pronounced. When sodium and potassium state was initially normal it remained unchanged during captopril treatment, while the full hypotensive effect took up to three weeks to be attained. The immediate, but not long-term, falls in arterial pressure with captopril were proportional to the immediate decrements of plasma angiotensin II. Nevertheless, while the immediate blood-pressure reduction with captopril variously overestimated and underestimated the eventual surgical response, the absolute blood-pressure values during long-term captopril related well with those after operation. Pretreatment plasma renin and angiotensin II concentrations, while closely predicting the immediate captopril response, are fallible guides to surgical prognosis. In contrast, long-term treatment with converting-enzyme inhibitors may provide an accurate indication of surgical outcome.

Topics: Adolescent; Adult; Aldosterone; Angiotensin I; Angiotensin II; Captopril; Female; Humans; Hypertension, Renal; Hypertension, Renovascular; Kidney; Male; Middle Aged; Preoperative Care; Prognosis; Proline; Renin

The spontaneous variations in renal vein renin activity (RVRA) and in peripheral vein renin activity (PVRA) were studied in one normotensive and nine hypertensive patients. Eight of the hypertensive patients had renal artery stenosis on one or both sides. Blood samples were drawn simultaneously from the two renal veins and from a peripheral vein every fifth or tenth minute for one hour. Plasma renin activity (PRA) was measured by radioimmunoassay. The precision of the PRA assay, expressed as coefficient of variation, was related to the PRA level. A large intra-individual variations was found in RVRA, the RVRA ratio and PVRA even in patients with unilateral renovascular hypertension. The intra-individual variation could not be explained by specimen collection error or by error of the assay procedure. The variation seems to be reflect a biological fluctuation. The clinical implication of these findings is that repeated, simultaneous collection from the two renal veins, avoidance of factors known to decrease renin secretion. and consideration of the relation between the RVRA ratio and RVRA level are of importance in the preoperative evaluation of patients with renal artery stenosis.

Topics: Adult; Angiotensin I; False Positive Reactions; Female; Humans; Hypertension, Renal; Hypertension, Renovascular; Male; Methods; Middle Aged; Renal Artery Obstruction; Renal Veins; Renin

Topics: Administration, Oral; Adult; Aldosterone; Angiotensin I; Angiotensin II; Captopril; Diagnosis, Differential; Female; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Middle Aged; Proline; Renin

Changes induced by i.v. and subcutaneous teprotide in plasma renin, angiotensin I, angiotensin II, aldosterone and bradykinin were studied in a renal transplant patient with severe high renin hypertension, before and after trinephrectomy. The immediate reduction in BP produced by teprotide was not solely attributable to the inhibition of conversion of angiotensin I to angiotensin II, because there was also a transient increase in serum bradykinin; however, the prolonged antihypertensive effect of teprotide appeared independent of bradykinin. After trinephrectomy, teprotide lowered systolic BP but had no significant effect on diastolic BP or plasma bradykinin. beta-Blockade prevented the secondary increase in plasma renin which followed teprotide, thereby potentiating its anti-hypertensive effect.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Female; Humans; Hypertension, Renal; Kidney Transplantation; Oligopeptides; Radioimmunoassay; Renin; Teprotide

The exact mechanism of action of angiotensin converting enzyme (ACE) inhibitors in reducing blood pressure is not known, although inhibition of angiotensin II formation is the generally accepted mechanism. Experiments were performed in two models of experimental hypertension to determine whether or not inhibition of the pressor response to angiotensin I, 300 ng/kg i.v., would correlate with the antihypertensive response to single oral doses of N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-Ala-L-Pro (MK-421), a new ACE inhibitor. Captopril, given as a single oral dose, was studied in spontaneously hypertensive rats (SHR) for comparative purposes. In SHR, MK-421 at 0.1-3 mg/kg p.o. and captopril at 0.1-3 mg/kg p.o. were approximately equipotent with regard to inhibiting the pressor response to angiotensin I (relative potency=1.7; 95% C.I.=0.7-4.5). The magnitude of ACE inhibition and onset of action were similar with both agents, but MK-421 had a longer duration of action. The decrement in systolic pressure following each ACE inhibitor consisted of an initial decrease in blood pressure corresponding to the maximal inhibition of angiotensin I pressor response and a secondary fall in blood pressure which was evident 5-6 h after treatment. At this time, the inhibition of the pressor response to angiotensin I was minimal. Thus, the time course for blockade of angiotensin I and the blood pressure reduction did not correspond. The dose-response regression lines for the antihypertensive effect of each inhibitor, unlike those for ACE inhibition, were flat. The potency ratio computed on the basis of the maximum fall in blood pressure over 6 h revealed that MK-421 was 11.5 times (P less than 0.05) more potent thant captopril. In 2-kidney Grollman renal hypertensive rats (RHR), MK-421 at 0.3-10 mg/kg p.o. inhibited the pressor response to angiotensin I by 65-95%, but produced significant decrements in blood pressure only at 10 mg/kg p.o. The finding that MK-421 was more potent than captopril in lowering blood pressure in SHR, yet equally active in its ability to block angiotensin I pressor responses, suggests that a mechanism(s) other than inhibition of plasma ACE is involved in the decrease in blood pressure was not reduced. However, a higher dose which produced a similar degree of blockade was associated with a significant decrease in blood pressure.

Topics: Angiotensin I; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dipeptides; Enalapril; Hypertension; Hypertension, Renal; Oligopeptides; Proline; Rats; Rats, Inbred Strains; Teprotide

Topics: Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dipeptides; Disease Models, Animal; Dogs; Drug Therapy, Combination; Enalapril; Female; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Male; Nephrectomy; Rats; Renin

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

1. The effects of a single 25 mg oral dose of captopril on blood pressure, heart rate and circulating renin, angiotensin I, angiotensin II, bradykinin and catecholamine levels were examined in untreated patients with essential (n = 10, Group I), accelerated (n = 6, Group II) and renal hypertension (n = 8, Group III) studied on a normal sodium diet. 2. Mean blood pressure fell only slightly in Group I patients, (113 +/- 3 to 109 +/- 3 mmHg at 60 minutes) but a greater fall was observed in Group II (153 +/- 8 to 135 +/- 11 mmHg) and a marked fall in Group III, (136 +/- 3 to 114 +/- 5 mmHg). There were no significant changes in heart rate in any group. 3. Plasma angiotensin II levels were significantly reduced 30 minutes after captopril in all three groups and returned toward resting values after four hours. The falls in plasma angiotensin II levels were accompanied by reciprocal increases in blood angiotensin I and plasma renin, but blood bradykinin and plasma catecholamine concentrations remained unchanged. 4. Resting plasma renin levels showed considerable overlap in the three groups and the mean renin values were not significantly different in the three groups. After captopril a marked rise in plasma renin concentration (greater than 2.5 ng/ml/hr) was observed in seven patients in Group III, including all six patients with renovascular disease. In contrast, none of the patients with essential hypertension and only one patient with accelerated hypertension had such an increase. Determination of the acute renin and blood pressure responses to converting enzyme inhibition with a single oral dose of captopril appears to be useful in identifying patients with renovascular hypertension.

Topics: Adult; Aged; Angiotensin I; Angiotensin II; Blood Pressure; Captopril; Female; Heart Rate; Humans; Hypertension, Renal; Male; Middle Aged; Proline; Renin

During the induction phase of low-renin, one-kidney, one-wrapped hypertension in rabbits,serum angiotensin converting enzyme (ACE) activity is depressed and correlates inversely with the degree of necrotic arterial disease that develops. Responses to the vasoactive polypeptides, bradykinin (BK), angiotensin I (AI), angiotensin II (AII), the ACE blocker teprotide, and the AII antagonist 1-sar-8-ile AII were studied. Responses to BK, AII, and AI showed significant changes in both magnitude and duration (recovery time). Recovery time for depressor responses to BK in hypertensive rabbits was approximately three times that in the control period. One-wrapped, two-kidney control rabbits without hypertension-associated arterial disease showed no change in BK recovery time, although serum ACE activity was significantly depressed. In the experimental period BK recovery time correlated directly with the degree of arterial disease and indirectly with the final serum ACE activity. Duration of the pressor responses after AII correlated directly with the degree of arterial disease and indirectly with final serum ACE activity. In untreated hypertensive rabbits the percentage of increases in blood pressure after AI relative to control animals were decreased, and for all hypertensive rabbits' the increase in blood pressure correlated directly with the final serum ACE activity. Long-term treatment with teprotide moderated the hypertension but had little effect on serum ACE activity or the responses to BK, AII, and AI. Short-term infusions of 1-sar-8-ile AII and teprotide caused significant decreases in blood pressure in both the control and experimental periods, although no change in response to either polypeptide occurred. These studies support other evidence that pressor components of the renin-angiotensin system do not sustain the elevation of blood pressure in this form of experimental hypertension. Alterations in response patterns following AII and AI suggest that a vasodepressor system may be altered. In addition, part of the altered response to BK, and possibly AII, appears related to the development of the hypertension-associated arterial disease.

Topics: Angiotensin I; Angiotensin II; Angiotensins; Animals; Bradykinin; Disease Models, Animal; Hypertension, Renal; Hypertension, Renovascular; Male; Nephrectomy; Peptidyl-Dipeptidase A; Perinephritis; Rabbits; Renin

The effects of an angiotensin-II analog (saralasin, i.v.) and of a converting enzyme inhibitor (captopril, oral) were compared in 12 sodium-depleted patients with hypertension. The decrease of the mean intraarterial pressure (MAP) with captopril (-21.5 +/- [SEM] 4.3 mm Hg) was more pronounced (P < 0.001) than the change of MAP during saralasin (-10.5 +/- 4.0 mm Hg). The pretreatment arterial plasma renin activity (log PRA) was closely related to the change of MAP during saralasin (r = -0.94; P < 0.001) and also to the captopril-induced change of MAP (r = -0.82; P < 0.001); similar results were obtained for the log plasma angiotensin (PA) I and II levels. The change of MAP was more pronounced, however, with captopril than during saralasin at any level of pretreatment PRA, PAI or PAII. Saralasin did not affect heart rate (P > 0.4), but during captopril the heart rate increased by 5.1 beats/min (P < 0.001). Captopril produced a 70% decrease of PAII, but the change of MAP was poorly related to the changes of PAII (r = -0.57; P < 0.05); PRA and PAI rose threefold to fourfold. PRA, PAI, and PAII all increased during saralasin. These observations may suggest that the antihypertensive action of captopril is not based solely on the inhibition of AII formation, but also the agonistic effect of saralasin has to be considered.

Topics: Adult; Angiotensin I; Angiotensin II; Blood Pressure; Captopril; Female; Heart Rate; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Peptidyl-Dipeptidase A; Proline; Renin; Saralasin

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Binding, Competitive; Blood Pressure; Bradykinin; Captopril; Hydralazine; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Protease Inhibitors; Rabbits; Rats; Snake Venoms; Structure-Activity Relationship

Topics: Adult; Angiotensin I; Blood Specimen Collection; Female; Humans; Hydrogen-Ion Concentration; Hypertension, Renal; Hypertension, Renovascular; Male; Renal Veins; Renin; Vena Cava, Inferior

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Hypertension, Renal; Hypertension, Renovascular; Male; Peptidyl-Dipeptidase A; Rats; Time Factors

1 Prolonged infusion (11 h) of both saralasin and angiotensin-converting enzyme inhibitor (SQ20881) gradually lowered BP in two-kidney hypertensive rats to levels similar to that in normotensive rats infused with dextrose. 2 Saralasin did not lower BP in DOCA-salt hypertensive rats. 3 These observations support the notion that in chronic renal hypertension, angiotensin II may maintain hypertension by a slowly developing action. 4 Plasma angiotensin II in rats infused with SQ20881 was suppressed relative to renin, but was not eliminated. 5 Chromatography of angiotensin II extracts from dogs infused with converting enzyme inhibitor (SQ14,225) showed that the very high levels of angiotensin I achieved after treatment with SQ14,225 can lead to falsely high estimated angiotensin II levels as a result of angiotensin I cross-reacting with the angiotensin II assay.

Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dogs; Female; Hypertension, Renal; Male; Oligopeptides; Proline; Rats; Saralasin; Teprotide

Topics: Aldosterone; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Dogs; Female; Hypertension, Renal; Nephrectomy; Proline; Renin

1. Aorta homogenate contains renin-like activity which on incubation generates angiotensin I over a wide pH range. 2. Rat aortic renin measured at an incubation pH of 6.5 rose and fell in parallel to plasma renin with salt depletion and salt-loading respectively. Renin little relationship with plasma renin. 3. Aortic renin (pH 6.5) was elevated in Goldblatt-two kidney hypertension and slowly fell for 24h after bilateral nephrectomy whereas the fall in plasma renin was complete by the first hour. Aortic renin (pH 5.3) was also high, but did not fall after bilateral nephrectomy. 4. Aortic renin (pH 6.5) is probably derived from plasma renin whereas renin measured at pH 5.3 is probably a tissue renin. 5. The prolonged half-life of aortic renin (pH 6.5) explains the observation that the renin-angiotensin system appears to be active in maintaining blood pressure for several hours after bilateral nephrectomy whereas the decline in plasma renin is rapid and does not continue significantly beyond 1 h.

Topics: Angiotensin I; Animals; Aorta; Female; Hypertension, Renal; Hypertension, Renovascular; Nephrectomy; Rats; Renin

Topics: Angiotensin I; Computers; Free Radicals; Humans; Hypertension, Renal; Radioimmunoassay; Renin; Scintillation Counting

A modification of the infusion test with saralasin, an angiotensin II antagonist for the detection of renin-dependent high blood pressure was studied in renal hypertensive rats and in normotensive and hypertensive subjects. Infusion was started at a rate of 0.01 microgram/kg x min saralasin and the dose was increased ten-fold at 15 min intervals. A significant fall of diastolic blood pressure was observed at the dose of 0.1 microgram/kg x min in renal hypertensive rats, in healthy subjects treated with diuretics, and in patients with renovascular hypertension (saralasin responders). Plasma concentrations of angiotensin I, angiotensin II and of saralasin as well as plasma renin activity were measured. At the lowest infusion rate of 0.01 microgram/kg x min, saralasin plasma levels were 40-fold higher than plasma angiotensin II levels. The decrease in arterial blood pressure occurred at lower doses of saralasin than the increase of plasma renin due to inhibition of feedback on the renin secreting cells. It is concluded that if the saralasin test is performed by a stepwise increase of the infusion rate, potentially dangerous complications such as hypo- or hypertensive reactions can be avoided. The diagnostic reliability is improved by such a procedure since false positive and false negative responses may be prevented. The pressor effect of saralasin in non-renin dependent patients is an advantage since it causes a more marked difference of blood pressure change between saralasin responders and non-responders.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Chlorthalidone; Diet, Sodium-Restricted; Female; Humans; Hypertension, Renal; Kinetics; Male; Rats; Renin; Saralasin

The renin inhibitory activity of 2-[4-(4'-chlorophenoxy)phenoxyacetylamino]ethylphosphorylethanolamine (PE-104) was examined in vitro and in vivo. PE-104 inhibited the reaction between dog renal renin and homologous plasma angiotensinogen. The Ki value was 2 mM and the inhibitory mode was competitive and reversible. Data concerning the relationship between renin inhibitory activity and the chemical structure indicated that the whole structure was required for inhibitory activity of PE-104. PE-104 did not inhibit the caseinolytic activities of pepsin, papain and trypsin at 10 mM, the dose of which inhibited renin activity by more than 80%. In normotensive rats, infusion of PE-104 (20 mg/kg/min) abolished increases in blood pressure, plasma renin activity and plasma angiotensin I concentration after injection of renin. In two kidney model renal hypertensive rats, infusion of PE-104 resulted in decreases in blood pressure, plasma renin activity and plasma angiotensin I concentration.

Topics: Angiotensin I; Animals; Blood Pressure; Caseins; Dogs; Ethanolamines; Hypertension, Renal; In Vitro Techniques; Organophosphorus Compounds; Protease Inhibitors; Rats; Renin

Plasma renin reactivity (PRR) is the in vitro rate of angiotensin generation after addition of exogenous renin to plasma. The purpose of the present study is to compare measurements of PRR in venous effluent from the involved and uninvolved kidneys in both experimental and clinical renovascular hypertension. A two-kidney model of experimental hypertension was created by placing an ameroid resin constrictor around one renal artery in each of seven dogs. Plasma renin activity (PRA) in venous plasma from the involved kidney increased (p less than 0.001); comparing PRA in venous effluent from the stenotic and nonstenotic kidneys, the PRA ratio also increased ( p less than 0.005). Renal venous PRR did not change on either side after occlusion of the renal artery (p greater than 0.1), and the renal venous PRR ratio did not differ from the mean control ratio of 1.0 +/- 1 SE (p greater than 0.1). Similarly, in 9 patients with renovascular hypertension, mean PRR in venous plasma from the two kidneys did not differ (p greater than 0.8). These results suggest that measurement of renal venous PRR is not helpful in confirming a diagnosis of renovascular hypertension.

Topics: Angiotensin I; Animals; Dogs; Hypertension, Renal; Kidney; Renal Veins; Renin