Decrease In Plasma Angiotensin Research Articles

Effect of Telmisartan on Arsenic-Induced (Sub-chronic) Perturbations in Redox Homeostasis, Pro-inflammatory Cascade and Aortic Dysfunction in Wistar Rats.

An experimental study was conducted in male Wistar rats to explore the antioxidant potential of telmisartan (an AT1 receptor blocker) to overcome arsenic ('As')-induced perturbations in redox homeostasis pro-inflammatory cytokines, prostaglandin-E2 levels and aortic dysfunction in Wistar rats. Wistar rats were randomly divided into four groups of six each. Group-I served as untreated control, while group-II received sodium (meta) arsenite (NaAsO2) (10mg/kg b.wt. p.o) for a period of 60days. Experimental rats in group-III received treatment similar to group-II, but in addition received telmisartan (with 1% aqueous solution of Tween 80) @ 10mg/kg b.wt. (p.o) for a similar duration, while rats in group-IV received telmisartan alone. Arsenic exposure resulted in significant (p < 0.05) elevation in the levels of superoxide anion ([Formula: see text]) radicals (control: 768.20 ± 126.77 vs group-II: 1232.75 ± 97.85pmol of NBT reduced/min/mg protein). Telmisartan administration showed significant (p < 0.05) reduction in [Formula: see text] generation (815.34 ± 43.41pmol of NBTreduced/min/mg protein). Sub-chronic exposure to 'As' significantly (p < 0.05) decreased the activities of SOD, CAT, GPx and GR activity and GSH levels in the aorta, thus induced lipid peroxidation (LPO) measured as measured in terms of thiobarbituric acid reactive substances (TBARS) called as malondialdehyde (MDA). However, the administration of telmisartan effectively countered the LPO (24.03 ± 1.18nmol of MDA/g) on account of restoring the levels of aforesaid antioxidant defense system. Telmisartan administration effectively attenuated the 'As'-induced surge in pro-inflammatory cytokines (viz., IL-1β, IL-6 and TNF-α) levels, as well as countered the activity of cyclooxygenase (COX2) as indicated by a significant (p < 0.05) decrease in PGE2 level in the aorta. In addition to it, there was a significant (p < 0.05) decrease in plasma angiotensin II (Ang-II) levels in experimental rats receiving telmisartan. Quantitative RT-PCR studies revealed that sub-chronic exposure to 'As' upregulated the Nox2 mRNA expression, but there was a 1.2-fold reduction in expression level upon co-administration of telmisartan. Histopathological examination revealed marked recovery from 'As'-induced disruption of tunica adventitia and loss of connective tissue in experimental rats receiving telmisartan. The study concludes that telmisartan can overcome aortic dysfunction induced by sub-chronic exposure to arsenic through drinking water in experimental rats through restoration of redox balance, attenuation of pro-inflammatory cytokines and mediators and downregulation of Nox2 mRNA expression.

Direct renin inhibition is not enough to prevent reactive oxygen species generation and vascular dysfunction in renovascular hypertension

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.

A metabolomics approach for investigating urinary and plasma changes in spontaneously hypertensive rats (SHR) fed with chicken skin protein hydrolysates diets

Plasma and urine metabolomics profiles of spontaneously hypertensive rats (SHRs) fed with chicken skin protein hydrolysates (CSPHs) were investigated to establish possible biomarkers of blood pressure regulation. SHR and wistar Kyoto (WKY) rats were randomised into groups that received casein-only (control), CSPHs (0.5 or 1%) or chicken skin meal (CSM 1%) diets for six weeks. Results showed that the diets significantly (P < 0.05) lowered systolic blood pressure (SBP) of SHRs (−36, −31 and −26 mmHg for CSPH 1%, CSPH 0.5% and CSM 1%, respectively) but not WKY. This correlated with decreased plasma angiotensin converting enzyme levels but not with superoxide dismutase activity. Partial least square discrimination analysis of detected metabolites in urine and plasma of rats showed significant changes in levels of symmetric dimethylarginine, N2-acetyl-L-ornithine, buthionine sulfoximine, uric acid, α-tocopherol succinate, L-isoleucine, creatinine, and phospholipids. CSPHs could therefore be used as ingredients in developing nutraceuticals and functional foods for hypertension management.

Multiple Ascending Dose Study With the New Renin Inhibitor VTP-27999

This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.

Renal responses to three types of renin–angiotensin system blockers in patients with diabetes mellitus on a high-salt diet

Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus. We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks. All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero. The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system.

Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis

Objectives: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I_f current, prevents cardiac dysfunction associated with dyslipidemia. Methods: New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays. Results: IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008). Conclusion: Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.

Angiotensin-(1–9) regulates cardiac hypertrophy in vivo and in vitro

Angiotensin-(1-9) is present in human and rat plasma and its circulating levels increased early after myocardial infarction or in animals treated with angiotensin-converting enzyme inhibitor. However, the cardiovascular effects of this peptide are unknown. To determine whether angiotensin-(1-9) is a novel anti-cardiac hypertrophy factor in vitro and in vivo and whether this peptide is involved in the pharmacological effects of cardiovascular drugs acting on the renin-angiotensin system. The administration of angiotensin-(1-9) to myocardial infarcted rats by osmotic minipumps (450 ng/kg per min, n = 6) vs. vehicle (n = 8) for 2 weeks decreased plasma angiotensin II levels, inhibited angiotensin-converting enzyme activity and also prevented cardiac myocyte hypertrophy. However, cardiac myocyte hypertrophy attenuation triggered by angiotensin-(1-9) was not modified with the simultaneous administration of the angiotensin-(1-7) receptor antagonist A779 (100 ng/kg per min, n = 6). In experiments in vitro with cultured cardiac myocytes incubated with norepinephrine (10 micromol/l) or with insulin-like growth factor-1 (10 nmol/l), angiotensin-(1-9) also prevented hypertrophy. In other experimental setting, myocardial infarcted rats (n = 37) were randomized to receive either vehicle (n = 12), enalapril (10 mg/kg per day, n = 12) or angiotensin II receptor blocker candesartan (10 mg/kg per day, n = 13) for 8 weeks. Both drugs prevented left ventricle hypertrophy and increased plasma angiotensin-(1-9) levels by several folds. Angiotensin-(1-9) levels correlated negatively with different left ventricular hypertrophy markers even after adjustment for blood pressure reduction. Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.

Abstract 837: A Novel -1364A/C Aquaporin 5 Gene Promoter Polymorphism Influences the Regulation of the Renin-Angiotensin-Aldosterone System in Young Healthy Men and Individuals with Coronary Artery Disease

Background: The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is an ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Method and Results : Sequencing of the whole AQP5 promoter revealed a novel -1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we investigated the phenotypic variability of the RAAS in two different independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 ± 3 years) healthy males under an increased salt diet. Increasing dietary salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (p=0.012), and decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (p =0.005). Both genotypes had increased blood pressure under salt diet (p&lt;0.01), which was significantly more pronounced in AA genotypes (p =0.029). Second, we investigated associations with the phenotypic variability of the RAAS in 96 old patients (68 ± 10 years) with coronary artery disease scheduled for coronary artery bypass grafting. ADH plasma concentrations did not differ between genotypes. However, aldosteron serum concentrations were 2-fold (p&lt;0.001) and angiotensin II plasma concentrations were 4-fold higher in AA genotypes in comparison to the AC/CC genotypes. Conclusion: A novel single nucleotide polymorphism in the AQP5 gene promoter evokes an alteration of both AQP5 expression in different in vitro systems and cells, and the regulation of the Renin-Angiotensin-Aldosterone System.

A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men

The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is a ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Sequencing of the whole AQP5 promoter revealed a novel-1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we associated AQP5 genotypes with the variability of the RAAS in two independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 +/- 3 years) healthy males under an increased dietary salt intake. Increasing salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (P = 0.012), and it decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (P = 0.005). Both genotypes had increased blood pressure under salt diet (P < 0.01), which was significantly more pronounced in AA genotypes (P = 0.029). Second, we investigated associations with variables of the RAAS in 96 old patients (68 +/- 10 years) with coronary artery disease scheduled for coronary artery bypass grafting. Aldosterone serum concentrations were 2-fold (P < 0.001) and angiotensin II plasma concentrations were 4-fold higher in AA genotypes than in AC/CC genotypes while ADH plasma concentrations did not differ. A novel single nucleotide polymorphism in the AQP5 gene promoter alters AQP5 expression in different in vitro systems and cells, and is associated with alterations of variables of the RAAS both in young healthy males and in patients with coronary artery disease.

Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

High- or low-salt diet from weaning to adulthood: Effect on body weight, food intake and energy balance in rats

Objective To get some additional insight on the mechanisms of the effect of salt intake on body weight. Design and methods Rats were fed a low (LSD), normal (NSD), or high (HSD) salt diet. In a first set, body weight, tail-cuff blood pressure, fasting plasma thyroid-stimulating hormone, triiodothyronine, l-thyroxine, glucose, insulin, and angiotensin II were measured. Angiotensin II content was determined in white and brown adipose tissues. Uncoupling protein 1 expression was measured in brown adipose tissue. In a second set, body weight, food intake, energy balance, and plasma leptin were determined. In a third set of rats, motor activity and body weight were evaluated. Results Blood pressure increased on HSD. Body weight was similar among groups at weaning, but during adulthood it was lower on HSD and higher on LSD. Food intake, l-thyroxine concentration, uncoupling protein 1 expression and energy expenditure were higher in HSD rats, while non-fasting leptin concentration was lower in these groups compared to NSD and LSD animals. Plasma thyroid-stimulating hormone decreased on both HSD and LSD while plasma glucose and insulin were elevated only on LSD. A decrease in plasma angiotensin II was observed in HSD rats. On LSD, an increase in brown adipose tissue angiotensin II content was associated to decreased uncoupling protein 1 expression and energy expenditure. In this group, a low angiotensin II content in white adipose tissue was also found. Motor activity was not influenced by the dietary salt content. Conclusions Chronic alteration in salt intake is associated with changes in body weight, food intake, hormonal profile, and energy expenditure and tissue angiotensin II content.

Peptide nucleic acids specifically cause antigene effects in vivo by systemic injection

Peptide nucleic acids (PNAs) are uncharged DNA analogs that hybridize to complementary sequences with high affinity and stability. We previously showed that PNAs, after intraperitoneal injection into rats, are effective antisense compounds in vivo. The present study was designed to test whether PNAs also have antigene effects in vivo. The renin-angiotensin system is critical in the control of blood pressure. We designed and synthesized sense (antigene) PNAs to angiotensinogen, which is the precursor protein that leads to angiotensin I and II. Spontaneously hypertensive rats received intraperitoneal injections of either 20 mg/kg sense-angiotensinogen-PNA, mismatch-angiotensinogen PNA, or saline. Only the sense-angiotensinogen PNA treatment resulted in a significant decrease in plasma angiotensin I, systolic blood pressure, and liver and brain angiotensinogen mRNA levels. Thus, these results demonstrate on the molecular, protein, and physiological levels that antigene PNAs are effective in vivo upon systemic administration.

ACE Inhibitor Causes Kinin-Mediated Renal Vasodilatation in Goldblatt Rabbit

P24 ACE inhibitors cause an increase in renal blood flow (RBF) by a kinin-mediated mechanism in the sodium-restricted dog with a high renin level. Previous findings of an inconsistent decrease in plasma angiotensin II after ACE inhibition in Goldblatt rabbits, lead to the hypothesis that a similar effect of ACE inhibition occurs in this high renin model. The systemic blood pressure (BP) and renal hemodynamic effects of enalaprilat (10 mg/kg IV) were compared in 2 groups of rabbits anesthetized with sodium pentobarbital. Blood pressure was measured from the carotid artery and right RBF determined by electroflowmetry. All rabbits underwent clipping of the left renal artery on the average 24 days prior to the acute experiment. Group 1 (n=7) was administered enalaprilat to elicit the normal response to ACE inhibition. Group 2 (n=5) was given the kinin B2 receptor antagonist icatibant as an IV infusion (5 μg/kg/min) during the administration of enalaprilat. This dose of icatibant blocked completely the depressor response to kallidin and itself had no effect on BP or RBF. Results of these experiments are summarized in the Table. Enalaprilat caused a marked rise in RBF and decrease in BP and renal vascular resistance in Group 1. No significant effect of enalaprilat was seen in Group 2. Thus, based on these results, it is concluded that the kallikrein-kinin system plays a major role in the BP and renal hemodynamic response of ACE inhibition in this high renin state.

ACE Inhibitor Causes Kinin-Mediated Renal Vasodilatation in Goldblatt Rabbit

P24 ACE inhibitors cause an increase in renal blood flow (RBF) by a kinin-mediated mechanism in the sodium-restricted dog with a high renin level. Previous findings of an inconsistent decrease in plasma angiotensin II after ACE inhibition in Goldblatt rabbits, lead to the hypothesis that a similar effect of ACE inhibition occurs in this high renin model. The systemic blood pressure (BP) and renal hemodynamic effects of enalaprilat (10 mg/kg IV) were compared in 2 groups of rabbits anesthetized with sodium pentobarbital. Blood pressure was measured from the carotid artery and right RBF determined by electroflowmetry. All rabbits underwent clipping of the left renal artery on the average 24 days prior to the acute experiment. Group 1 (n=7) was administered enalaprilat to elicit the normal response to ACE inhibition. Group 2 (n=5) was given the kinin B2 receptor antagonist icatibant as an IV infusion (5 μg/kg/min) during the administration of enalaprilat. This dose of icatibant blocked completely the depressor response to kallidin and itself had no effect on BP or RBF. Results of these experiments are summarized in the Table. Enalaprilat caused a marked rise in RBF and decrease in BP and renal vascular resistance in Group 1. No significant effect of enalaprilat was seen in Group 2. Thus, based on these results, it is concluded that the kallikrein-kinin system plays a major role in the BP and renal hemodynamic response of ACE inhibition in this high renin state.

Adrenal renin-angiotensin-aldosterone system in streptozotocin-diabetic rats.

Previous studies have indicated that the local renin-angiotensin system (RAS) plays an important role in the regulation of aldosterone release. We focused this study on examining the dissociating changes in circulating RAS and adrenal RAS, and we produced a low plasma renin status in streptozotocin (STZ)-induced diabetic rats. Four and six weeks after treatment with STZ, the rats showed hyperglycemia, hyporeninemia, decrease in plasma angiotensin II (AII), and a slight, but non-significant increase in plasma aldosterone in the rats. The adrenal renin activity and aldosterone concentration were significantly increased in the group of rats six weeks after induction of diabetes compared to those in control rats. The group of rats four weeks after induction of diabetes showed an increase in adrenal aldosterone concentration and a slight, but non-significant increase in adrenal renin activity. Plasma ACTH, serum sodium, and potassium were unchanged in both treatment groups compared to the control. The present results indicate that hyperactivity or residual activity of adrenal RAS under hyporeninemia is associated with severe diabetes mellitus.

Preventive effect of iganidipine on renal and cerebral injuries in salt-induced hypertension.

Iganidipine, a new water-soluble calcium antagonist, was administered at a nonhypotensive dose (NHD) of 0.3 mg/kg/day, a moderate-hypotensive dose (MHD) of 1.0 mg/kg/day, and a sustained-hypotensive dose (SHD) of 3.0 mg/kg/day to Dahl salt-sensitive (Dahl-S) rats fed a high-salt diet for 8 weeks. The effects on survival, and on renal and cerebral injuries, were then examined. Iganidipine completely prevented hypertensive death at the SHD and tended to increase the survival at the NHD and MHD. Iganidipine reduced glomerulosclerosis and renal arterial and tubular injuries in a dose-dependent manner. Iganidipine at the SHD, but not NHD or MHD, improved plasma creatinine, serum urea nitrogen, and glomerular filtration rate. Iganidipine at all doses examined increased the urinary prostaglandin (PG) I2 and PGE2, but not PGF2alpha or thromboxane B2, and decreased plasma angiotensin II (AII) level and renin activity. The renal glomerular, tubular, and arterial injuries were significantly correlated with blood pressure (r = 0.56 to 0.80) and plasma AII level (r = 0.50 to 0.71) but not with urinary prostanoids. Iganidipine also reduced the incidence of cerebral infarction. The infarction area was slightly and significantly correlated with urinary PGI2 (r = 0.42) and PGE2 (r = 0.41) but not with blood pressure or plasma AII. In conclusion, iganidipine prevented renal and cerebral injuries in Dahl-S rats. In addition to the reduced blood pressure, the reduction of plasma AII and the increase of vasodilatory prostanoids may also partially contribute to the renal and cerebral protective effects of iganidipine.

Hormones as long-term error signals for the sympathetic nervous system: importance of a new perspective.

1. A hormonal-sympathetic reflex model for long-term control of arterial pressure is presented. It is hypothesized that the hormonal-sympathetic reflex regulates arterial pressure during chronic dietary salt loading by decreasing sympathetic tone. This sympathetic response is mediated by an increase in plasma vasopressin (AVP) and a decrease in plasma angiotensin (AngII). 2. Three new models of neurogenic salt-dependent hypertension are presented. All models are theoretically based on an impaired hormonal-sympathetic reflex. 3. In the first model, sympathetic responsiveness is 'clamped' by long-term alpha-adrenergic blockade with prazosin. Prazosin treated rats exhibit marked salt-dependent hypertension despite normal suppression of the renin-angiotensin system. 4. In the second model, the ability of the central nervous system to respond to salt-induced changes in AVP and AngII concentrations was prevented by long-term administration of antagonists selective for the AVP-V1 and AT1. This 'clamp' of the afferent hormonal signal resulted in salt-dependent hypertension identical in magnitude to that observed in prazosin treated rats. 5. In the third model, the long-term arterial pressure responses to increasing dietary salt were examined in sino-aortic denervated (SAD) rats. SAD rats exhibited salt-dependent hypertension, of lesser magnitude than that observed with 'clamped' afferent and efferent pathways of the hormonal-sympathetic reflex. 6. A primary role for hormonal 'error signals' is presented and the impact this perspective has on past and future investigations of central mechanisms of long-term arterial pressure regulation is discussed.

Differential Regulation of Angiotensin Peptides in Plasma and Kidney: Effects of Adrenalectomy and Estrogen Treatment

Eight angiotensin peptides [angiotensin-(1–7), angiotensin II, angiotensin-(1–9), angiotensin I, angiotensin-(2–7), angiotensin-(2–8), angiotensin-(2–9), and angiotensin-(2–10)] were measured in plasma and kidney of adrenalectomized rats and estrogen-treated rats. In comparison with sham-operated rats, adrenalectomy increased plasma renin levels by 50-fold and reduced plasma angiotensinogen levels by 67%. Adrenalectomy increased plasma angiotensin peptide levels by 9- to 30-fold, but the increases in renal angiotensin peptide levels were much less than those seen for plasma. In comparison with vehicle-treated rats, estrogen treatment increased plasma angiotensinogen levels by 3-fold and reduced plasma renin levels by 41%. Estrogen treatment decreased plasma angiotensin peptide levels, whereas renal angiotensin peptide levels increased by as much as 2- to 3-fold. These results confirm the differential regulation of angiotensin peptide levels in plasma and kidney, and provide further support for the essential role of angiotensinogen in modulating plasma and tissue angiotensin peptide levels.

Natriuretic effect of non-pressor doses of endothelin-1 in conscious dogs.

1. Renal, endocrine and haemodynamic responses to separate intravenous infusions of three doses of endothelin-1 (40, 400 and 4000 fmol kg-1 min-1) were investigated in conscious dogs. 2. Administration of 40, 400 and 4000 fmol kg-1 min-1 endothelin-1 for 120 min increased plasma endothelin-1 levels by two-, seven- and 250-fold, respectively. 3. The two low doses did not have measurable effects on mean arterial blood pressure and heart rate but tended to increase glomerular filtration rate. The high dose increased mean arterial blood pressure (MABP; from 104 +/- 4 to 138 +/- 4 mmHg, P < 0.05) and decreased heart rate (from 71 +/- 4 to 46 +/- 3 beats min-1, P < 0.05) as well as glomerular filtration rate (from 47 +/- 3 to 19 +/- 5 ml min-1, P < 0.05). 4. At rates of 40 and 400 fmol kg-1 min-1, endothelin-1 increased sodium excretion about five- and eightfold, respectively. Relative changes in fractional sodium excretion were very similar. The high dose was markedly antinatriuretic (reducing sodium excretion from 8.3 +/- 1.1 to 1.2 +/- 0.2 mumol min-1, P < 0.05). 5. Diuresis increased during the administration of the two lower doses, which did not change plasma atrial natriuretic peptide or vasopressin concentrations. Urine flow increased after termination of the infusion of the pressor dose despite elevated plasma vasopressin and subnormal glomerular filtration rate. 6. Infusion of endothelin-1 at 40 fmol kg-1 min-1 did not change the concentrations of angiotensin II and atrial natriuretic peptide in plasma. Infusion of 400 fmol kg-1 min-1 was associated with a decrease in plasma angiotensin II, while plasma atrial natriuretic peptide was unchanged. The high dose of endothelin-1 markedly increased plasma levels of both hormones. 7. It is concluded that endothelin-1 at low plasma concentrations increases sodium excretion while a higher pressor dose of endothelin-1 is antinatriuretic. However, increases in plasma endothelin-1 seem to elicit diuresis over a wide concentration range, although possibly by different mechanisms.

Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene.

Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2d)27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determined the effects of a 13-day therapy with losartan (10 mg/kg) or lisinopril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiotensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawley (SD) rats. The contribution of endothelium-derived nitric oxide (NO) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either NG-monomethyl-L-arginine (L-NMMA) or endothelin-1. Hypertension in TG rats was associated with decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both strains, the chronic fall in BP produced by lisinopril was accompanied by significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produced by either lisinopril or losartan in SD controls. In contrast, administration of L-NMMA to TG rats given the same therapy did not. The transient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and lisinopril in TG rats. These studies indicate that hypertension in female TG rats is mediated by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)