Circulatory Renin-angiotensin System Research Articles

Regulation of aminopeptidases by the renin - angiotensin system: monitoring seasonal variations in red deer and fallow deer from a Mediterranean ecosystem

The circulating renin–angiotensin system (RAS) is well known for its systemic role in the regulation of blood pressure, renal hemodynamics and fluid homeostasis. However, in mammals several organs also contain a local RAS, including male and female reproductive tissues. In the present study we analysed serum from a free-living population of red deer (Cervus elaphus hispanicus) and fallow deer (Dama dama) to determine the activity of four RAS-regulating aminopeptidases (aminopeptidase A, aspartyl aminopeptidase, aminopeptidase N and aminopeptidase B) as part of a study of annual cycles of growth and condition. Our aim was to detect seasonal variations in the activities of these aminopeptidases and their relationship to the reproductive behaviour of both species in a Mediterranean environment. In both males and females there was a maximum peak of activity in autumn. A second peak was detected in spring for males while in females activity was also higher in summer. These changes may be related to a different endocrine status according to their seasonal cycle, the decreased photoperiod in autumn and the normal timing of the seasonal growth cycle. Thus, changes in the activity of RAS-regulating aminopeptidases could reflect the functional role of angiotensins through the annual cycle of both species, also suggesting an important role of these peptide hormones in the regulation of these biological processes.

Effects of the new angiotensin II type 1 receptor antagonist KRH-594 on several types of experimental hypertension.

The antihypertensive effect of dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2- ylidene]aminocarbonyl]-1-cyclopentenecarboxylate (CAS 169328-25-0, KRH-594), a new angiotensin II type 1 (AT1) receptor antagonist, was studied in several experimental hypertensive models. The effects of KRH-594 on the circulating reninangiotensin system and on renal function were also investigated. Oral administration of KRH-594 (0.3 or 1 mg/kg) dose-dependently inhibited the angiotensin II-induced pressor response in common marmosets. KRH-594 (1, 3, or 10 mg/kg p.o.) dose-dependently exerted a long-lasting antihypertensive effect in spontaneously hypertensive rats (SHRs) and in 2-kidney 1-clip renal hypertensive rats (RHRs). Furthermore, repeated oral administration of KRH-594 (3 or 10 mg/kg/d) reduced blood pressure dose-dependently in SHRs, RHRs, and renal hypertensive dogs without tachycardia and with no evidence of a rebound phenomenon following drug withdrawal. On the other hand, in deoxycorticosterone acetate salt rats and normotensive rats, KRH-594 (10 or 30 mg/kg p.o.) did not have significant effects on systolic blood pressure. In SHRs, KRH-594 (3 or 10 mg/kg/d p.o. for 2 weeks) dose-dependently increased both plasma renin activity and the plasma angiotensin I concentration, but had no effect on the urinary excretion of sodium, potassium, and chloride or on creatinine clearance. These results suggest that KRH-594 should be effective in patients with essential or renal hypertension.

Augmented intratubular renin and prorenin expression in the medullary collecting ducts of the kidney as a novel mechanism of angiotensin II-induced hypertension

Augmented intratubular renin and prorenin expression in the medullary collecting ducts of the kidney as a novel mechanism of angiotensin II-induced hypertension

Local Ocular Renin-Angiotensin System - A Target for Glaucoma Therapy?

An active local intraocular renin-angiotensin system (RAS) has recently been shown to exist in the human eye, and evidence is now accumulating that antihypertensive drugs acting on RAS can also lower intraocular pressure. They seem also to work as neuroprotective agents against retinal ganglion cell loss in vivo; though no compounds are in ophthalmological use at present. Classically, the highly vasoconstrictive angiotensin II (Ang II) is the key peptide in the circulatory RAS. However, the final effect of RAS activation at tissue level is more complex, being based not only on the biological activity of Ang II but also on the activities of other products of angiotensinogen metabolism, often exerting opposite effects to Ang II action.

The renin–angiotensin system is modulated by swimming training depending on the age of spontaneously hypertensive rats

AimTo investigate the effects of swimming training on the renin–angiotensin system (RAS) during the development of hypertensive disease. Main methodsMale spontaneously hypertensive rats (SHR) were randomized into: sedentary young (SY), trained young (TY), sedentary adult (SA), and trained adult (TA) groups. Swimming was performed 5 times/wk/8wks. Key findingsTrained young and adult rats showed both decreased systolic and mean blood pressure, and bradycardia after the training protocol. The left ventricular hypertrophy (LVH) was observed only in the TA group (12.7%), but there was no increase on the collagen volume fraction. Regarding the components of the RAS, TY showed lower activity and gene expression of angiotensinogen (AGT) compared to SY. The TA group showed lower activity of circulatory RAS components, such as decreased serum ACE activity and plasma renin activity compared to SA. However, depending on the age, although there were marked differences in the modulation of the RAS by training, both trained groups showed a reduction in circulating angiotensin II levels which may explain the lower blood pressure in both groups after swimming training. SignificanceSwimming training regulates the RAS differently in adult and young SHR rats. Decreased local cardiac RAS may have prevented the LVH exercise-induced in the TY group. Both groups decreased serum angiotensin II content, which may, at least in part, contribute to the lowering blood pressure effect of exercise training.

Prevention of dementia by ACE inhibitors and angiotensin receptor blockers - potential but not proven

Dementia currently exacts a substantial economic burden on societies, health and social care systems and carers in addition to the devastating personal and emotional cost to patients and families (1,2). This burden is predicted to increase substantially in the coming decades and is the major public health issue of this century (1). Currently available therapies are symptomatic only (3), with little or no prospect of disease-modifying treatments entering routine clinical use in the short to medium term. Strategies to prevent or delay the onset of dementia or retard its' progression are, therefore, urgently required and will be of extreme importance to individuals and societies. Currently available medications that could achieve these goals would have many advantages ― potential for immediate use; established safety profile; familiarity to clinicians; relatively low cost giving favourable cost-effectiveness breakdown.

Tumor Necrosis Factor Receptor-associated Factor-6 and Ribosomal S6 Kinase Intracellular Pathways Link the Angiotensin II AT1 Receptor to the Phosphorylation and Activation of the IκB Kinase Complex in Vascular Smooth Muscle Cells

Activation of NF-κB transcription factors by locally produced angiotensin II (Ang II) is proposed to be involved in chronic inflammatory reactions leading to atherosclerosis development. However, a clear understanding of the signaling cascades coupling the Ang II AT1 receptors to the activation of NF-κB transcription factors is still lacking. Using primary cultured aortic vascular smooth muscle cells, we show that activation of the IKK complex and NF-κB transcription factors by Ang II is regulated by phosphorylation of the catalytic subunit IKKβ on serine residues 177 and 181 in the activation T-loop. The use of pharmacological inhibitors against conventional protein kinases C (PKCs), mitogen-activated/extracellular signal-regulated kinase (MEK) 1/2, ribosomal S6 kinase (RSK), and silencing RNA technology targeting PKCα, IKKβ subunit, tumor growth factor β-activating kinase-1 (TAK1), the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor-6 (TRAF6), and RSK isoforms, demonstrates the requirement of two distinct signaling pathway for the phosphorylation of IKKβ and the activation of the IKK complex by Ang II. Rapid phosphorylation of IKKβ requires a second messenger-dependent pathway composed of PKCα-TRAF6-TAK1, whereas sustained phosphorylation and activation of IKKβ requires the MEK1/2-ERK1/2-RSK pathway. Importantly, simultaneously targeting components of these two pathways completely blunts the phosphorylation of IKKβ and the proinflammatory effect of the octapeptide. This is the first report demonstrating activation of TAK1 by the AT1R. We propose a model whereby TRAF6-TAK1 and ERK-RSK intracellular pathways independently and sequentially converge to the T-loop phosphorylation for full activation of IKKβ, which is an essential step in the proinflammatory activity of Ang II.

Circulating renin–angiotensin system and catecholamines in childhood: is there a role for birthweight?

There have been only a few reports on the sympathoadrenal and renin-angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n=31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n=35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls (P=0.036). In addition, angiotensin II and ACE activity were higher in SGA boys (P=0.024 and P=0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin-angiotensin systems into later childhood.

The pregnancy-induced increase of plasma angiotensin-(1–7) is blunted in gestational diabetes

Background and objective It has been shown that the circulating Renin–Angiotensin System (RAS) is activated during normal pregnancy, but little is known about RAS in pregnancies complicated by gestational diabetes (GDM). GDM is considered not merely a temporary condition, but a harbinger of hypertension and type 2 diabetes. The aim of this study was to evaluate the circulating RAS profile in normotensive women with GDM at the third trimester of pregnancy and to compare the results with healthy pregnant and non-pregnant age-matched women. Methods The diagnostic criteria for GDM followed the recommendations of the American Diabetes Association. Angiotensin I (Ang I), Angiotensin II (Ang II) and Angiotensin 1–7 [Ang-(1–7)] were determined in 24 pregnant patients with GDM; 12 healthy pregnant women and 12 non-pregnant women by radioimmunoassay. Results Levels of Ang I, Ang II and Ang-(1–7) were higher in pregnant women ( p < 0.05), but showed a different pattern in the GDM group, in which reduced Ang-(1–7) circulating levels were found ( p < 0.05). This observation was confirmed by the significantly lower Ang-(1–7)/Ang I ratio ( p < 0.05). Conclusion Our data suggest that reduced levels of the vasodilator Ang-(1–7) could be implicated in the endothelial dysfunction seen in gestational diabetic women during and after pregnancy.

The renin–angiotensin system in a rat model of hepatic fibrosis: Evidence for a protective role of Angiotensin-(1–7)

The circulating renin-angiotensin system (RAS) [plasma renin activity (PRA), Angiotensin (Ang) I, Ang II and Ang-(1-7)] was evaluated in a model of hepatic fibrosis in rats. To investigate the pathophysiological involvement of Ang-(1-7), animals were treated with the Ang-(1-7) Mas receptor antagonist, A-779. RAS components, liver function and histology were examined in male Wistar rats (220-300 g). Animals were submitted to sham-surgery or ligature of the bile duct and evaluated 1, 2, 4 and 6 weeks later. Blood samples were obtained to determine biochemical parameters and RAS components. A second group was treated with A-779 or vehicle to measure liver hydroxyproline and total transforming growth factor beta-1 (TGFbeta1). PRA and Ang I were significantly elevated in rats at 4 and 6 weeks compared to sham-operated animals. Ang II and Ang-(1-7) progressively increased over the 6 weeks. Changes in RAS profile correlated with histological signs of fibrosis and deterioration in liver function. Pharmacological blockade of the Ang-(1-7) receptor aggravated liver fibrosis with a significant elevation in hydroxyproline and total TGFbeta(1). Hepatic fibrosis was associated with RAS activation in our model. Our data also suggested that Ang-(1-7) played a protective role in hepatic fibrosis.

Circulating Renin Angiotensin System in Childhood Chronic Renal Failure: Marked Increase of Angiotensin-(1–7) in End-Stage Renal Disease

The aim of the present study was to evaluate plasma renin activity (PRA) and Angiotensin (Ang) levels [Ang I, Ang II and Ang-(1-7)] to examine the circulating Renin-Angiotensin System (RAS) in renal disease among children with different forms and stages of chronic renal failure (CRF). Subjects were divided as follows: 32 normotensive healthy subjects, 23 normotensive CRF subjects, 34 hypertensive CRF subjects and 21 subjects with end-stage renal disease (ESRD). Radioimmunoassays for PRA (ngAngI/mL/h) and angiotensin (pg/mL) measurements were performed on all subjects. PRA, Ang I, Ang II and Ang-(1-7) levels were significantly higher in hypertensive CRF subjects when compared with normotensive CRF and healthy subjects (p < 0.05 for all comparisons). No differences were observed between normotensive CRF and healthy subjects. ESRD subjects exhibited a dramatic increase in Ang-(1-7) (25-fold higher than control values). In hypertensive CRF subjects, treatment with angiotensin-converting enzyme inhibitors (ACEi) increased (1.4-fold) plasma Ang-(1-7) and decreased (2.4-fold) Ang II. In ESRD, the use of ACEi produced a similar (1.5-fold) elevation of Ang-(1-7), but no changes in plasma Ang II. Our data showed different circulating RAS profiles between hypertensive and in normotensive CRF subjects. Marked changes in plasma Ang-(1-7) were associated with the presence of hypertension and progression of kidney dysfunction.

Prenatal exposure to interleukin‐6 results in hypertension and alterations in the renin–angiotensin system of the rat

Cytokines are emerging as important in developmental processes. They may induce alterations in normal gene expression patterns, activate angiotensinogen transcription, or alter expression of the renin-angiotensin system (RAS). To determine whether prenatal exposure to interleukin-6 (IL-6) influences gene expression of the intrarenal RAS and contributes to renal dysfunction and hypertension in adulthood, we exposed female rats to IL-6 early (EIL-6 females) and late (LIL-6 females) in pregnancy and analysed blood pressure in the offspring at 5-20 weeks of age. Renal fluid and electrolyte excretion was assessed in clearance experiments, mRNA expression by real-time PCR, and protein levels by Western blot. Systolic pressure was increased at 5 weeks in IL-6 females and at 11 weeks in males. Circulatory RAS levels were increased in all IL-6 females, but angiotensin-1-converting enzyme (ACE) activity was increased only in LIL-6 females. LIL-6 males and IL-6 females showed decreased urinary flow rate and urinary sodium and potassium excretion. Dopamine excretion was decreased IL-6 females. In adult renal cortex, renin expression was increased in all IL-6 females, but angiotensinogen mRNA was increased only in LIL-6 females; AT(1) receptor (AT(1)-R) mRNA and protein levels were increased in LIL-6 females, whereas AT(2) receptor (AT(2)-R) levels were decreased in LIL-6 females and EIL-6 males. In adult renal medulla, AT(1)-R protein levels were increased in LIL-6 females, and AT(2)-R mRNA and protein levels were decreased in EIL-6 males and LIL-6 females. Prenatal IL-6 exposure may cause hypertension by altering the renal and circulatory RAS and renal fluid and electrolyte excretion, especially in females.

Renal function in transgenic rats expressing an angiotensin-(1–7)-producing fusion protein

Transgenic rats [TGR(A1–7)3292] present a chronic 2.5-fold increase in plasma Angiotensin-(1–7) [Ang-(1–7)] concentration. In the present study, we investigated the effects of this chronic elevation on renal function, vasopressin levels, kidney morphology, expression of Ang-(1–7) and vasopressin receptors in TGR(A1–7)3292. Urine volume and water intake were measured for 24 h. At the end of this period, plasma and urine samples were collected to evaluate renal function parameters and circulating vasopressin levels. Expression of renal V 2 receptors and Mas was assessed by ribonuclease protection assay. Renal slices were processed for histological analysis. The urine flow of TGR(A1–7)3292 was significantly lower in comparison with Sprague–Dawley rats. The reduced urine volume of TGR(A1–7)3292 was accompanied by a significant increase in urinary osmolality and decrease free water clearance. Glomerular filtration rate, urinary sodium and potassium excretion were similar in both strains. No significant changes were observed in vasopressin levels as well as in V 2 receptor and Mas mRNA expression in renal tissue. No changes in kidney structure of TGR(A1–7)3292 were detected. These data suggest that changes in circulating renin–angiotensin system produced by chronic increase of Ang-(1–7) levels can lead to adjustments in the water balance that are independent of vasopressin release and V 2 receptor expression.

The effect of sodium and angiotensin-converting enzyme inhibition on the classic circulating renin–angiotensin system in autosomal-dominant polycystic kidney disease patients

It has been suggested that inappropriate stimulation of the renin-angiotensin system (RAS) is responsible for the increase in blood pressure that occurs in autosomal-dominant polycystic kidney disease (ADPKD) before the development of renal failure. However, the interpretation of previous studies in ADPKD patients is confounded by inadequate matching with control populations for blood pressure and renal function, or failure to control the sodium intake of participants. A double-blind, placebo-controlled study of two different sodium intakes (350 and 50 mmol/day for 5 days) in a group of 11 hypertensive ADPKD patients and eight matched control subjects with essential hypertension. In addition, blood pressure and hormonal responses were measured after the administration of the angiotensin-converting enzyme inhibitor enalapril for 3 days. Blood pressure and hormonal responses of the RAS after a reduction in sodium intake and after the administration of enalapril were identical in ADPKD patients and controls. Activation of the classic circulating RAS is no greater in hypertensive ADPKD patients than in individuals with essential hypertension.

Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct–ligated rats†

Recent evidence indicates that the renin-angiotensin system (RAS) plays a major role in liver fibrosis. Here, we investigate whether the circulatory RAS, which is frequently activated in patients with chronic liver disease, contributes to fibrosis progression. To test this hypothesis, we increased circulatory angiotensin II (Ang II) levels in rats undergoing biliary fibrosis. Saline or Ang II (25 ng/kg/h) were infused into bile duct-ligated rats for 2 weeks through a subcutaneous pump. Ang II infusion increased serum levels of Ang II and augmented bile duct ligation-induced liver injury, as assessed by elevated liver serum enzymes. Moreover, it increased the hepatic concentration of inflammatory proteins (tumor necrosis factor alpha and interleukin 1beta) and the infiltration of CD43-positive inflammatory cells. Ang II infusion also favored the development of vascular thrombosis and increased the procoagulant activity of tissue factor in the liver. Livers from bile duct-ligated rats infused with Ang II showed increased transforming growth factor beta1 content, collagen deposition, accumulation of smooth muscle alpha-actin-positive cells, and lipid peroxidation products. Moreover, Ang II infusion stimulated phosphorylation of c-Jun and p42/44 mitogen-activated protein kinase and increased proliferation of bile duct cells. In cultured rat hepatic stellate cells (HSCs), Ang II (10(-8) mol/L) increased intracellular calcium and stimulated reactive oxygen species formation, cellular proliferation and secretion of proinflammatory cytokines. Moreover, Ang II stimulated the procoagulant activity of HSCs, a newly described biological function for these cells. In conclusion, increased systemic Ang II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events.

Chronic ethanol intake modifies renin–angiotensin system-regulating aminopeptidase activities in mouse cerebellum

In developing cerebellum, where critical periods of vulnerability have been established for several basic substances, it has been extensively studied the wide array of abnormalities induced by exposure to ethanol (EtOH). However, little is known about the effects of EtOH consumption on cerebellar functions in adult individuals. Several studies show participation in cognitive activities to be concentrated in the lateral cerebellum (hemispheres), whereas basic motor functions such as balance and coordination are represented in the medial parts of the cerebellum (vermis and paravermis). In addition to the circulating renin angiotensin system (RAS), a local system has been postulated in brain. The effector peptides of the RAS are formed via the activity of several aminopeptidases (AP). The present work analyses the effect of chronic EtOH intake on the RAS-regulating AP activities in the soluble and membrane-bound fractions of two cerebellar locations: the hemispheres and the vermis. We hypothesize that cerebellar RAS is involved in basic motor functions rather than in cognitive activities.

The upregulation of ICAM-1 and P-selectin requires high blood pressure but not circulating renin-angiotensin system in vivo.

To investigate the separate contributions of blood pressure and the circulating renin-angiotensin system to the upregulation of vascular endothelial adhesion molecules in vivo. One or 4 weeks after constriction of the abdominal aortas of Wistar rats, the expressions of intercellular adhesion molecule-1 (ICAM-1), P-selectin, nuclear factor (NF) kappa B p65 subunit and monocytes were assessed at sites proximal and distal to the site of constriction, by western blot, immunohistochemistry, or both. At 1 week, the mean arterial pressure was increased significantly at the cervical artery in the group with aortic constriction (160 +/- 4 mmHg, compared with 104 +/- 2 mmHg before constriction), but not at the femoral artery (111 +/- 10 mmHg, compared with 100 +/- 2 mmHg before constriction) (P < 0.05), and circulating angiotensin II was increased significantly only in the group with aortic constriction (124 +/- 28 pg/ml, compared with 14 +/- 2 pg/ml in the sham-operated group; P < 0.05). In the aorta-constricted group, the expressions of ICAM-1, P-selectin, and NF-kappa B p65 subunit were significantly upregulated (2-3.1-fold) at the aorta proximal to the constriction compared with those distal to it, which were the same as those in the sham-operated group. Immunolocalization of these molecules was observed to be on the endothelial cells. Adhesive monocytes on the endothelium were also increased significantly only proximal to the constriction in the aorta-constricted group. At 4 weeks the findings were the same, except that circulating angiotensin II was within the normal range in both the aorta-constricted and the sham-operated groups. Our results indicate that the high blood pressure, but not the circulating renin-angiotensin system, upregulates the expression of ICAM-1 and P-selectin, suggesting that mechanical forces may be more important than humoral factors in the upregulation of adhesion molecules in hypertension.

Depressor effect induced by dipeptide, Val-Tyr, in hypertensive transgenic mice is due, in part, to the suppression of human circulating renin-angiotensin system.

1. In the present study, the depressor action of the dipeptide Val-Tyr, with an in vivo antihypertensive effect, was investigated in transgenic mice carrying the human renin gene cross-mated with mice bearing the human angiotensinogen gene (Tsukuba Hypertensive Mouse; THM). 2. Single oral administration of Val-Tyr (0.1 mg/g) to 11-week-old THM resulted in a prolonged reduction of blood pressure for up to 9 h. The effect clearly demonstrated that the Val-Tyr absorbed acted on the enhanced human renin-angiotensin system (RAS). 3. After Val-Tyr administration, an approximate eightfold higher increment of plasma Val-Tyr was observed at 1 h (3406 +/- 211 fmol/mL plasma) compared with the level observed at 0 h; plasma concentrations of Val-Tyr returned to baseline levels at 6 h. 4. Transient changes in plasma concentrations of angiotensin (Ang) I and AngII only at 1 h were consistent with plasma Val-Tyr concentrations, suggesting that that the long-lasting reduction in blood pressure was achieved by the latent hypotensive mechanism of Val-Tyr and not by transient suppression of the circulatory RAS. 5. Ageing of the THM greatly affected the depressor action of Val-Tyr, with no significant reduction in blood pressure observed in 18- and 24-week-old THM.

Variation in the renin angiotensin system throughout the normal menstrual cycle.

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system.

To assess the possible contribution of the circulatory and cardiac renin-angiotensin system (RAS) to the cardiac hypertrophy induced by a beta-agonist, the present study evaluated the effects of isoproterenol, alone or combined with an angiotensin I-converting enzyme inhibitor or AT(1) receptor blocker, on plasma and LV renin activity, ANG I, and ANG II, as well as left ventricular (LV) and right ventricular (RV) weight. Male Wistar rats received isoproterenol by osmotic minipump subcutaneously and quinapril or losartan once daily by gavage. Plasma and LV ANGs were measured by radioimmunoassay after separation by HPLC. Isoproterenol alone decreased blood pressure, more markedly when combined with losartan or quinapril. Isoproterenol significantly increased LV and RV weight and total collagen. Neither losartan nor quinapril inhibited the increases in LV or RV weight. Losartan prevented the increase in RV collagen but enhanced the increase in LV collagen. Isoproterenol increased plasma renin, ANG I, and ANG II three- to fourfold. Isoproterenol combined with losartan or quinapril, caused marked further increases except for a significant decrease in plasma ANG II with quinapril. Isoproterenol alone did not increase LV ANG II and, combined with losartan or quinapril, actually decreased LV ANG II. These results indicate that isoproterenol-induced cardiac hypertrophy is associated with clear increases in plasma ANG II, but not in LV ANG II. Both losartan and quinapril lower LV ANG II below control levels, but do not prevent the isoproterenol-induced cardiac hypertrophy. These findings do not support a role for the circulatory or cardiac RAS in the cardiac trophic responses to beta-receptor stimulation.