Effects of continuous angiotensin I-converting enzyme blockade on blood pressure, sympathetic activity and renin-angiotensin system in stroke-prone spontaneously hypertensive rats

The purpose of this study was to examine the effects of continuous angiotensin converting enzyme (ACE) blockade in stroke-prone spontaneously hypertensive rats (sp-SHR) on the renin-angiotensin system and on sympathetic activity. The pressor response to angiotensin II (AII) and norepinephrine (NE) were also examined after chronic blockade of ACE and compared to that of saline-treated controls. Captopril treatment had no effect on body weight. Serum ACE was significantly reduced on day 1; an effect that persisted through day 6 and day 10. Plasma renin activity (PRA) was elevated significantly on day 1 and remained at this high level throughout the 10 day observation period. Plasma NE was not altered by the chronic ACE blockade except on day 1, where there was a slight elevation of plasma NE in both groups. Pressor responses to AII and NE were not changed after chronic captopril treatment. It is observed that chronic inhibition of the renin-angiotensin system with captopril in sp-SHR resulted in a reduction of blood pressure, reduced serum ACE activity and elevated PRA. The constant plasma NE levels suggest that chronic inhibition of the renin-angiotensin system does not affect sympathetic activity. This study also indicates that long term inhibition of ACE does not alter pressor responses to either AII or NE.     

Role of the renal nerve in glucocorticoid hypertension

The present study was designed to investigate the involvement of the renal nerve in glucocorticoid hypertension and to assess the role of the renin-angiotensin system in dexamethasone-induced hypertension. The elevated blood pressure in dexamethasone treated rats showing a significant increase in plasma renin concentration (PRC) and activity (PRA) was attenuated dose-dependently by the angiotensin I converting enzyme (ACE) inhibition. Bilateral renal denervation caused a partial decrease in the elevated blood pressure, abolished the increased PRC and PRA, and reduced the dose-dependent decrease in blood pressure with ACE inhibition in dexamethasone treated rats. Although the reduction in body weight and increases in urine volume, urinary sodium excretion and hematocrit were clearly seen following dexamethasone administration, dexamethasone-treated renal denervated rats showed the same degree of change in any of the variables as dexamethasone-treated sham-operated rats. Thus, our results indicate that the stimulation of the renin-angiotensin system through the activation of the renal nerve may be partially responsible for the dexamethasone-induced high blood pressure and, therefore, bilateral renal denervation reduces, partially but significantly, the elevated blood pressure, suggesting that the attenuation of oversecretion of renin contributes to the lowering of the blood pressure.     

Local renin-angiotensin systems

The existence of a local cardiovascular renin-angiotensin system (RAS) is often invoked to explain the long-term beneficial effects of RAS inhibitors in heart failure and hypertension. The implicit assumption is that all components of the RAS are synthesized in situ, so that local angiotensin II formation may occur independently of the circulating RAS. Evidence for this assumption however is lacking. The angiotensin release from isolated perfused rat hearts or hindlimbs depends on the presence of renal renin. When calculating the in vivo angiotensin production at tissue sites in humans and pigs, taking into account the extensive regional angiotensin clearance by infusing radiolabeled angiotensin I or II, it was found that angiotensin production correlated closely with plasma renin activity. Moreover, in pigs the cardiac tissue levels of renin and angiotensin were directly correlated with their respective plasma levels, and both in tissue and plasma the levels were undetectably low after nephrectomy. Similarly, rat vascular renin and angiotensin decrease to low or undetectable levels within 48 h after nephrectomy. Aortic renin has a longer half life than plasma renin, suggesting that renin may be bound by the vessel wall. In support of this assumption, both renin receptors and renin-binding proteins have been described. Like ACE, renin was enriched in a purified membrane fraction prepared from cardiac tissue. Binding of renin to cardiac or vascular membranes may therefore be part of a mechanism by which renin is taken up from plasma. It appears that the concept of a local RAS needs to be reassessed. Local angiotensin formation in heart and vessel wall does occur, but depends, at least under normal circumstances, on the uptake of renal renin from the circulation. Tissues may regulate their local angiotensin concentrations by varying the number of renin receptors and/or renin-binding proteins, the ACE level, the amount of metabolizing enzymes and the angiotensin receptor density.Abbreviations RAS renin-angiotensin system - ANG angiotensin - ACE angiotensin-converting enzyme - PRA plasma renin activity     

Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n?=?100) and healthy controls (age 45 yrs, 26% male, n?=?50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p?=?0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p?=?0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients.     

Current trends on cholinergic effect on secretion and activity of renin and angiotensin-converting enzyme

This article concerned to insufficiently studied subject on regulatory influence of cholinergic system on key parameters of renin-angiotensin system (renin and angiotensin converting enzyme activity and secretion). Literature data and author's investigations are considered. Influence of systemic and intrarenal infusions of acetylcholine, its analogues and antagonists, inhibition of vagal activity, denervation of kidney, increased and decreased parasympathetic tonus on renin and angiotensin converting enzyme secretion is discussed. Molecular mechanisms of acetylcholine influence on juxtaglomerular cells are considered. Regulatory significance of cholinergic influence on reninangiotensin system is discussed.     

Altered angiotensin-converting enzyme in lung and extrapulmonary tissues of hypoxia-adapted rats

The effects of exposing rats to hypoxia (10% O2) at normal atmospheric pressure for periods of 14 or 28 days on angiotensin-converting enzyme (ACE) activity and stores of angiotensin I (ANG I) and angiotensin II (ANG II) in lung, kidney, brain, and testis were examined. ACE activity was measured by spectrophotometric assay, and active sites of ACE were estimated by measuring the binding of 125I-351A [N-(1-carbonyl-3-phenyl-propyl)-L-lysyl-L-proline], a highly specific active site-directed inhibitor of ACE, to tissue homogenates and perfused lungs. Hypoxia exposure produced progressive reductions in ACE activity in lung homogenates and in ACE inhibitor binding to perfused lungs. ANG II levels in lungs from hypoxia-adapted animals were significantly less than air controls, suggesting that the reduction in intrapulmonary ACE activity was associated with reduced local generation of ANG II. ACE activity was increased in kidney and unchanged in brain and testis of hypoxia-adapted rats compared with air controls. Thus the effects of chronic hypoxia on catalytically active ACE and ACE active sites in the intact animal were organ specific. Adaptation to chronic hypoxia did not significantly alter plasma renin activity or ANG I or ANG II levels or serum ACE content. The hypoxia-induced alterations in lung and kidney ACE were reversible after return to a normoxic environment.     

Captopril normalises systolic blood pressure in rats with hypertension induced by fetal exposure to maternal low protein diets

Recent studies have demonstrated that the feeding of low protein diets to rats during pregnancy induces hypertension in their offspring. Maternal-diet-induced hypertension has been previously associated with elevated pulmonary angiotensin converting enzyme (ACE) activity. In the present study, the importance of the renin angiotensin system, and in particular ACE, in the maintenance of the hypertensive state, is investigated. Pulmonary and plasma ACE activity were determined in rats of different ages, following in utero exposure to 18 (control) or 9% (deficient) casein diets. No maternal diet induced changes in pulmonary ACE were noted, but at 4 and 13 weeks of age, plasma ACE activity was increased by 34 and 134%, respectively in 9% casein exposed rats relative to controls (P<0.001). Thirteen-week-old rats had significantly raised systolic blood pressure (28 mmHg, P<00.05), and tended to have higher diastolic blood pressure (not significant). These hypertensive animals had slightly raised plasma angiotensin II concentrations (30% higher, not significant), but similar renin activities, when compared with normotensive controls. Treatment of normotensive and hypertensive rats with the ACE inhibitor captopril demonstrated that higher plasma ACE activity may play a major role in the maintenance of maternal-diet-induced hypertension. Whilst normotensive rats showed no significant response to drug treatment, systolic blood pressure in the hypertensive rats fell rapidly to the level observed in the normotensive control group. Blood pressure remained at this lower level until treatment was withdrawn, at which time pressure began to increase slowly, but steadily. A period of 7–8 weeks was required following cessation of captopril administration for the restoration of hypertension.The data are consistent with the hypothesis that components of the renin-angiotensin system, and in particular plasma ACE, are involved in the maintenance of maternal-diet-induced hypertension.     

Immunoreactive renin and angiotensin II in the afferent glomerular arterioles of rats with hypertension due to unilateral renal artery constriction

Summary The immunoreactivity for renin and angiotensin II (ANG II) in the ischaemic and non-ischaemic kidney of rats with renovascular hypertension was compared with that of the kidneys of sham operated controls. In addition, the renin concentration of these kidneys and the plasma level of ANG II were determined in hypertensive and control animals. In parallel with the renin concentration of kidney cortex, the immunoreactivity, i.e. the JG-index for renin of the afferent arterioles from the ischaemic kidney was slighly increased, that from the nonischaemic kidney drastically decreased as compared to control kidneys. Similarly, the JG-index for ANG II was increased in the ischaemic and decreased in the non-ischaemic kidney although the plasma level of ANG II was elevated in the animals with renovascular hypertension. This difference in the immunocytochemically detectable ANG II and especially the decrease of ANG II in the non-ischaemic kidney in spite of elevated plasma ANG II levels is interpreted to result from similar differences in the local (extravascular) formation of ANG II by the intrarenal renin-angiotensin system.These studies were supported by the Deutsche Forschungsgemeinschaft within the SFB 90 Cardiovasculäres System     

Differentiation of nephrotensin from the renin angiotensin system.

An investigation of the relationship between nephrotensin and the renin angiotensin system was carred out. Nephrotensin was found in the plasma of rats with renal clip hypertension and with chemically induced kidney damage. There was no demonstrable correlation between presence of nephrotensin and plasma renin activity, and the pressor activity of nephrotensin was not altered by previous immunization of test animals with angiotensin II nor by pretreatment with angiotensin I converting enzyme inhibitor. These results indicate that nephrotensin is different from the components of the renin-angiotensin system.     

Expression of components of the renin-angiotensin system in autosomal recessive polycystic kidney disease.

Hypertension is a common complication in children with autosomal recessive polycystic kidney disease (ARPKD) who have survived the neonatal period. No information is available regarding the mechanism of hypertension in this condition. The renin-angiotensin system (RAS) is thought to play a role in hypertension associated with the more common autosomal dominant polycystic kidney disease (ADPKD). Occasional reports have documented increased activity of the intrarenal RAS in ADPKD, with ectopic renin expression within cysts and dilated tubules. Because of similarities between ARPKD and ADPKD, we hypothesized that increased intrarenal RAS activity might also be found in ARPKD. We performed immunohistochemical studies on kidney tissues from two infants with ARPKD and two control kidneys. The cystic dilated tubules showed staining with the peanut lectin arachis hypogaea, a marker of distal tubules and collecting ducts, but not with lotus tetragonolobus, a marker of proximal tubules. Strong renin staining was seen in many cysts and tubules of ARPKD kidneys, but only in the afferent arterioles of the normal control kidneys. Angiotensinogen staining was also observed in some cysts and in proximal tubules. Staining for angiotensin-converting enzyme, angiotensin II type 1 receptor, and angiotensin II peptide was present in many cystic dilated tubules. These immunohistochemical studies document for the first time ectopic expression of components of the RAS in cystic-dilated tubules of ARPKD and suggest that overactivity of RAS could result in increased intrarenal angiotensin II production, which may contribute to the development of hypertension in ARPKD.     

Comparison of ACE activity in amphibian tissues: Rana esculenta and Xenopus laevis

Angiotensin converting enzyme (ACE) is the dipeptidyl-carboxypeptidase of the renin-angiotensin system involved in the control of blood pressure and hydromineral metabolism. It converts angiotensin I to angiotensin II, the biologically active octapeptide. Angiotensin converting enzyme-like activity has been demonstrated in a wide range of vertebrates. The presence of ACE was investigated in tissues of two amphibian species, the frog Rana esculenta and the toad Xenopus laevis. ACE activities were determined by specific substrate hydrolysis in gut, gonads, lung, kidney, heart, liver, skin, erythrocytes, and muscle homogenates and plasma by means of high performance liquid chromatography. Significant ACE activity was found in gut, gonads, lung and kidney, while that in heart, liver, skin, erythrocytes, muscle, and plasma was very low. Testis of toad contained the highest ACE activity, while that in erythrocytes of male and female frogs was notable.     

Chronic infusion of angiotensin-(1-7) reduces heart angiotensin II levels in rats

We tested the hypothesis that the actions of Angiotensin (Ang)-(1-7) in the heart could involve changes in tissue levels of Ang II. This possibility was addressed by determining the effect of chronic infusion of Ang-(1-7) on plasma and tissue angiotensins. Ang-(1-7) was infused subcutaneously (osmotic minipumps) in Wistar rats. Angiotensins were determined by radioimmunoassay (RIA) in plasma, heart, and kidney. Tissue and plasma angiotensin-converting enzyme (ACE) activity and plasma renin activity (PRA) were also measured. Cardiac and renal ACE2 mRNA levels and cardiac angiotensinogen mRNA levels were assessed by semi-quantitative polymerase chain reaction (PCR). AT1 receptor number was evaluated by autoradiograph. Chronic infusion of Ang-(1-7) (2 microg/h, 6 days) produced a marked decrease of Ang II levels in the heart. A less pronounced but significant decrease of Ang-(1-7) was also observed. No significant changes were observed for Ang I. Ang II was not altered in the kidney. In this tissue, a significant increase of Ang-(1-7) and Ang I concentration was observed. A significant increase of plasma Ang-(1-7) and Ang II was also observed. Ang-(1-7) infusion did not change ACE activity or PRA. A selective slight significant increase in ACE2 expression in the heart was observed. Heart angiotensinogen mRNA as well as the number of Ang II binding sites did not change. These results suggest that AT1 receptors-independent changes in heart Ang II concentration might contribute for the beneficial effects of Ang-(1-7) in the heart. Moreover, these results reinforce the hypothesis that this angiotensin plays an important site-specific role within the renin-angiotensin system.     

Changes in central and peripheral renin-angiotensin system after furosemide injection

To examine the effects of acute stimulation on the peripheral and central renin-angiotensin system, simultaneous sampling of blood and cerebrospinal fluid (CSF) for measurements of plasma renin activity (PRA), plasma angiotensin I-immunoreactivity (PAng I-ir), plasma angiotensin II-immunoreactivity (PAng II-ir), plasma angiotensinogen and cerebrospinal fluid angiotensin II-ir (CSF Ang II-ir) and CSF angiotensinogen was carried out following intravenous injection of furosemide (5 mg/kg) in conscious dogs. Administration of furosemide induced marked increases in PRA, Ang I-ir, PAng II-ir and CSF Ang II-ir, however, neither plasma nor CSF angiotensinogen was changed. Furthermore, a relatively large dose (20 mg/kg/min) of intravenously infused synthetic Ang II for 20 min produced a five-fold increase in PAng II-ir compared with no significant increase in CSF Ang II-ir. In spite of significant suppression of PRA and PAng I-ir, there were no significant changes in either plasma or CSF angiotensinogen. These results primarily suggest that the peripheral and the brain renin-angiotensin systems may be linked and that acute changes in the peripheral renin-angiotensin system do not alter either plasma or CSF angiotensinogen.     

Effect of enalapril (MK-421), an orally active angiotensin I converting enzyme inhibitor, on blood pressure, active and inactive plasma renin, urinary prostaglandin E2, and kallikrein excretion in conscious rats

The angiotensin I converting enzyme (ACE) inhibitor enalapril (MK-421), at a dose of 1 mg/kg or more by gavage twice daily, effectively inhibited the pressor response to angiotensin I for more than 12 h and less than 24 h. Plasma renin activity (PRA) did not change after 2 or 4 days of treatment at 1 mg/kg twice daily despite effective ACE inhibition, whereas it rose significantly at 10 mg/kg twice daily. Blood pressure fell significantly and heart rate increased in rats treated with 10 mg/kg of enalapril twice daily, a response which was abolished by concomitant angiotensin II infusion. However, infusion of angiotensin II did not prevent the rise in plasma renin. Enalapril treatment did not change urinary immunoreactive prostaglandin E2 (PGE2) excretion and indomethacin did not modify plasma renin activity of enalapril-treated rats. Propranolol significantly reduced the rise in plasma renin in rats receiving enalapril. None of these findings could be explained by changes in the ratio of active and inactive renin. Water diuresis, without natriuresis and with a decrease in potassium urinary excretion, occurred with the higher dose of enalapril. Enalapril did not potentiate the elevation of PRA in two-kidney one-clip Goldblatt hypertensive rats. In conclusion, enalapril produced renin secretion, which was in part beta-adrenergically mediated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renin-angiotensin system: oral contraception and exercise in healthy female subjects

The effect of oral contraception and of exercise on the renin-angiotensin system was studied in 20 highly trained athletes, of whom 10 were ingesting oral contraceptives (users) and 10 were not (nonusers), and in 24 sedentary age-matched healthy female subjects, of whom 13 were users and 11 were nonusers. No training-related effects were observed with the exception of renin substrate, which was significantly higher in the athletes. The plasma concentrations of active renin and of trypsin-activatable prorenin were significantly lower in the subjects taking oral contraceptives. Renin substrate, however, was significantly higher in the oral contraceptives group. No difference in plasma renin activity (PRA) was observed between users and nonusers. The results demonstrate the well-known estrogen-induced stimulation of renin substrate synthesis by the liver and suggest a decreased secretion of renin by the kidney. Exhaustive exercise of short duration, performed by the trained athletes only, stimulated the renin-angiotensin system. An increase in PRA and in active renin concentration was observed. The prorenin concentration did not change significantly. The magnitude of the exercise-induced changes was considerably influenced by oral contraceptive medication. Nonusers showed a significantly greater increase in PRA and active renin and total renin concentration than users. Renin substrate decreased significantly during exercise in the nonusers only. These results demonstrate that oral contraceptives have a suppressive effect on renin secretion at rest, an effect that becomes more prominent during exercise, i.e., physiological stimulation.     

Immunoradiometric assay of active renin versus determination of plasma renin activity in the clinical investigation of hypertension, congestive heart failure, and liver cirrhosis

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.     

Cyclical changes in the renin-angiotensin-aldosterone system during the menstrual cycle of the baboon (Papio hamadryas)

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

The renin-angiotensin system in rats made hypertensive by ligation of the kidney poles (38584).

The renin-angiotensin system was studied in experimental renal hypertension produced by ligation of the poles of the left kidney followed by contralateral nephrectomy. Plasma renin concentration of renin substrate was lower and that of angiotensin I converting enzyme was higher in hypertensive animals. The juxtaglomerular index decreased in the medial zone of the kidney, while heavily granulated areas appeared in the poles. Ligated kidneys of rats that remained normotensive showed juxtaglomerular indices intermediate between the control and the hypertensive rats. Differences in renal renin content between the groups correspond to those for the juxtaglomerular index, but were smaller. No differences between the experimental groups were observed in iso-renin content in the brain; however in all animals with ligated kidney poles, hypertensive or normotensive, there was a tendency for iso-renin in the adrenals, left ventricular myocardium, and especially aorta to be lower than in controls.     

Localization of components of the renin-angiotensin system within the kidney

Evidence accumulates that intrarenal angiotensin II (AngII) plays important roles in the regulation of renal functions. To determine the mechanism and site of the intrarenal formation of AngII, we employed histochemical and cell biological methods. Immunohistochemical studies have revealed the coexistence of renin and AngII in juxtaglomerular (JG) cells, and electron microscopic studies and subcellular organelle fractionation have demonstrated the colocalization of renin and angiotensin in renin granules. The mechanism of this AngII accumulation has been investigated. Immunoreactive angiotensin I (AngI) appeared slowly in JG cells after prolonged administration of angiotensin-converting enzyme (ACE) inhibitors. Cloned and cultured renin-containing cells derived from rat kidney were also found to contain renin, ACE, and AngI and AngII. The subcellular fractionation of renin granules from rat kidney homogenate demonstrated AngI and AngII in the renin granule fractions. These findings suggest the formation of both angiotensins in JG cells. To study the release of AngII, we determined the presence of the angiotensins in renal lymph. Renin was found in renal lymph at a high concentration. Both AngI and AngII were also present in renal lymph in moderate concentrations. It is possible that AngII in the interstitial fluid may play a role in the regulation of renal functions. From these results it has been concluded that AngII is formed in JG cells in the kidney and is secreted with renin into interstitial fluid and plasma, and that AngII formed in the kidney cells may participate in various renal functions.     

Plasma renin activity and forearm blood flow in paraplegic humans

We recently found that paraplegic humans respond to hyperthermia with subnormal increase in skin blood flow (SkBF), based on measurements of forearm blood flow (FBF). Is this inhibition of SkBF a defect in thermoregulation or a cardiovascular adjustment necessary for blood pressure control? Since high resting plasma renin activity (PRA) is found in unstressed individuals with spinal cord lesions and since PRA increases during hyperthermia in normal humans, we inquired whether the renin-angiotensin system is responsible for the attenuated FBF in hyperthermic resting paraplegics. Five subjects, 28-47 yr, with spinal transections (T1-T10), were heated in water-perfused suits. Blood samples for PRA determinations were collected during a control period and after internal temperature reached approximately 38 degrees C. Some subjects with markedly attenuated FBF had little or no elevation of PRA; those with the best-developed FBF response exhibited the highest PRA. Clearly, circulating angiotensin is not the agent that attenuates SkBF. Rather, increased activity of the renin-angiotensin system may be a favorable adaptation that counters the locally mediated SkBF increase in the lower body and thus allows controlled active vasodilation in the part of the body subject to centrally integrated sympathetic effector outflow.