Plasma Renin Activity and Angiotensin Pressor Dose in Hypertension: Correlation and Diagnostic Implications

Data obtained from 65 hypertensive patients showed a clear-cut positive correlation between peripheral plasma renin activity and the pressor response to exogenous angiotensin II (r =+0.75). For the various causes of hypertension, the mean values of plasma renin concentration were found to correspond closely to the mean values of the angiotensin pressor dose. In individual cases, however, the pressor dose of angiotensin was not found to be a reliable gauge of peripheral venous renin activity.It was impossible to establish a causal diagnosis from the results of the angiotensin infusion test or the renin level in peripheral blood under normal conditions. If, however, determinations are carried out on the renal venous effluent with sodium restriction and with the patient in the upright position the renin level is very valuable both in the diagnosis of renovascular hypertension and in predicting the probable outcome of surgical treatment.     

肾素-血管紧张素系统与子痫前期关系的研究进展

子痫前期是妊娠期特有的疾病。目前子痫前期的病因和发病机制尚未完全阐明,在其发生和发展过程中涉及到多种因素, 其中肾素- 血管紧张素系统（RAS）失调是子痫前期重要发病原因之一,参与子痫前期的病理生理学变化。本文就系统循环和子宫 胎盘RAS 各组分,尤其胃促胰酶(Chymase)和AT1 受体自身抗体（AT1-AA）,在子痫前期的发生和发展中的变化和作用进行阐 述。     

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

BackgroundAccumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1–7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury.ObjectiveThe objective of this study was to investigate the role of angiotensin converting enzyme (ACE)—chymase—angiotensin II (Ang II)—angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection.MethodsIsolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels.ResultsCardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway.ConclusionsThis study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway.     

Inhibition of Renin Angiotensin Axis May Be Associated with Reduced Risk of Developing Venous Thromboembolism in Patients with Atherosclerotic Disease

Background

Arterial and venous thrombosis may share common pathophysiology involving the activation of platelets and inflammatory mediators. A growing body of evidence suggests prothrombotic effect of renin angiotensin system (RAS) including vascular inflammation and platelet activation. We hypothesized that the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) plays a role in protecting against venous thromboembolism (VTE) in patients atherosclerosis.

Methods

We conducted a retrospective study, reviewing 1,100 consecutive patients admitted to a teaching hospital with a diagnosis of either myocardial infarction or ischemic stroke from 2005 to 2010. Patients who had been treated with anticoagulation therapy before or after the first visit were excluded. The occurrence of VTE during the follow up period, risk factors for VTE on admission, and the use of ACEIs or ARBs during the follow up period were recorded.

Results

The mean age of the entire study population was 68.1 years. 52.0% of the patients were female and 76.5% were African American. 67.3% were on RAS inhibitorsThe overall incidence of VTE was 9.7% (n = 107). Among the RAS inhibitor users, the incidence of VTE events was 9.0% (54/603) for the ACEI only users, 7.1% (8/113) for the ARB only users, and 0% (0/24) for the patients taking combination of ACEI and ARB. Among patients on RAS inhibitors, 8.4% (62/740) developed a VTE, compared with 12.5% (45/360) in the nonuser group [HR (hazard ratio), 0.58; 95% CI (confidence interval), 0.39–0.84; P<0.01]. Even after controlling for factors related to VTE (smoking, history of cancer, and immobilization, hormone use) and diabetes, the use of RAS inhibitors was still associated with a significantly lower risk of developing VTE (AHR, 0.59; 95% CI, 0.40–0.88; P = 0.01).

Conclusions

The use of RAS inhibitors appears to be associated with a reduction in the risk of VTE.     

Astrocytes and the Renin Angiotensin System: Relevance in Disease Pathogenesis

The presence of a brain renin angiotensin system (RAS) is well documented. An overactive brain RAS contributes to the development and progression of cardiovascular and renal disorders among other conditions. In hypertension, an augmented brain RAS leads to an increase in sympathetic nervous system activity. In addition, impaired baroreceptor reflex function, increased vasopressin activity and neuroinflammation are important contributors as well. The relevance of angiotensins in central and peripheral systems, such as neurons and vascular smooth muscle cells, in cardiovascular disease pathogenesis is fairly understood. However, the role of astrocytes is less well studied. Astrocytes are a major contributor to neuroinflammation by increased synthesis and secretion of inflammatory mediators, dysregulated astrogliosis and impaired astrocyte proliferation. Astrocytes may also contribute to impaired neuromodulation. The precise molecular mechanisms by which astrocytes mediate these effects are still not fully understood. Here, we summarize the role of astrocytes in RAS -mediated pathogenesis of hypertension and other cardiovascular diseases.     

β-Blockers and Plasma Renin Activity in Hypertension

Long-term treatment with propranolol was shown to produce a sustained suppression of the renin-aldosterone system in hypertensive patients, despite concurrent diuretic treatment. However, the antihypertensive effect of this treatment correlated poorly with its effects on plasma renin activity and urinary aldosterone excretion. When prindolol, another β-adrenergic blocking drug, was substituted for propranolol, blood pressure control was retained, but there was a prompt rise in plasma renin activity, which was not attributable to changes in electrolyte balance. These observations suggest that the antihypertensive action of propranolol and other β-blockers does not result from their effects on plasma renin activity.     

A Continuous Fluorescence Assay of Renin Activity

A sensitive fluorescence assay that employs a new fluorogenic peptide substrate has been developed to continuously measure the proteolytic activity of human renin. The substrate, DABCYL-gaba-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS, has been designed to incorporate the renin cleavage site that occurs in the N-terminal peptide of human angiotensinogen. The assay relies upon resonance energy transfer-mediated, intramolecular fluorescence quenching that occurs in the intact peptide substrate. Efficient fluorescence quenching occurs as a result of favorable energetic overlap of the EDANS excited state and the DABCYL absorption, and the relatively long excited state lifetime of the EDANS fluorophore. Cleavage of the substrate by renin liberates the peptidyl-EDANS fragment from proximity with the DABCYL acceptor, restoring the higher, unattenuated fluorescence of the EDANS moiety. This leads to a time-dependent increase in fluorescence intensity, directly related to the extent of substrate consumed by renin cleavage. The kinetics of renin-catalyzed hydrolysis of this substrate have been shown to be consistent with a simple substrate inhibition model with a substrate K_m 1.5 μM at physiological pH; Cleavage of the substrate occurs specifically at the Leu-Val bond and corresponds to the renin cleavage site of angiotensinogen, as reported earlier. In this report, we describe in detail the synthesis of the fluorogenic renin substrate and its application in assays of renin activity. Assay sensitivity has been evaluated by a series of enzyme dilution experiments using the continuous assay format, showing that the assay can detect renin as low as 30 ng/ml after a incubation of only 3-5 min. It was estimated that with extended incubation time (2-3 h) the assay can detect renin at 0.5 ng/ml concentration level. An automated, high throughput fluorometric renin assay has been developed for a 96-well microtiter-plate fluorescence reader, which is useful for studies of enzyme inhibitors and enzyme stability.     

Angiotensin II in epitheloid (Renin containing) cells of rat kidney

Summary The PAP-method was used for immunocytochemical investigations with antisera against angiotensin (ang) I, ang II and renin in kidneys of rats and mice. In 14 rats, ang II was found in the media of the afferent arteriole — both in the region of the JGA and upstream until the interlobular artery. Serial sections alternately reacted for ang II and renin revealed that the octapeptide is contained in the well known renin positive epitheloid cells of the afferent arteriole and, beyond that, together with renin probably in the same specific granules. Fixation conditions were critical for the visualization of immunoreactivity. With ang I antisera, comparable in terms of titer and affinity to the ang II antisera, specific immunoreactivity could not be found in the kidneys of rats. With horse radish peroxidase and ferritin as tracers it could be shown that the epitheloid cells of the JGA have the ability to pinocytize and incorporate macromolecules into their granules. It is suggested that ang II is taken up by these cells through the same route. Intracellular generation of ang II appears unlikely as an explanation. Functionally the selective uptake of ang II by epitheloid cells might be a specific process, possibly connected with the negative feedback of the octapeptide on renin secretion. Negative results in mice may be explained by a small uptake or more rapid degradation of ang II by the epitheloid cells.These studies were supported by the Deutsche Forschungsgemeinschaft within the SFB 90 Cardiovasculäres System. A first brief report of the results was given at the Rottach-Egern Satellite Symposium of the VIIth International Congress on Nephrology: The Juxtaglomerular Apparatus and the Tubulo-Glomerular Feedback Mechanism — Morphology, Biochemistry and Function, June 3 to 5, 1981     

The Influence of Angiotensin Infusion on the Urine Composition in Individual Kidney Function Tests

Thirty-two patients with hypertension were given a pressor dose of angiotensin in the course of individual kidney function tests. In eight patients with unilateral renal artery stenosis the differences in urine sodium and creatinine concentration between the affected and the nonaffected kidney did not become greater with angiotensin infusion. In four patients with unilateral pyelonephritis and falsely positive individual kidney function tests, these tests became normal following angiotensin infusion. It is concluded that angiotensin infusion is not a useful means of improving the results of individual kidney function tests.     

新型一次性输液器在手术病人输液护理中的应用

目的:探讨手术病人应用新型一次性输液器在防进气、测量中心静脉压(CVP)等方面的效果.方法:将1201例在我院手术中心手术患者,采用自身对照方法,随机分为新型组与传统组,比较两组进气例数、排气时间;分为管测组(使用新型输液器)与机测组(采用心电监护仪)测量同一手术病人CVP,比较两组测量值.结果:新型组在进气例数、排气时间方面少于传统组,差异有统计学意义(P＜0.05),管测组在测量CVP方面与机测组差异无统计学意义(P＞0.05).结论:应用新型一次性输液器防进气,可提高护理工作效率,也增强了输液治疗的安全性,提供了一种观测患者CVP的简易有效装置,临床应用性强.     

Intrarenal Renin Angiotensin System Revisited: ROLE OF MEGALIN-DEPENDENT ENDOCYTOSIS ALONG THE PROXIMAL NEPHRON

The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligand-binding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a “self-contained” renal RAS.     

Characterization of the Cardiac Renin Angiotensin System in Oophorectomized and Estrogen-Replete mRen2.Lewis Rats

The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17) or sham-operation (Sham; n = 13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 β-estradiol (E2, 36 µg/pellet, 60-day release, n = 8) or vehicle (OVX-V, n = 9) for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang) II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1–7) content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R). E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1–7) mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.     

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol.The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.     

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5 - 10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms.