Extrarenal renin and blood pressure regulation. An alternative viewpoint

There is increasing evidence that a major site of production of angiotensin I and II is peripheral tissue. Both angiotensin I and II are present in venous blood in amounts far too high to be explained by their generation in blood alone, given the extensive conversion of angiotensin I to angiotensin II and clearance of both peptides across peripheral tissues. Much indirect evidence supports this argument for angiotensin production in tissues, and indicates that tissue production of angiotensin plays an important role in regulation of blood pressure. Tissue renin may represent uptake from plasma and/or local synthesis, but despite the ease with which renin-like activity can be measured in tissues, its interpretation is problematic because of interference by nonrenin enzymes and inadvertent activation of inactive renin. Moreover, given that enzymes other than renin are able to liberate angiotensin I and angiotensin II from angiotensinogen, there is no obligatory role for renin in angiotensin production in tissues. Inasmuch as tissue production is the major source of plasma angiotensin, the fall in plasma angiotensin levels after bilateral nephrectomy indicates that kidney-derived renin is the major contributor to tissue angiotensin production. This argument is supported by evidence that vascular renin-like activity is kidney-derived, and plays a dominant role in angiotensin-dependent pressor mechanisms. Near-normal levels of inactive renin in plasma of anephric subjects indicates extrarenal synthesis of inactive renin, and renin mRNA has been identified in various nonrenal tissues. Whether these tissues are also able to process inactive renin to active renin, and its role in local angiotensin production and blood pressure regulation, are currently being investigated.     

Vascular renin and hypertension. Uptake versus synthesis

Conventional radioimmunoassay techniques demonstrated in the aortic wall a renin-like activity which is derived from plasma but has a longer half-life than plasma renin. Blood pressure elevation after renin injection into nephrectomized rats correlates better with aortic renin than with plasma renin. Vascular and other extrarenal tissue can also synthesize renin. Using a ribonuclease protection technique for the detection of renin messenger RNA we have been able to demonstrate that a wide variety of extrarenal tissues contain the renin message. In at least two of these, the brain and the liver, renin messenger RNA levels are unaffected by changes in dietary salt or by changes in systemic blood pressure. Functional studies using isolated human resistance vessels also demonstrate the presence of renin-like activity by a contractile response to added renin substrate. It is suggested that extrarenal tissues therefore contain renin-like activity derived both from uptake and from local synthesis. These systems may be regulated in different ways and may carry out different functions.     

老年原发性高血压患者动态血压参数与部分体液因素的相关性研究

目的观察老年原发性高血压患者动态血压参数与血浆肾素、血管紧张素Ⅱ及醛固酮的相关性及其临床意义。方法将162例患者分为A纽82例（〉60岁）,B组80例（〈60岁）,采用放射免疫法检测162例原发性高血压患者的血浆肾素、血管紧张素Ⅱ及醛固酮水平,同时测定24h动态血压,进行相关分析。结果（1）老年高血压具有是脉压增大,波动性大,晨峰高血压现象及并发症多的特点;（2）A组血浆肾素、血管紧张素Ⅱ及醛固酮水平明显高于B组;（3）血浆肾素、血管紧张素Ⅱ及醛固酮与老年高血压的特点,特别是脉压增大、波动性大、晨峰高血压现象有关。结论老年原发性高血压患者血浆肾素和血管紧张素Ⅱ浓度升高,提示血浆肾素、血管紧张素一醛固酮系统对老年原发性高血压心血管系统有影响,导致老年原发性高血压患者血压特征性的变化,血浆肾素、血管紧张素Ⅱ和醛固酮的测定可作为老年原发性高血压患者病情监测及治疗指标之一。     

Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness

A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested. Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses. Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials. Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.     

Arterial renin--partial characterization and its possible role in the pathogenesis of hypertension

1) Renin-like enzyme of rat aorta was purified by chromatography with DEAE-cellulose and Sephadex G-200. 2) The molecular weight of renin-like enzyme was 124,000 and 72,000 on Sephadex G-200 gel filtration. The isozymes, however, migrated as a single band with molecular weight of 71,000 on SDS/polyacrylamide gel electrophoresis. These isozymes showed the same optimal pH (6.5) and temperature (37 degrees C). 3) Renin-like enzyme showed high activity in the microsomal fraction of the aorta. 4) In one-clip, two-kidney Goldblatt hypertensive rats, the aortic renin concentration increased significantly, but not parallel with the activity in plasma. 5) Renin, widely distributed in subcellular fractions of the aorta, may play a possible role in the local control of vascular tone. It is likely that renin in vascular wall is of local origin.     

Active and Inactive Renin-like Enzymes in the Arterial Wall of the Spontaneously Hypertensive Rat

Renin-like enzyme(s) in the arterial wall of the spontaneously hypertensive rat (SHR) were activated markedly by either acidic pH or treatment of proteolytic enzymes (trypsin and glandular kallikrein). The highest concentration of renin-like enzyme (active form) was localized in the renal artery (2.51±0.59 ng angio-tensin I generated/mg of protein per h, mean±S.D.), followed by the mesenteric (1.58±0.31), the carotid (1.44±0.27) and the major aortic trunk (0.20±0.10), while the highest concentration of the inactive renin-like enzyme was localized in the major aortic trunk (0.97±0.18), followed by the carotid (0.72±0.41), the renal (0.71±0.31) and the mesenteric (0.60±0.29) arteries. In addition, the active renin-like activity from the mesenteric and the carotid arteries of SHR rats was higher significantly than that of age-matched normotensive Wistar-Kyoto (WKY) rats, despite a similar concentration of total renin-like enzyme of the corresponding arteries of both groups. These results suggest that increased interconversion of the inactive to the active renin-like enzymes in the arterial wall of SHR rats may result in local vasospasm through generation of angiotensin II, which may contribute in part at least to systemic hypertension of SHR rats.     

Use of Captopril in the Diagnosis of Renal Hypertension

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

Brain Renin

Although the brain contains cathepsins at high concentrations which exhibit a non-specific renin-like activity at acidic pH, the presence of specific renin in the brain has been demonstrated by characterizing its specific properties. Renin was separated from cathepsin by affinity chromatography on casein-Sepha-rose. Brain renin showed neutral pH optima for the reaction to generate angiotensin I. The presence of inactive prorenin was also found. The isoelectric points of brain renin were significantly lower differences from that of renal or plasma renin.

Immunohistochemical studies demonstrated a wide-spread localization of renin in many different regions. Angiotensin II, the final product of the prohor-mone-to-hormone conversion reaction mediated by renin and angiotensin converting enzyme, was found to exist in the same cell as renin by immunohistochemical studies of brain sections and with cloned and cultured neuroblastoma cells. This is the first demonstration of the mechanism of peptide hormone formation in neuronal cells. Similar intracellular formation was demonstrated in gonadotrophs of adenohypophysis.

Coexistence of renin and angiotensin II was demonstrated in some cells. Electrophysiological studies have shown that angiotensin II functions to disinhibit the inhibition of neuronal response to electrical stimuli in the hippocampus.     

Methodologic features of determining renin-like activity in human arteries]

Human arterial tissue was shown to have renin-like activity. For its determination the authors propose methodological approaches. The optimum pH of renin activity in the vascular wall was found to be 5.8-6.0. The renin-like enzyme was ascertained to be present in the vascular wall as inactive and to be activated by trypsin. The renin activity was compared in the human vascular wall and human plasma. Their optimum pHs were nearly identical. The methodological features determined in this paper allowed one to differentiate the true renin-like activity from the activity of acid proteases.     

Facilitation of adrenergic transmission by locally generated angiotensin II in rat mesenteric arteries.

When studied on isolated rat mesenteric arteries perfused with Tyrode's solution, angiotensin I and angiotensin II (1 ng/ml), a synthetic tetradecapeptide renin substrate, and a purified hog renin substance (50-100 ng/ml) potentiated vasoconstrictor responses to sympathetic nerve stimulation and to injected norepinephrine without altering basal pressure. These agents produced a greater augmentation of the vasoconstrictor responses to nerve stimulation than to injected norepinephrine. The potentiation of vasoconstrictor responses to sympathetic nerve stimulation and injected norepinephrine which was elicited by renin substrate and angiotensin I was abolished by an inhibitor of angiotensin I-converting enzyme, SQ 20,881, and by an angiotensin II receptor antagonist, [Sar1-Ile8]angiotensin II. In contrast, the potentiating effect of angiotensin II was blocked only by the latter compound. We conclude that utilization of renin substrate within the vascular wall by renin or renin-like enzymes results in the formation of angiotensin I, which is converted to angiotensin II. Angiotensin in turn potentiates the vasoconstrictor responses to adrenergic stimuli presumably by augmenting release of the adrenergic transmitter and inhibiting its neuronal reuptake as well as by increasing vascular reactivity to norepinephrine.     

Increase of angiotensin converting enzyme gene expression in the hypertensive aorta.

To investigate the possible role of vascular angiotensin converting enzyme (ACE) in the development and maintenance of hypertension, we examined aortic ACE messenger RNA (mRNA) levels in two-kidney, one clip (2K1C) hypertensive rats. The blood pressure was increased remarkably at 4 weeks (early stage) after clipping and remained elevated at 12 weeks (chronic stage). The aorta ACE mRNA levels were significantly elevated in both early and chronic stages concurrently with the increases in aortic ACE activity and blood pressure. The plasma renin activity rose markedly at 4 weeks, but returned to the normal level at 12 weeks. Neither ACE activity in the lung and plasma, nor ACE mRNA level in the lung was altered at either stage. The aorta and liver angiotensinogen mRNA levels and renal renin mRNA level were increased at 4 weeks but decreased at 12 weeks. These results indicate that the acceleration of all components in the renin-angiotensin system may contribute to the development of 2K1C hypertension in the early stage. In the chronic stage, the increased vascular ACE induced by the elevated ACE mRNA levels in the aorta may play the primary role in the acceleration of local angiotensin II formation and thus may sustain the hypertension.     

Biochemical and immunological properties of dog brain isorenin

A neutral protease with angiotensin I-forming activity which could readily be separated from acid proteases and plasma and renal renin was obtained from extracts of dog brain. This enzyme has an apparent mol wt of 40,000 by Sephadex chromatography. On chromatofocusing, it displays isoelectric points of 7.92, 7.73, and 7.42, and thus, it is a basic protein, in contrast to either renal or plasma renin which are acidic proteins. This brain enzyme does not react with antibodies specific for dog kidney renin. Since the brain enzyme forms angiotensin I from renin substrate at neutral pH, yet can be separated from and has isoelectric points different from renal renin, it is an isoenzyme of the kidney counterpart. The majority of the renin-like activity of dog brain is due to this isoenzyme.     

Role of Renin-Angiotensin and Kallikrein-Kinin Systems on the Mechanism of the Hypotensive Effects of Converting Enzyme Inhibitor,Alacepril

In four patients with essential hypertension and one patient with renovascular hypertension, decreases in blood pressure and plasma angiotensin II levels, and increases in plasma renin activity and plasma kinin levels were observed during eight days of alacepril treatment. Significant correlations between the changes in mean arterial pressure and those in plasma angiotensin II or kinin levels were observed positively or negatively, respectively, in the essential hypertensives. These findings suggest that the hypotensive effect of alacepril might be caused mainly by a decrease in plasma angiotensin II levels and, at least in part, by an increase in plasma kinin levels.     

Effect of the angiotensin II blocker 1-Sar-8-Ala-angiotensin II on renal artery clip hypertension in the rat.

Twenty-four conscious male Wistar rats with hypertension induced by left renal artery clipping (two-kidney hypertension) were infused intravenously with 1-Sar-8-Ala-angiotensin II a competitive angiotensin II antagonist. The spectrum of responses was wide, ranging from a mild elevation in blood pressure to a marked fall in blood pressure, despite effective and specific angiotensin blockade in all cases. The change in blood pressure during 1-Sar-8-Ala-AII infusion activity showed a significant correlation with the level of plasma renin prevailing immediately before the infusion (r = - 0.78, P less than 0.01) but not with the prevailing blood urea level (r = 0.27, 0.1 greater than P greater than 0.05), the drgree of hypertension (r = 0.42, 0.1 greater than P greater than 0.05), or the time since clipping (r = 0.02, P greater than 0.05). There was no significant correlation between the degree of hypertension and the plasma renin activity (r = 0.42, 0.1 greater than P greater than 0.05). In rats with blood pressure drops greater than 20 mm Hg in response to 1-Sar-8-Ala-AII, the final blood pressure level was still above the normotensive range. Excision of the clipped kidney reduced blood pressure to normal or to near normal within 24 hours in all of the rats tested. It is concluded that the degree of dependence of renal hypertension on the renin-angiotensin system is directly related to the increase in circulating angiotensin itself and not to an increase in sensitivity to angiotensin. Other factors appear to be involved in renal clip hypertension in addition to circulating renin and angiotensin, especially when the measured activity of plasma renin is normal.     

Myocardial enzymatic activity of renin and cathepsin D before and after bilateral nephrectomy

A local renin-angiotensin system is present within the myocardium and can play a role in the initiation and maintenance of cardiac hypertrophy. The source of myocardial renin may be direct cardiac renin gene expression, or plasma renin of renal origin. A primary indication that myocardial renin is derived from plasma renin of renal origin was from work showing that cardiac renin activity was no longer detected 30 hours after bilateral nephrectomy (BNX). However, more recent studies have been able to detect myocardial renin after BNX. We measured normal rat cardiac renin before and after 48-hour BNX using a myocardial renin assay with improved sensitivity. The myocardial renin assay was also used to assess normal rat cardiac myocyte renin levels. Since cardiac tissue contains cathepsin D, a lysosomal enzyme capable of renin-like activity, a rat cathepsin D assay was also developed to assess cathepsin D contribution to renin-like activity. Several artifacts were shown to contribute to myocardial renin-like enzymatic activity levels after BNX, including initial plasma renin stimulation during BNX surgery, assay pH, and cardiac cathepsin D activity. Myocardial renin concentration after 48-BNX was found to be only ∼1 % of normal control levels, and renin concentration in normal cardiac myocytes was only 2-fold greater than assay blanks. Both results were probably overestimated due to cathepsin D contamination. In conclusion, no evidence was found for myocardial renin synthesis in the normal adult rat heart, and myocardial renin decays to near zero levels after 48-hour BNX. Received: 5 March 2001, Returned for revision: 12 March 2001, Revision received: 9 April 2001, Accepted: 10 April 2001     

Failure of renin suppression by angiotensin II in hypertension

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.     

A renin-like enzyme in luteal tissue

The aim of this study was to identify immunologically and biologically a renin-like enzyme (RLE) in rat corpora lutea (CL). The biological activity of partially purified extracts of CL was tested in vivo by injection into anesthetized pentolinium-treated rats, obtaining a pressor response similar to renal renin. The enzyme activity in vitro was inhibited to about 50% by pretreatment with a specific antibody against renal renin. When the extracts were incubated with angiotensinogen, the product was inhibited mainly by angiotensin I antibody. The fact that there was no change in RLE content in 24 or 48 h nephrectomized rats, suggested the idea of a local production rather than an active blood renin sequestration.     

Chronic MK421 fails to modify evolution of hypertension in neonatally coarcted pups

In inbred dogs with neonatally induced coarctation hypertension, prior serial studies during the first year after aortic banding showed extracellular volume excess with normal plasma renin activity (PRA). The present studies test the hypothesis that slowly evolving aortic constriction in this model will yield intrarenal angiotensin II excess, peripherally undetectable, with continuous slightly positive sodium balance, and thus that chronic blockade of angiotensin II formation will prevent generation of hypertension. Accordingly, we used MK421 (enalapril, 3 mg/kg twice daily), a long-acting angiotensin converting enzyme inhibitor, or placebo, administered orally, from the time of banding through 4 months after banding in sex-matched littermates randomly assigned to one of four groups: coarcted/MK421; control/MK421; coarcted/placebo; control/placebo. Results indicate that MK421 caused identical lowering of absolute forelimb systolic blood pressure in coarcted and control pups but failed to modify evolution of a significant (p less than 0.005) systolic blood pressure difference in coarcted versus control dogs. Thus, neither temporal course nor final magnitude of relative hypertension was altered by MK421. Efficacy of MK421 was documented by 83% inhibition of the pressor response to angiotensin I at nadir of drug effect and by sustained increases in angiotensin I and renin concentration throughout the period of study. Coarcted and control pups responded similarly to MK421 for all measured variables. Glomerular filtration rate and extracellular volume (measured by [14C]inulin disappearance) did not differ among groups. Thus, chronic administration of MK421 failed to prevent hypertension and did not impair maintenance of normal renal function in the evolving phase of neonatally induced coarctation hypertension. We conclude that, although angiotensin II may participate in the untreated model, it does not appear essential to generation of hypertension. We propose that the renal pressure-natriuresis mechanism regulates distal pressure, that stenosis-related resistance independently determines the proximal-distal difference, and that chronic converting enzyme inhibition lowers the set point of the former without influencing stenosis evolution, thus secondarily lowering proximal pressure by an equal degree.     

原发性高血压患者血浆肾素活性水平与血压和尿钠的关系

目的分析原发性高血压患者血浆肾素活性水平与血压、尿钠排泄的关系。方法原发性高血压患者479例,根据血浆肾素活性水平的5分位排序,分为3组,低肾素组93例,中间肾素组291例,高肾素组95例。各组血浆肾素活性与24 h动态血压及24 h尿钠排泄情况进行相关性分析。结果与低肾素组比较,中间肾素组和高肾素组年龄明显偏低,血浆肾素活性明显增高,差异有统计学意义(P<0.05,P<0.01)。低肾素组老年人、女性、非杓型血压比例明显高于高肾素组,差异有统计学意义(P<0.01)。血浆肾素活性水平与24 h尿钠排泄、24 h血压呈负相关(P<0.05,P<0.01)。结论老年和女性原发性高血压患者血浆肾素活性水平较低。低肾素患者血压昼夜节律改变更明显,以非杓型血压多见。     

Converting Enzyme Inhibition in Mild and Moderate Essential Hypertension. II

ABSTRACT. In 24 patients with mild/moderate essential hypertension, we studied the effects of captopril with/without hydrochlorothiazide (Htz) on blood pressure, the renin-angiotensin system, blood bradykinin concentration (BBK), plasma volume, exchangeable sodium and glomerular filtration. Daily captopril doses of 75 and 150 mg were equally effective in reducing the blood pressure. Addition of Htz caused further blood pressure reductions. Nineteen patients attained a diastolic blood pressure ≤90 mmHg. Angiotensin converting enzyme inhibition with captopril led to a fall in plasma concentrations of angiotensin II (PAII) and renin substrate, and an increase in plasma concentrations of renin and angiotensin I. Patients starting with Htz had a higher PAII and subsequently a larger fall in blood pressure on captopril than untreated patients. BBK remained unchanged, indicating that the hypotensive action of captopril does not involve an accumulation of circulating kinin. Body fluid volumes and renal function were not affected by the various treatment regimens.