Renin activity in the brain, the kidneys and the peripheral plasma or rats with different experimental models of hypertension

Renin activity (RA) in peripheral plasma, as well as in renal cortex and brain (cortex, stem and medulla) homogenates of rats with spontaneous, Goldblatt, NaCl, adrenal-regeneration and neurogenic hypertension was biologically assayed. The results suggest that RA exists not only in the brain of normotensive but of hypertensive rats as well. RA in the medulla is higher than in other brain areas and in the kidney, both in normotensive and in hypertensive rats with the exception of rats with adrenal regeneration and NaCl hypertension. In most of the experimental forms of hypertension (neurogenic, renal, spontaneous) in which RA in the medulla is increased, the role of the brain renin-angiotensin system seems to predominate, while in forms in which renal RA is elevated (adrenal regeneration) the kidney renin system most probably plays a more important role. A definite inverse interrelation between the brain and the kidney renin-angiotensin systems was established. The interrelation between the two renin systems in NaCl hypertension could not be evaluated, since exogenous factors (Na), which interfere with the kidney renin system, play a considerable role in the pathogenesis of NaCl hypertension.     

Tissue renin-angiotensin systems in renal hypertension.

Angiotensinogen messenger RNA (mRNA) levels were measured in the brain (hypothalamus, lower brain stem, cerebellum), liver, kidneys, and adrenal glands of rats made hypertensive by ligation of the aorta between the renal arteries. We also measured renin mRNA in the kidneys of these renal hypertensive rats. The early phase of hypertension (day 6) was associated with significant increases in plasma renin activity and levels of circulating angiotensin II. The circulating renin-angiotensin system was not activated in the later phase of hypertension (day 24). Angiotensinogen mRNA levels were elevated in the lower brain stem of hypertensive rats at both stages of hypertension. In contrast, angiotensinogen mRNA levels in the hypothalamus were increased only at day 6 after aortic ligation. Decreased levels of angiotensinogen mRNA were observed in the cerebellum in both the early and later phases of the hypertension. Angiotensinogen mRNA levels in the adrenal gland below the ligature fell in the early phases but rose in the later phases of hypertension. Renin mRNA levels of the ischemic kidney remained elevated at both the early and later phases, whereas in both ischemic and nonischemic kidneys, levels of angiotensinogen mRNA remained below sham values throughout the period of study. These results indicate differential expression of renin-angiotensin system mRNAs in tissues of renal hypertensive rats. The differential changes in the expression of angiotensinogen mRNA over the course of development and maintenance of renal hypertension suggest that factors in addition to angiotensin II are important in modulating the expression of renin-angiotensin system genes.     

Angiotensin-converting enzyme inhibitor (SQ 20881) in the diagnosis of renovascular hypertension.

SQ 20881, an angiotensin-converting enzyme inhibitor, was given to 12 patients with renovascular hypertension and to 1 patient with unilateral parenchymatous renal disease in order to evaluate the role of renin-angiotensin systems in their hypertension. Plasma renin activity (PRA) and aldosterone were assayed in systemic blood before and after the injection of SQ 20881. In 5 patients PRA was also measured separately in each renal vein. Blood pressure decreased, PRA increased, and aldosterone level decreased in the 12 renin-dependent patients. When PRA was sampled separately from each renal vein, the increase was larger on the side of the affected kidney. Four patients with a positive test underwent corrective surgery, and in all blood pressure became normal. SQ 20881 is a useful agent in evaluating the contribution of renin in patients with hypertension.     

Concentration and molecular forms of active and inactive renin in human fetal kidney, amniotic fluid and adrenal gland: evidence for renin-angiotensin system hyperactivity in 2nd trimester of pregnancy

In a study of 38 fetuses total kidney renin was significantly correlated with gestational age (r = 0.63). Although whole fetal kidney renin specific activity was found to decrease with gestational age (r = -0.65), the mean value of the specific activity was about 20 times greater than in normal adult cortex and double that in tissue from patients with renal artery stenosis, suggesting renin-angiotensin system hyperactivity. In approximately 40% of fetal kidneys examined, evidence for an inactive (trypsin-activatable) renin precursor was found. The molecular weight of this form was indistinguishable from active renin (45 000 daltons) by Sephadex chromatography. Amniotic fluid from nine cases (100%) contained angiotensin (ANG) 1, angiotensin converting enzyme (ACE), renin substrate, active and inactive renin (both 45 000 daltons). Five of the 38 (13%) fetal adrenal glands contained renin, but no evidence for trypsin-activatable forms. Aldosterone was present in low concentration in the earliest adrenals examined, and a positive correlation existed between total tissue aldosterone and gestational age (r = 0.73). These findings suggest that the fetal renin-angiotensin system has an important role to play in the maintenance of extracellular fluid volume and blood pressure in the developing fetus.     

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.     

Severe hypertension with segmental renal infarction following surgical removal of a retroperitoneal malignant hemangiopericytoma: a case report

Severe hypertension developed in a fifty-five year-old woman after surgical removal of a retroperitoneal tumor, when the renal artery was injured. Renal arteriography after the surgery demonstrated a segmental infarction of the right kidney. A close relationship between activation of the renin-angiotensin system and the development of severe hypertension was observed. Satisfactory control of blood pressure concomitant with reduction of plasma renin activity was achieved by a combination of an angiotensin-converting anzyme inhibitor, beta-blocking agent, and calcium-entry blocker. The mechanism of activation of the renin-angiotensin system in renal infarction is discussed.     

Malignant hypertension resulting from deoxycorticosterone acetate and salt excess: role of renin and sodium in vascular changes.

The evolution of malignant hypertension was studied under metabolic balance conditions in 11 uninephrectomized rats given deoxycorticosterone acetate and 1% NaCl as drinking water. Changes in sodium and potassium balance were related to changes in blood pressure, plasma renin activity, hematocrit, and kidney histology. After 3-4 weeks of steadily positive sodium balance accompanied by continuously increasing blood pressure up to 185 plus or minus 19 (SE) mm Hg, periods of sodium loss accompanied by evidence of hemoconcentration were observed marking the onset of the malignant phase as defined by the development of fibrinoid necrosis in the kidney. Plasma renin activity remained markedly suppressed both at the fourth week (0.33 plus or minus 0.02 ng/ml hour-1) when the sodium balance was positive and the kidney biopsy negative and at the end of the experiment (0.35 plus or minus 0.36 ng/ml hour-1) when the sodium balance was negative and the kidney histology revealed malignant vasculitis. Infusion of the angiotensin II inhibitor 1-Sar-8-Ala-angiotensin II consistently failed to affect blood pressure, and the kidney tissue norepinephrine level was reduced (0.054 plus or minus 0.01 mug/g) compared with the control level (0.132 plus or minus 0.02 mug/g). We conclude that malignant vasculitis in this model is preceded by hypertension associated with sodium and water retention and is accompanied by negative sodium balance, decreases in body weight, falling blood pressure, and hemoconcentration without demonstrable participation of the renin-angiotensin system or the renal catecholamines.     

Markedly elevated specific renin levels in the adrenal in genetically hypertensive rats.

The specific renin (EC 3.4.99.19) activity in the adrenal of spontaneously hypertensive rats was determined by a method that is capable of distinguishing renin from nonspecific renin-like activity of proteases by using specific antibody to renin. The renin level in the adrenals of adult spontaneously hypertensive rats with established hypertension was found to be 6-8 times as high as that of the normotensive control Wistar-Kyoto strain. The large difference in the adrenal renin level was observed even in 3-wk-old rats in which hypertension has not yet developed. The adrenal renin level was increased by bilateral nephrectomy in both the hypertensive and normotensive strains. A larger quantity of renin was found in the adrenal cortex than in the medulla, and the difference between the hypertensive strain and the normotensive strain was more prominent in the cortex than in the medulla. These results suggest possible involvement of adrenal renin in the development and in the early maintenance phase of hypertension in this animal mode of human essential hypertension by affecting the adrenocortical or adrenomedullary activity, or both.     

The role of renal hemodynamics in the antihypertensive effect of captopril

To evaluate the role of regional hemodynamics in mediating the long-term depressor effect of the converting enzyme inhibitor, captopril, at a low dose (37.5 mg/day), for 2 weeks, its systemic, renal, and forearm circulatory actions were determined in 12 patients with mild to moderate essential hypertension. After administration of captopril, there was a significant decline in mean blood pressure (average -12.1 +/- 1.9%) accompanied by a decrease in systemic vascular resistance (-9.1 +/- 3.3%), but cardiac output did not change. Although forearm vascular resistance was not altered, renal vascular resistance decreased considerably (-17.1 +/- 5.0%). Moreover, there was a highly significant (r = 0.891) correlation between the changes in mean blood pressure and renal vascular resistance. Plasma renin activity increased after therapy as plasma aldosterone decreased, while plasma norepinephrine slightly increased. The change in renal vascular resistance significantly (r = -0.617) correlated with the pretreatment level of plasma renin activity. These findings suggest that suppression of the renin-angiotensin system in essential hypertension induces selective vasodilation in the renal vasculature, which may play an important role in the long-term antihypertensive effect of the converting enzyme inhibitor. This renal vasodilator action appears to be the feature that distinguishes the converting enzyme inhibitor from conventional vasodilator drugs.     

Specific inhibition of the renin-angiotensin system: A key to understanding blood pressure regulation

The availability of specific inhibitors of the renin-angiotensin system has made it possible to evaluate precisely the contribution of this system to the maintenance of normal blood pressure and of various hypertensive situations encountered in animal models and in man. Furthermore, by combining the blockade of the renin system with accurate measurements of sodium balance, it is possible to expose and quantify latent or manifest abnormalities in renal sodium handling that operate directly or by interacting with the renin system.Experimental and clinical observations made with these inhibitors support the hypothesis that the level of blood pressure, normal or abnormal, is largely determined by two components: (1) the renin system (i.e., the angiotensin II-vasoconstrictor factor) and (2) the sodium extracellular and intravascular volume factor, which in the longer term may be indirectly supported by the renin system via angiotensin-induced aldosterone secretion.Normally, without threat to the homeostasis, the sodium volume component appears to be the main factor determining blood pressure and sustaining renal perfusion via adequate or—if necessary—increased blood pressure. However, whenever renal perfusion is compromised due to such events as hemorrhage, sodium depletion, upright posture, exercise, cardiac failure, cirrhosis, or renal vascular impairment, renin is secreted by the kidney. It seems that the renin-angiotensin system is the main vasoconstrictor system used by the body to support the sodium volume component to maintain or restore adequuate renal perfusion. There is little evidence that the catecholamines and the nervous system play any major or direct role in sustaining blood pressure, although indirectly they may be critically involved in monitoring renal renin release.Two models of renal hypertension have served as the experimental basis for development of this concept. Established two-kidney Goldblatt hypertension (one renal artery clipped, contralateral kidney intact) was found to be renin-dependent, since angiotensin II blockade induced a marked fall in blood pressure. Clinical counterparts to this predominantly “vasoconstrictor” type of hypertension are renovascular hypertension with unilateral renal artery stenosis, malignant and essential hypertension with high renin levels, and possibly normotensive situations with reduced “effective” blood volume such as cirrhosis and congestive heart failure.Chronic one-kidney Goldblatt hypertension (one renal artery clipped, contralateral nephrectomy) under conditions of unrestricted sodium intake appeared on the other hand to be predominantly sodium-volume-dependent, so that angiotensin II blockade did not alter the pressure level. However, sodium (and volume) depletion did not lower the blood pressure either in this model but resulted instead in a compensatory rise of renin release, and thus in a transition from a sodium-volume to vasoconstrictor-maintained type of hypertension. Accordingly, under conditions of sodium depletion, angiotensin II blockade did markedly reduce the blood pressure. Clinical counterparts to this model in which simultaneous sodium depletion plus blockade of the renin system are necessary to reduce blood pressure appear to be most patients with normal renin essential hypertension, chronic renal failure with normal or low renin levels, renovascular hypertension with bilateral renal artery stenoses, and possibly coarctation of the aorta.In contrast to these two model situations, low-renin essential hypertension as well as the hypertension induced by an excess of various mineralocorticoids appears to represent a pure volume type of hypertension, in which a diuretic-induced volume reduction does not result in a compensatory rise in renin release and a shift to vasoconstrictor support but instead results in a parallel reduction of blood pressure.     

Antihypertensive effects of captopril and saralasin in essential and renal hypertension

The antihypertensive effect of captopril and its mechanism of action were studied in patients with essential and renal hypertension. In mild essential hypertension (n = 12), during monotherapy with captopril (50 to 450 mg, 4 to 12 weeks) blood pressure was normalized in seven, improved in two and remained unchanged in three patients, plasma levels of active and acid-activatable inactive renin significantly increased and angiotensin II decreased, whereas no consistent changes in urinary kallikrein excretion occurred. In severe renal (n = 14) and essential (n = 9) hypertension, blood pressure was normalized in eight (seven with renal hypertension), improved in seven and unchanged in eight patients, when captopril (50 to 450 mg, 3 to 15 months) was added to the antihypertensive medication. In one patient with stenosis in a transplanted renal artery reversible renal failure occurred during captopril therapy possibly because of a steep initial decrease in blood pressure, although a toxic effect of the drug cannot be excluded. In another series of 12 renal and 8 essential hypertensive patients, a significant correlation between the acute effect of captopril (within 90 minutes) and saralasin on blood pressure was demonstrated (r = 0.71, p < 0.001). The change in blood pressure after either drug was significantly related to the initial plasma renin concentration.In conclusion, captopril sems to be an effective antihypertensive agent in essential and renal hypertension. Renal function should be monitored during captopril therapy. Our studies suggest that captopril decreases blood pressure by inhibiting the vasopressor action of the renin-angiotensin system.     

Evidence for the existence of inactive renin in the rat brain. Part II. Distribution of inactive renin in the brain of spontaneously hypertensive rats

Inactive renin in the brain of spontaneously hypertensive rat was investigated. The results are as follows. Treatment with either trypsin or glandular kallikrein of the brain tissue extract caused a rapid and apparent increase in the renin activity at either 0 or 27 degrees C. The molecular weight of the active renin was estimated to be 41,000 or 50,000 daltons, while that of the trypsin-activatable inactive renin was found to be 44,000 or 57,000 daltons on a column chromatography with Sephadex G-100. The contents of the active renin was the highest in the hypothalamus, followed by the striatum, thalamus, midbrain, medulla oblongata, cerebral cortex and cerebellum, while the contents of the trypsin-activatable inactive renin was the highest in the hypothalamus, followed by the striatum, thalamus, cerebellum, midbrain, cerebral cortex and medulla oblongata. These results suggest that inactive renin(s) exist in the brain of spontaneously hypertensive rat. It seems likely that the brain renin-angiotensin system is modulated by the conversion of inactive to active renin(s), which, in turn, plays at least in part a role in the blood pressure regulation through generation of angiotensin II in spontaneously hypertensive rats.     

Role of vascular wall renin: intracellular and extracellular mechanism

Inhibitors of angiotensin-converting enzyme, renin and angiotensin II receptor lower the blood pressure of spontaneously hypertensive rats (SHRs) used as a model of essential hypertension. Since their plasma renin levels were normal or subnormal, renin in the vascular tissue was considered to play a key role in the maintenance of the hypertension. To clarify the source and localization of vascular renin in SHRs, the effects on blood pressure of antirenin antibodies, the converting enzyme inhibitors delapril and enalapril, and the angiotensin II receptor antagonist DuP 753 were examined in intact and bilaterally nephrectomized SHRs and their normotensive controls. The efficient hypotensive action of the renin antibody indicated that renin of the renal origin is a dominant factor. The gradual but complete disappearance of the antihypertensive action of these inhibitors of the renin-angiotensin system upon bilateral nephrectomy indicated the importance of membrane-associated renin of the renal origin and angiotensin-converting enzyme in the maintenance of the spontaneous hypertension.     

Role of nitric oxide in the control of renal function and salt sensitivity

Nitric oxide (NO) plays critical roles in the control of renal and glomerular hemodynamics, tubuloglomerular feedback response, release of renin and sympathetic transmitters, tubular ion transport, and renal water and sodium excretion. This paper explores the importance of NO in the control of renal water and sodium excretion and in the long-term control of arterial blood pressure. Synthesis of NO, characteristics of NO tissue redox forms, NO synthase activity, and NO synthase isoforms in the kidney are reviewed. To define the role of NO as a natriuretic and antihypertensive factor, the most supportive evidence is summarized, and some contradictory results are also noted. Given the evidence that high salt intake results in high NO concentrations and great NO synthase expression and activity selectively in the renal medulla of the kidney, as well as evidence of a deficiency of the NO synthase activity in Dahl salt-sensitive rats confined in the renal medulla, this report emphasizes the mechanisms by which the renal medullary L-arginine/NO system controls sodium excretion and arterial blood pressure. Other mechanisms for the action of NO on sodium homeostasis such as the action on glomerular filtration rate and the direct effect on tubules are also discussed. We conclude that there is strong evidence that under physiologic conditions, NO plays an important role in the regulation of renal blood flow to the renal medulla and in the tubular regulation of sodium excretion. It is thereby involved in the long-term control of arterial blood pressure, and inhibition or deficiency of NO snythase may result in a sustained hypertension.     

大剂量雌二醇对大鼠血浆和组织中P物质和锌离子含量的影响

采用放射免疫和原子吸收方法．检测雌二醇诱发高血压过程中大鼠血浆和部分组织中P物质和微量元素锌含量的改变。结果表明雌二醇诱发高血压大鼠下丘脑、延脑中P物质含量显著升高．脑垂体、肾上腺和血浆中P物质含量显著降低（P＜0.05～0.01）。延脑、肾上腺和血浆中锌离子升高，肾脏锌离子显著降低（P＜0．05～0．01）。提示P物质参与雌二醇诱发高血压过程；雌二醇可能通过影响心血管中枢、肾上腺、肾脏及血浆中依赖于锌离子的酶的活性而使血压升高。     

Historical perspectives on the renin-angiotensin-aldosterone system and angiotensin blockade

Advances leading to recognition of the relation of the renin-angiotensin system to aldosterone include: (1) development of analytic techniques for measuring aldosterone, (2) discovery of an aldosterone-stimulating factor in circulating plasma, (3) the finding that a potent aldosterone-stimulating factor is secreted by the kidney, (4) evidence that synthetic angiotensin II increases aldosterone secretion, (5) fractionation of crude kidney extracts and the finding that aldosterone-stimulating factor is renin, (6) the observation that high plasma renin activity occurs in secondary aldosteronism, and (7) recognition that the renin-angiotensin-aldosterone system occurs in congestive heart failure and in renovascular and malignant hypertension. The early use of blocking agents for the renin-angiotensin system is described along with the landmarks of progress. These include the observations that: (1) arterial pressure decreases in experimental renovascular hypertension in response to angiotensin blockade, (2) angiotensin provides important support for arterial pressure in low cardiac output states including congestive heart failure, (3) the kidney participates in this important compensatory mechanism, and (4) cellular receptors for angiotensin are present in the two inner zones of the adrenal cortex.     

Effect of converting enzyme inhibitors on tissue converting enzyme and angiotensin II: therapeutic implications

Local tissue renin-angiotensin systems have recently been discovered in various organs, and evidence is accumulating that inhibition of these local renin-angiotensin systems may contribute to the actions of converting enzyme (CE) inhibitors. Measurements of CE activity and angiotensin II concentrations revealed that after oral administration of CE inhibitors, CE was inhibited not only in lung vascular endothelium and blood, but also in the heart, kidney, vascular wall, brain and other organs. The functional significance of tissue CE inhibition is suggested first by the antihypertensive effect of brain CE inhibition in spontaneously hypertensive rats, second by the concomitant persistence of blood pressure decrease and CE inhibition in vascular wall and kidney after long-term oral CE inhibitor treatment and third by ex vivo experiments demonstrating marked effects of oral CE inhibitor pretreatment on cardiac function in isolated rat hearts. Local inhibition of tissue renin-angiotensin systems may be an important factor involved in the beneficial effects of CE inhibitors in such cardiovascular diseases as arterial hypertension, congestive heart failure and cardiac arrhythmias.     

Renal prostaglandins and the regulation of blood pressure and sodium and water homeostasis

In addition to its well known prohypertensive role in various states of experimental and human hypertension, the kidney has also been shown to exert an antihypertensive “endocrine” function. According to this hypothesis, certain forms of experimental and human hypertension might not solely be the result of an excess in the activity of such renal pressor systems as the reninangiotensin system and the sympathetic nervous system, but might also result from an absolute or relative deficiency of intrarenal vasodilator antihypertensive factors which might allow pressor systems to act unopposed to produce peripheral arteriolar vasoconstriction and sustained hypertension. At least four factors have been characterized in the kidney of various animal species and man which might be responsible for such an antihypertensive function. These are (1) the renomedullary prostaglandins (PGs), (2) the renomedullary antihypertensive neutral lipid, (3) antirenin phospholipid and (4) the renal kinins. This review is restricted to an examination of the possibility that the vasodepressor renomedullary prostaglandins (PGA and/or PGE) may, at least in part, mediate the so-called antihypertensive function of the kidney and participate in the regulation of renal blood flow and natriuresis by physiologic antagonism of various renal vasoconstrictor stimuli such as the renal renin-angiotensin and the sympathetic nervous systems.     

Specific prorenin/renin binding (ProBP) Identification and characterization of a novel membrane site

Renin can be detected in cardiovascular and other tissues but it disappears after bilateral nephrectomy indicating that tissues can take up or bind renal renin from the circulation. If renin uptake is the result of specific binding, plasma prorenin may be a natural antagonist of tissue directed renin-angiotensin systems.To investigate if specific prorenin/renin uptake occurs in rat tissues, binding studies were performed with rat microsomal membrane preparations using recombinant rat prorenin metabolically labeled with ³⁵S-methionine as a probe. A high affinity binding site for both renin and prorenin was identified. Affinities for prorenin and renin were approximately 200 and 900 pmol/L, respectively. Binding was reversible, saturable, and pH and temperature dependent. The relative binding capacities of membranes from various rat tissues were as follows (fmol/mg): renal cortex (55), liver (54), testis (63), lung (31), brain (18), renal medulla (15), adrenal (17), aorta (7), heart (4), and skeletal muscle (1). Bound prorenin was displaced by rat and human renin or prorenin but not by the prosequence of rat prorenin, angiotensin I or II, rat or human angiotensinogen, the renin inhibitor SQ30697, atrial natriuretic factor, amylase, insulin, bovine serum albumin, hemoglobin, heparin, lysozyme, ovalbumin, cytochrome C, pepsin, pepsinogen, ribonuclease A, mannose-6-phosphate, α-methyl mannoside, gonadotropin releasing hormone, or an antibody to hog renin binding protein.These results demonstrate specific binding of prorenin to a site in rat tissues, herein named ProBP, that also binds renin. It is possible that differences in prorenin/renin binding capacity determine the activity of tissue-directed renin-angiotensin systems and that prorenin is a natural antagonist. Alternatively, a prorenin/renin receptor may have been identified that may function by transducing an intracellular signal.