SERUM ANGIOTENSIN CONVERTING ENZYME ACTIVITY AND PLASMA RENIN ACTIVITY IN EXPERIMENTAL MODELS OF RATS

1. Serum angiotensin converting enzyme activity (ACEA) and plasma renin activity (PRA) were determined in rats under different experimental conditions such as: nephrotic syndrome (NS), bilateral nephrectomy (BN), renovascular hypertension (RH), dehydration (DEH), anaesthesia (AN), low sodium diet (LSD) and high sodium diet (HSD), and injection with propranolol (PRO) and isoprenaline (ISO). 2. PRA increased in LSD, AN, NS, RH, DEH and IPT groups, and decreased in HSD, BN, and PRO groups. Serum ACEA did not change in RH, HSD, IPT, DEH, AN, and PRO groups, increased in NS group, and decreased in LSD and BN groups. 3. Serum ACEA changed in the opposite direction to PRA only in the LSD group. This finding suggests that ACE may limit the full expression of the renin-angiotensin system in the LSD group, but not in the other groups.     

PLASMA RENIN ACTIVITY OF RATS AND RABBITS IMMUNIZED AGAINST ANGIOTENSIN II

SUMMARY 1. Plasma renin activity (PRA) was studied in rats and rabbits actively immunized against angiotensin II (A II).
2. The mean PRA values (in ng angiotensin I/ml per h) were 3.5 (s.e.m. = 0.4) in ten control mock-immunized rats, and 3.3 (s.e.m. = 0.5) in seven rats having demonstrable sustained immunity to A II.
3. In six unanaesthetized rabbits, the appearance of antibody directed against A II was associated with a 263% increase in PRA during the first week, whereas the PRA of five control mock-immunized rabbits, tested at the same stage, exhibited no such change.
4. The PRA returned to control values by 3 months in the rabbits immunized against A II, although the antibody titres remained high.
5. The finding of significantly elevated PRA early in the course of production of antibody against A II is consistent with the properties of a negative feedback system, the renin hypersecretion being provoked by partial blockade of the normal inhibitory effect of A II on renin release. However, in chronically immune animals, the PRA is normal.     

EFFECT OF LONG-TERM TREATMENT WITH AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR ON THE RENIN-ANGIOTENSIN SYSTEM IN SPONTANEOUSLY HYPERTENSIVE RATS

1. To obtain information on regulation of the brain renin-angiotensin system, the effect of long-term administration of angiotensin-converting enzyme (ACE) inhibitor on brain renin and angiotensinogen mRNA was studied. 2. Spirapril (3 mg/kg) was orally administered daily for 8 weeks to spontaneously hypertensive rats (SHR) from 12 weeks after birth. Renin and angiotensinogen mRNA in the brain and kidney were then quantitated by Northern blot analyses with [32P]-labelled rat renin and angiotensinogen cDNA as hybridization probes. Plasma renin activity (PRA), angiotensin II (AII) concentration, plasma ACE activity and brain tissue ACE activity were also measured. 3. Compared with the control group, the Spirapril-treated group had significantly lower blood pressure (P less than 0.01), significantly higher PRA (P less than 0.01), a not significantly different plasma AII concentration, and lower plasma and brain ACE activities (P less than 0.01). Interestingly, the brain renin and angiotensinogen mRNA levels of the two groups were similar, but the renal renin mRNA level was significantly higher in the Spirapril-treated group (P less than 0.01). 4. These results indicate that the mRNA levels of brain renin and angiotensinogen were not affected by chronic ACE inhibition in the circulation and suggest that AII in the brain might not be affected by systemic ACE inhibition.     

RENIN, PRORENIN, AND RENIN GENE EXPRESSION IN RATS WITH ACUTE NEPHROTIC SYNDROME

1. The concentration of total, active and inactive renin was analysed in plasma, urine and kidney from control (C), pair-fed (PF) and nephrotic (NS) rats, as well as renin mRNA levels in kidney, liver and brain. 2. Nephrotic syndrome were induced by a single subcutaneous injection of puromycin aminonucleoside (PAN) and determinations were made 6 days after PAN injection. 3. Plasma total renin did not change, active renin increased in NS rats with respect to PF and C groups and in PF rats with respect to C. In contrast, the inactive renin percentage decreased in NS rats with respect to PF and C groups and in PF animals with respect to C. Total, active and inactive renal renin content did not change and active and inactive renin were significantly excreted by urine with no changes in the prorenin percentage with respect to C and PF groups. 4. In both NS and PF groups, renin mRNA levels did not change in any of the tissues studied. In another group of rats, kidney renin mRNA levels were measured on days 1, 3, 5 and 7 after PAN injection and no time-course changes in its expression were found. 5. These results suggest that renin gene expression is not altered in acute nephrotic syndrome and that plasma renin concentration is regulated at the translational or post-translational level in this experimental model.     

CORRELATION OF PLASMA ANGIOTENSIN II CONCENTRATION AND PLASMA RENIN ACTIVITY DURING ACUTE HYPOXIA IN DOGS

The effects of isocapnic hypoxia on plasma renin activity (PRA) and angiotensin II (AII) concentration were studied in anaesthetized, artificially ventilated dogs. Regression analysis of plasma AII concentration vs PRA, both measured by radioimmunoassay (RIA), was used as an index of converting enzyme activity in vivo. PaO2 decreased from 82 to 30 mmHg but regression analysis did not reveal any inhibition of AII production within the limits of detection of this method (less than 20% inhibition). We conclude that systemic converting enzyme activity, assessed by in vivo measurement and correlation of PRA and AII, is not inhibited by severe hypoxia.     

RENIN AND ANGIOTENSIN-CONVERTING ENZYME GENOTYPES IN PATIENTS WITH ESSENTIAL HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY

1. The associations between left ventricular hypertrophy (LVH) and specific alleles of the renin and angiotensin-converting enzyme (ACE) genes were studied in patients with essential hypertension and normal blood pressure. 2. LVH was present in 42% of those with essential hypertension (n= 72) and 17% of those with normal blood pressure (n= 44). 3. The frequency of each renin allele was the same in hypertensive and in normotensive patients. Renin allele frequencies were also the same for those with LVH and those with normal cardiac mass. When only hypertensives were considered, renin alleles were in the same proportion for the groups with and without LVH. Similarly, ACE alleles were not associated with essential hypertension nor with elevated cardiac mass. 4. We conclude that, in this population, variations in the renin or ACE genes do not contribute significantly to the development of LVH or to essential hypertension.     

EFFECTS OF ENALAPRIL AND DUP753 ON RENIN SYNTHESIS IN MICE WITH ONE HYDRONEPHROTIC KIDNEY

1. Renin synthesis and secretion were investigated in mice with one hydronephrotic kidney. 2. Enalapril and Dup753 stimulated renin synthesis to a similar extent in the hydronephrotic and normal kidney. 3. Hydronephrosis did not prevent an increase in renin mRNA caused by enalapril and Dup753. 4. The results therefore indicate that the macula densa does not appear to be crucial for renin synthesis in the kidney under the inhibition of angiotensin II. 5. Thus angiotensin II plays an important role controlling renin gene expression in both the normal and hydronephrotic kidneys.     

PLASMA RENIN RESPONSE TO ACUTE BLOCKADE OF ANGIOTENSIN II IN THE ANAESTHETIZED RAT

SUMMARY 1. Anaesthetized rats were infused intravenously for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113), at a rate of 5 μ/kg per min, or with saline.
2. Blood samples were taken, before and after infusion, for measurement of plasma renin activity (PRA) and plasma renin concentration (PRC).
3. Saline infusion did not affect PRA or PRC.
4. Infusion of P-113 produced steep and highly significant increases in PRA (652%) and PRC (724%), despite a slight rise in mean arterial pressure.
5. Within 30 min of terminating P-113 infusion, PRA fell to 300%, and PRC to 278% of pre-infusion levels, and subsequently continued to fall.
6. It is suggested that the hypersecretion of renin produced by P-113 is due to blockade of the inhibitory control normally exerted by endogenous angiotensin II on renin release.     

DYNAMIC CHANGES IN PLASMA INACTIVE RENIN LEVELS IN BARTTER''S SYNDROME AFTER ADMINISTRATION OF CAPTOPRIL AND ANGIOTENSIN II

Changes in plasma active and inactive renin concentration (ARC and IRC) after captopril administration and angiotensin II (AII) infusion were studied in six patients with Bartter's syndrome. A single oral dose of captopril (8-25 mg) lowered the blood pressure and increased both ARC and IRC. AII infusion elevated blood pressure, suppressed ARC and increased IRC. In this syndrome of high renin levels, infused AII appeared to increase inactive renin secretion by reducing its conversion to active renin. On the other hand, an acute fall in AII levels and/or renal perfusion pressure by captopril increased both active and inactive renin. This indicates that the increase in the secretion of inactive renin, stimulated by captopril, might exceed any increase in its conversion to active renin in patients with Bartter's syndrome, in whom the production of renin is accelerated, and conversion of inactive renin to active renin probably already operates near its maximum.     

血管紧张素转换酶基因多态性与血管紧张素转换酶抑制剂的降压作用

目的:从基因多态性研究药效的差异。方法:选择健康志愿者99 例,未治疗的原发性高血压病人40 例,用PCR 方法检测血管紧张素转换酶(ACE) 基因的插入与缺失(I/D) 多态性, 用血管紧张素转换酶抑制剂(ACEI) 卡托普利治疗高血压病人。结果:正常人与原发性高血压患者的ACE等位基因频率及基因型频率无显著差异(P>0.05) 。卡托普利降压有效病人与无效病人ACE 基因的I/D等位基因频率及基因型频率,基因缺失型纯合子(DD)或/ 和杂合子(ID) 与非缺失型(II) 也均无显著差异(P>0.05) 。结论: ACE基因的I/ D多态性与原发性高血压的发病无关, ACEI降压作用的个体差异与ACE基因的I/D多态性无关。     

INCREASED CARDIAC ANGIOTENSIN-CONVERTING ENZYME IN RATS WITH CHRONIC HEART FAILURE

1. Chronic heart failure was induced in rats by ligation of the left coronary artery to produce a left ventricular myocardial infarct. 2. Cardiac angiotensin-converting enzyme (ACE) was estimated by radioligand binding in myocardial homogenates and by autoradiography studies of radioligand binding to ACE in heart sections. 3. Radioligand binding studies demonstrated an increase in binding sites in animals with myocardial infarction, compared with sham operated animals. Mean increases were 457% in right atrium, 295% in left atrium, 326% in right ventricle, 187% in left ventricle and 530% in the region of the left ventricular infarct, compared with the sham left ventricle. 4. Autoradiography studies confirmed tissue homogenate binding studies, demonstrating (i) a marked increase in ligand binding in the infarct area and (ii) an increase in binding density in the hypertrophied myocardium of right and left atrium, and right and left ventricle. 5. The induction of cardiac ACE in the myocardium of rats with chronic heart failure may participate in the pathophysiology of cardiac hypertrophy.     

EFFECT OF GENOTYPE ON THE ANGIOTENSIN-CONVERTING ENZYME mRNA LEVEL IN HUMAN ATRIA

1. To clarify the mechanism of the association between I/D polymorphism of the angiotensin-converting enzyme (ACE) gene and various cardiovascular diseases, ACE mRNA levels in human atrial appendages were assessed in relation to the genotype of the ACE gene. 2. Angiotensin-converting enzyme mRNA levels were positively correlated with age and tended to show a positive correlation with mean pulmonary pressure (niPA). Multiple regression analysis indicated that age and mPA, but not the genotype of the ACE gene, were predictors of ACE mRNA levels in human atrial appendages. 3. The present study indicates that I/D polymorphism of the ACE gene is not simply reflected in ACE mRNA levels and that further study is needed to determine the mechanism of the association between this polymorphism and various cardiovascular diseases.     

ANGIOTENSIN II BLUNTS, WHILE AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AUGMENTS, REFLEX SYMPATHETIC INHIBITION IN HUMANS*

1. The role of angiotensin (Ang)II in and the effects of angiotensin-converting enzyme (ACE) inhibitors on the regulation of sympathetic neural activity were examined in humans. 2. We measured baseline values of muscle sympathetic nerve activity (MSNA) and its reflex inhibition in 28 patients with essential hypertension with elevated plasma renin activity (PRA; > 1.0 ng/mL per h = 0.28 ng/L per s) before and after either acute or chronic oral administration of an ACE inhibitor or placebo and in 20 normotensive subjects before and after infusion of either AngII (5 ng/kg per min = 4.8 pmol/kg per min) or vehicle (5% dextrose). Muscle sympathetic nerve activity was recorded from the tibial nerve and its reflex inhibition was evaluated during pressor responses to bolus injection of phenylephrine (2 micrograms/kg, i.v.). 3. Blood pressure was significantly decreased (P < 0.01) after the acute oral administration of captopril (25 mg), accompanied by a slight increase in MSNA in patients with essential hypertension compared with control patients who received placebo administration. Reflex changes in MSNA were significantly augmented after oral administration of captopril (-4.1 +/- 0.5 vs -6.2 +/- 0.6%/mmHg, respectively; P < 0.01), with a significant reduction of plasma AngII, while they were not affected by placebo administration. 4. In contrast, acute AngII infusion was accompanied by decreases in both PRA and MSNA in normotensive subjects. Reflex changes in MSNA were significantly reduced after AngII infusion (-11.0 +/- 0.8 vs -7.4 +/- 1.0%/mmHg, respectively; P < 0.01) but not after vehicle alone. 5. Chronic ACE inhibition by 12 week oral imidapril administration (5-10 mg/day) significantly (P < 0.05) decreased baseline values of MSNA, which were accompanied by a significant (P < 0.05) increase in the reflex inhibition of MSNA, while plasma concentrations of noradrenaline were unaffected. 6. These results indicate that AngII blunts reflex inhibition of sympathetic neural activity and that inhibition of the renin-angiotensin system by an ACE inhibitor augments reflex regulation of sympathetic neural activity and reduces baseline values in patients with essential hypertension.     

ACUTE AND CHRONIC EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS ON TISSUE ANGIOTENSIN-CONVERTING ENZYME

1. The effects of angiotensin-converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitative in vitro autoradiography after acute and chronic administrations of the drugs.
2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier.
3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I.
4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two-threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment.
5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the drugs.     

ANGIOTENSINS II AND III PREVENT CAPTOPRIL-INDUCED RENIN RELEASE IN THE RAT

1. The effects of exogenous angiotensins II and III (50 pmol/min i.v.) on plasma renin release following captopril injection (5 mg/kg, i.v.) were studied in anaesthetized Sprague-Dawley rats, to determine whether angiotensin II blockade is the major mechanism by which captopril induces renin release. 2. Captopril produced a 12-fold increase in plasma renin concentration compared with saline-injected controls. This was completely reversed by pre-infusion of angiotensin II or III. 3. The fall in blood pressure following captopril treatment was also abolished by angiotensins II and III pre-infusion. Noradrenaline pre-infusion (200-800 ng/min, i.v.) also prevented the captopril-induced hypotension but did not alter the rise in plasma renin. 4. Ureteric ligation did not significantly reduce captopril-induced renin release suggesting that acute changes in sodium excretion or delivery of electrolyte to the macula densa were not involved in renin release. 5. These findings suggest that captopril induces renin release by inhibiting angiotensin II feedback control of renin secretion and that angiotensin III may also modulate renin release.     

EFFECT OF MINERALOCORTICOIDS AND SALT LOADING ON RENIN RELEASE, RENAL RENIN CONTENT AND RENAL RENIN mRNA IN MICE

1. DOCA and 9 alpha-fludrocortisone were given to mice on a high-sodium diet for periods of up to 20 weeks, resulting in decreases in plasma renin concentration, renal renin concentration and renal renin mRNA with both treatments. 2. Plasma renin concentration was suppressed prior to suppression of renin mRNA and renal renin levels, indicating that suppression of synthesis and secretion of renin occur separately. 3. The decrease in renal renin concentration that occurred with DOCA was greater and more rapid than the decrease that occurred with 9 alpha-fludrocortisone, suggesting that DOCA caused intra-renal breakdown of renin. 4. When DOCA was given to mice on a low-sodium diet, plasma renin concentration and renal renin concentration increased, indicating that the effects of DOCA on renin levels were dependent on dietary sodium. 5. Renin secretion and synthesis appeared to be controlled by different mechanisms and sodium balance has an important effect on both processes.     

THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR, PERINDOPRIL, PREVENTS CARDIAC HYPERTROPHY IN LOW-RENIN HYPERTENSIVE RATS

1. To examine whether an angiotensin-converting enzyme (ACE) inhibitor prevents left ventricular (LV) hypertrophy even in low-renin hypertension, we studied the effect of the administration of perindopril on cardiac hypertrophy induced by partial renal ablation in hypertensive rats. 2. Rats that had undergone partial nephrectomy were randomly divided into four groups that received the following as drinking water: Group A, tap water; Group B, 1% sodium chloride (NaCl); Group C, NaCl + perindopril 3 mg/ kg per day; and Group D, NaCl + perindopril 1 mg/ kg per day. Plasma renin activity (PRA), angiotensin-II (AII) concentration and cardiac tissue AII were measured. 3. Supplementation of NaCl following nephrectomy increased the blood pressure and cardiac weight compared with rats that had undergone nephrectomy alone (P<0.05). Treatment with perindopril (3 mg/kg per day) did not affect the blood pressure and plasma AII but inhibited the increase of cardiac weight (P<0.05). Left ventricular AII was decreased in cases of reduced renal mass hypertension, but was not changed by treatment with perindopril. 4. These results demonstrate that perindopril may be able to prevent LV hypertrophy even in low-renin hypertension, which was not mediated by a reduction of blood pressure or suppression of the circulating and cardiac renin-angiotensin systems. Other mechanisms of ACE inhibitors may contribute to the cardioprotective effects.     

THE ROLE OF THE MACULA DENSA IN RENIN SYNTHESIS

1. The role of the macula densa in renin synthesis was studied using mice with one hydronephrotic kidney. 2. Renin synthesis was assessed by measurement of renal renin, renal mRNA for renin and plasma renin. 3. Sodium depletion stimulated mRNA and renal renin to a similar extent in the hydronephrotic and contralateral kidney. 4. Enalapril stimulated mRNA concentration in both kidneys but renal renin did not rise in the hydronephrotic kidney. 5. Propranolol did not alter the response to sodium depletion in either kidney. 6. The macula densa is not crucial for the stimulation of renin synthesis following sodium depletion. However, it may regulate renin production after mRNA synthesis, possibly by controlling the conversion of prorenin to renin.     

ANGIOTENSIN-CONVERTING ENZYME INHIBITION CAUSES DETERIORATION IN RENAL FUNCTION IN ONE-KIDNEY GOLDBLATT HYPERTENSIVE RATS WITH AND WITHOUT RENAL ARTERIAL STENOSIS

1. The renal and hypotensive effects of a new angiotensin-converting enzyme (ACE) inhibitor, cilazapril, were evaluated in 18 one-kidney, one-clip Goldblatt hypertensive rats (1K1C), 10 one-kidney normotensive rats (1K) and eight 1K1C rats with acute unclipping (1KU). Cilazapril was infused intravenously (25 micrograms/kg per min) into anaesthetized rats, and the arterial blood pressure (BP) and renal clearance of rats were measured. 2. In 1K rats, cilazapril reduced BP from 123 +/- 4 to 117 +/- 4 mmHg (P < 0.05), and produced diuresis, natriuresis and kaliuresis without significantly changing glomerular filtration rate (GFR). 3. In 1K1C rats, cilazapril significantly reduced BP (from 157 +/- 5 to 143 +/- 6 mmHg; P < 0.05), GFR (14.4 +/- 6.7%), urine flow (27.1 +/- 8.5%) and sodium excretion (39.4 +/- 7.4%). Mechanically graded reductions of renal arterial pressure alone also produced parallel decreases in GFR and renal excretory function. 4. In 1KU rats, removal of the renal arterial clip significantly decreased BP and increased renal function. Subsequent infusion of cilazapril further reduced BP and urinary excretions of sodium and water but did not significantly change GFR. 5. These results suggest that the renal function of the 1K1C hypertensive model is pressure-dependent, and that ACE inhibitor exerts a mild antihypertensive effect but causes a pressure associated reduction in renal function. Furthermore, the detrimental effect of ACE inhibitor on the residual kidney persists after acute surgical correction of the stenosis.