ALDOSTERONE-PRODUCING ADENOMAS RESPONSIVE TO ANGIOTENSIN POSE PROBLEMS IN DIAGNOSIS

1. A subgroup of patients with aldosterone-producing adenoma (APA) have been identified who lack many of the biochemical features regarded as characteristic of APA and used to distinguish APA from bilateral adrenal hyperplasia. 2. In these patients, aldosterone is responsive to infused angiotensin II (angiotensin-responsive APA), which explains their uncharacteristic responses to upright posture, saline infusion and fludrocortisone acetate administration. 3. The angiotensin-responsiveness of these patients may derive from the contralateral adrenal gland, since renin levels are less completely suppressed in angiotensin-responsive APA than in angiotensin-unresponsive APA. 4. However, while the excretion of 18-oxo-cortisol was consistently increased in angiotensin-unresponsive APA, it was normal in angiotensin-responsive APA, consistent with biochemical and biosynthetic distinctiveness residing in the tumours. 5. Angiotensin-responsive APA should always be considered as an alternative diagnosis to bilateral hyperplasia causing primary aldosteronism.     

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.     

Graded effects of saralasin on prostaglandin E, plasma renin activity and renal blood flow in anaesthetized dogs

The objective of this study was to examine in anaesthetized dogs the graded effect of saralasin on renal prostaglandin E (PGE) release and to attempt to associate this change with its effects on plasma renin activity and renal blood flow. Blood pressure and renal blood flow were monitored. Renal PGE concentration and plasma renin activity were measured by radioimmunoassay. Saralasin or saline vehicle was infused into the renal artery for 20 min. Infusion of saralasin at the lowest dose of 0.25 micrograms/kg per min or saline vehicle did not alter either renal blood flow or plasma renin activity. Saralasin increased renal blood flow and caused a complete blockade of the renal vasoconstrictor response to exogenous angiotensin II at the two higher doses used (0.5 and 1 micrograms/kg per min). Only the highest dose of saralasin increased plasma renin activity significantly. Renal venous PGE concentration at the 5, 10 and 20 min periods of infusion was not changed significantly by any of these three doses of saralasin. We conclude therefore that the increases in renal blood flow and plasma renin activity caused by saralasin in the anaesthetized dog occur by mechanisms independent of changes in renal PGE.     

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.     

DETECTION OF RENIN mRNA IN ALDOSTERONE-PRODUCING ADENOMAS BY POLYMERASE CHAIN REACTION

1. Ribonucleic acid (RNA) was extracted from two normal human adrenal cortices and from five aldosterone-producing adenomas (APA). 2. The five APA could be categorized, on the basis of in vivo aldosterone responsiveness to angiotensin infusion and upright posture, into two APA responsive to both stimuli, two responsive only to angiotensin infusion, and one unresponsive to either stimulus. 3. RNA was reverse transcribed and coamplified by polymerase chain reaction (PCR) with an internal standard of renin complementary DNA (cDNA) containing a 60 base pair insertion. Renin mRNA in the APA was compared with normal adrenals. 4. Renin mRNA was greater than normal in the two APA responsive to both stimuli and less than, or similar to normal, in the two APA responsive only to angiotensin infusion. Renin mRNA was also less than, or similar to normal, in the APA unresponsive to either stimulus. 5. These findings support a possible role for adrenal renin in the development and biochemical behaviour of angiotensin-responsive APA.     

ALTERING ANGIOTENSIN LEVELS BY ADMINISTRATION OF CAPTOPRIL OR INDOMETHACIN, OR BY ANGIOTENSIN INFUSION, CONTRIBUTES TO AN UNDERSTANDING OF ATRIAL NATRIURETIC PEPTIDE REGULATION IN MAN

1. Plasma atrial natriuretic peptide (ANP) levels were positively correlated with plasma renin activity (PRA) levels, when blood volume and blood pressure (BP) were not raised in normal subjects (NLS) or patients with postoperative aldosterone-producing adenoma (APA), Bartter's syndrome (BS), Addison's disease, anorexia nervosa, diuretic abuse or salt-losing congenital adrenal hyperplasia. 2. Angiotensin II infusion raised ANP levels in NLS, and patients with BS, pre- and postoperative APA, only when BP rose, suggesting that this effect might be mediated by the rise in BP. 3. Captopril lowered aldosterone and ANP levels in renal artery stenosis, but falling BP levels could mediate this effect. Captopril lowered aldosterone and BP in BS, but did not lower ANP, perhaps because angiotensin remained elevated. 4. Indomethacin lowered ANP when PRA was initially normal or raised (NLS and BS), but not when PRA was suppressed (APA). This effect could not be mediated by BP, which rose, but could be mediated by renin-angiotensin, which fell. 5. Factors other than central blood volume and atrial stretch may modulate ANP levels. Plasma angiotensin II may be such a factor, and may exert an important influence at high levels, especially when blood volume is low.     

Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart

1. Aliskiren is a renin inhibitor with an IC₅₀ of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin‐converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen‐2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen‐2)27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague–Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren‐induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.     

HYPERTENSION CORRECTED AND ALDOSTERONE RESPONSIVENESS TO RENIN-ANGIOTENSIN RESTORED BY LONG-TERM DEXAMETHASONE IN GLUCOCORTICOID-SUPPRESSIBLE HYPERALDOSTERONISM

Two males with glucocorticoid-suppressible hyperaldosteronism had hyperaldosteronism, hypertension and hypokalaemia corrected by continuous administration of physiological doses of dexamethasone for more than a year. During long-term dexamethasone treatment: (a) Plasma renin activity increased from subnormal to high normal levels, with normal posture-mediated increases; (b) Plasma aldosterone became responsive to angiotensin infusion, a new observation; (c) A fall in plasma aldosterone between 0800 h (recumbent) and 1000 h (upright) was replaced by a rise; (d) Plasma aldosterone became suppressible with salt loading. These findings are consistent with a shift to more normal control of aldosterone by renin-angiotensin, once abnormal responsiveness to ACTH has been nullified.     

ANGIOTENSIN-RESPONSIVEALDOSTERONE-PRODUCING ADENOMAS: POSTOPERATIVE DISAPPEARANCE OF ALDOSTERONE RESPONSE TO ANGIOTENSIN

1. Nineteen out of 47 patients (40%) with confirmed unilateral aldosterone-producing adenoma (APA) were responsive to low-dose angiotensin II infusion (AH-R), as defined by an increase in plasma aldosterone concentration of >50% over basal at 2 ng/kg per min for 60 min. 2. Seven to ten days after unilateral adrenalectomy, aldosterone was no longer responsive to angiotensin infusion in AII-R APA (100%, n = 17). Therefore, angiotensin responsiveness resides within the adenoma in AII-R APA. 3. The upright posture test for the differentiation of adenoma from hyperplasia was unreliable for the AII-R APA (26%), but generally reliable in the angiotensin-unresponsive subtype, (AH-U APA, 96%). 4. The reported predominance of females in APA was seen in AII-U APA (68%), but was reversed in AII-R APA (37%).     

INHIBITION OF RENIN-ANGIOTENSIN INDUCED DRINKING IN THE CAT BY ENZYME INHIBITORS AND BY ANALOGUE ANTAGONISTS OF ANGIOTENSIN II

SUMMARY 1. Intracerebroventricular (icv) administration of the renin inhibitor pepstatin inhibited the dipsogenic response to icv renin but did not affect drinking induced by icv angiotensin I and II.
2. Intracerebroventricular administration of an angiotensin converting enzyme inhibitor, SQ 20881, reduced the dipsogenic effect of icv renin and angiotensin I but did not affect angiotensin II induced drinking.
3. Intracerebroventricular administration of SQ 20881 reduced the dipsogenic effect of intravenous angiotensin I but did not reduce drinking elicited by intravenous angiotensin II.
4. Intracerebroventricular administration of Sar¹-Ala⁸-angiotensin II, a competitive antagonist of angiotensin II, inhibited drinking elicited by icv renin, angiotensin I and angiotensin II. The dipsogenic response to intravenous infusion of both angiotensins I and II was reduced after central administration of this antagonist.
5. Four analogue antagonists of angiotensin II given icv reversibly inhibited the dipsogenic response to icv angiotensin II. These analogues themselves possessed weak dipsogenic effects.
6. Renin-angiotensin induced drinking in the cat is mediated by the action of angiotensin II on receptors in the central nervous system.     

Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats

The pressor effect induced by acute hyperglycemia is not well understood, therefore, it was of interest to study the effect of intravenous glucose infusion on the mean arterial pressure of anesthetized Wistar rats. Animals received glucose (100 mg/kg/min, i.v.), mannitol or saline during 30 min, but only glucose increased the mean arterial pressure (about 40 mm Hg), plasma glucose, insulin and nitric oxide (NO). Pretreatment with reserpine or indorenate (a central antihypertensive) inhibited completely the pressor effect of glucose. Reserpine also decreased the plasma NO levels. Pretreatment with ramipril or with streptozotocin decreased the late phase of the glucose-induced pressor response and the NO levels, the latter treatment also abolishes insulin plasma concentrations. The present results suggest that the pressor effect induced by glucose has an early phase due to an increase of efferent sympathetic discharges and a delayed phase produced by the activation of the renin angiotensin system.     

TRIFLUOPERAZINE ANTAGONIZES INHIBITION OF RENIN RELEASE BY ANGIOTENSIN II

The influence of trifluoperazine (TFP) treatment on angiotensin II-induced inhibition of renin release from the rat isolated perfused kidney was examined. Angiotensin II, 1 mumol/l, in the presence of 1 mmol/l calcium, reduced basal renin secretion by 70%. When calcium was omitted from the perfusion medium, inhibition of renin release no longer occurred. Pretreatment of the rat isolated perfused kidney with the calmodulin inhibitor trifluoperazine (TFP), 10 mumol/l for 6 min, interfered with the inhibitory action of angiotensin II on renin release as well as angiotensin II-induced renal vasoconstriction. Our data suggest a role for calmodulin in mediating the effects of angiotensin II on both renin release and renal vascular resistance.     

BIOCHEMICAL CORRECTION IN THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA BY SEVERE DIETARY SALT RESTRICTION SUGGESTS RENIN-ALDOSTERONE SUPPRESSION CRITICAL IN PATHOPHYSIOLOGY

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.     

Calcium dependence of the inhibitory effect of angiotensin on renin secretion in the isolated perfused kidney of the rat

1 The effect of calcium on the inhibition of renin secretion by biologically active angiotensin was investigated in the isolated rat kidney perfused with Krebs-Ringer saline.2 In the presence of calcium (3.7 mM), asp(NH(2))'-angiotensin II suppressed both basal and isoprenaline-stimulated renin secretion. Renal perfusion pressure, which was increased by the infusion of angiotensin, returned to control levels when isoprenaline was added.3 When the calcium concentration was reduced to 0.32 mM, the vasoconstriction produced by angiotensin was abolished although the inhibitory effect on renin secretion was still evident.4 In the absence of calcium, angiotensin no longer suppressed basal renin secretion and a prompt increase in renin secretion occurred when isoprenaline was added.5 The higher basal renin levels which were observed in calcium-free perfusions, suggest the existence of an intrarenal calcium-dependent mechanism that regulates basal renin secretion.6 These observations indicate that the inhibitory effect of biologically active angiotensin, on basal and isoprenaline-stimulated renin secretion, is functionally related to the contractor response by its dependence on calcium. The recognition that the renin-producing cells are modified smooth muscle cells supports this association     

HAEMODYNAMIC, RENAL AND HORMONAL RESPONSES TO ENALKIREN IN FOUR PATIENTS WITH POST-SURGICAL OLIGURIA

1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output <0.5 mL/kg perh) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg perh for up to 4h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 ± 19 to 327± 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL perh) fell from 1.9 ± 0.5 to 0.02 ± 0.01 (P<0.04), plasma angiotensin II (pg/mL) fell from 104 ± 93 to 7.7 ± 1.5, and plasma aldosterone (ng/dL) fell from 32 ± 8 to 21 ± 9 (P= 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.     

Acute changes in cyclic AMP levels of certain brain areas following intraventricular injection of renin in rats

Actions of the central angiotensin system on brain cAMP concentrations were studied after intraventricular injection of renin. Biosynthesis of endogenous brain angiotensin II was stimulated by 0.1 U renin and the blood pressure was elevated 40 min after the application.Stimulation of the brain angiotensin system affected cAMP metabolism in several brain areas, mostly expressed as decreased cAMP levels.Significant decreases in cAMP concentrations were found in the cerebral cortex, hippocampus, basal ganglia, various hypothalamic nuclei, substantia nigra, central grey matter and in the locus coeruleus.The unchanged cAMP levels in the nucleus of the solitary tract might indicate that intraventricular injection of renin induced an acute blood pressure elevation which is not associated with changes in the cAMP system in the primary baroreceptor area.     

Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis

BACKGROUND AND PURPOSE

Inhibition of the renin angiotensin system (RAS) has been consistently demonstrated to reduce atherosclerosis. However, there has been no direct comparison among the three available pharmacological modes of inhibiting the RAS, which are inhibitors of renin, ACE and angiotensin II type 1 receptor. The purpose of this study was to determine the relative effects of these three modes of pharmacological RAS inhibition in reducing atherosclerosis by determining the dose–response relationships.

EXPERIMENTAL APPROACH

Male LDL receptor -/- mice were administered either vehicle or any of three doses of aliskiren, enalapril or losartan through s.c. infusion for 12 weeks. All mice were fed a saturated fat-enriched diet during drug infusions. Systolic and diastolic BPs were measured during the study using a non-invasive tail-cuff system. Plasma cholesterol and renin concentrations, atherosclerotic lesions, and renal angiotensin II concentrations were determined at the termination of the study.

KEY RESULTS

Plasma renin concentrations were increased by all three drugs. None of the drugs changed plasma cholesterol concentrations. All drugs produced a dose-related decrease in BP. All three drugs also profoundly reduced atherosclerosis in a dose-dependent manner. The highest dose of each drug markedly attenuated lesion size, with no significant differences between the different drugs. The highest dose of each drug also similarly reduced renal angiotensin II concentrations.

CONCLUSION AND IMPLICATIONS

Drugs that inhibit the RAS, irrespective of their mode of inhibition, profoundly affect atherosclerotic lesion development in a dose-dependent manner.     

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): New Therapy for CKD by a (Pro)Renin-Receptor–Blocking Decoy Peptide

Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II–dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II– independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.     

(Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation

1. (Pro)renin receptor (PRR) binding to renin or prorenin mediates angiotensin (Ang) II‐dependent and ‐independent effects. Expression of the PRR is increased in kidneys of diabetic rats, but its role in diabetic nephropathy is unknown. In the present study, we investigated the contribution of the PRR to the development of diabetic nephropathy through enhancement of renal production of tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β. 2. Normoglycaemic control and streptozotocin‐diabetic Sprague‐Dawley rats were used in the study. The urine albumin : creatinine ratio (UACR), renal interstitial fluid (RIF) levels of AngII, TNF‐α and IL‐1β and renal expression of TNF‐α and IL‐1β were evaluated in control, untreated diabetic and diabetic rats treated with either a PRR blocker (PRRB; 0.2 mg/kg per day NH3‐RILLKKMPSV‐COOH), the AT₁ receptor antagonist valsartan (2 mg/kg per day) or combined therapy, administered directly into the renal cortical interstitium for 14 days via osmotic minipumps. 3. Compared with values in normoglycaemic control rats, UACR and RIF AngII, TNF‐α and IL‐1β were significantly higher in untreated diabetic rats. Treatment of diabetic rats with the PRRB or valsartan alone and in combination significantly reduced UACR and RIF TNF‐α and IL‐1β levels. Renal expression of TNF‐α and IL‐1β was higher in untreated diabetic rats than in control rats, but was reduced significantly following treatment with PRRB or valsartan alone and in combination. Renal PRR expression was increased in untreated and PRRB‐treated diabetic rats and reduced in rats receiving valsartan alone or combination therapy. The PRRB had no effect on RIF AngII levels, whereas valsartan alone and in combination with the PRRB significantly increased AngII levels. 4. In conclusion, the PRR is involved in the development and progression of kidney disease in diabetes by enhancing renal production of the inflammatory cytokines TNF‐α and IL‐1β, independent of renal AngII effects.