Chronic Blockade Of Renin-angiotensin System Research Articles

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria.

Albuminuria is an indicator of cardiovascular risk and renal damage in hypertensive individuals. Chronic renin–angiotensin system (RAS) suppression facilitates blood pressure control and prevents development of new-onset-albuminuria. A significant number of patients, however, develop albuminuria despite chronic RAS blockade, and the physiopathological mechanisms are underexplored. Urinary exosomes reflect pathological changes taking place in the kidney. The objective of this work was to examine exosomal protein alterations in hypertensive patients with albuminuria in the presence of chronic RAS suppression, to find novel clues underlying its development. Patients were followed-up for three years and were classified as: a) patients with persistent normoalbuminuria; b) patients developing de novo albuminuria; and c) patients with maintained albuminuria. Exosomal protein alterations between groups were identified by isobaric tag quantitation (iTRAQ). Confirmation was approached by target analysis (SRM). In total, 487 proteins were identified with high confidence. Specifically, 48 proteins showed an altered pattern in response to hypertension and/or albuminuria. Out of them, 21 proteins interact together in three main functional clusters: glycosaminoglycan degradation, coagulation and complement system, and oxidative stress. The identified proteins constitute potential targets for drug development and may help to define therapeutic strategies to evade albuminuria progression in hypertensive patients chronically treated.

Renin-angiotensin system phenotyping as a guidance toward personalized medicine for ACE inhibitors: can the response to ACE inhibition be predicted on the basis of plasma renin or ACE?

Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT). Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study. Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

REGULATION OF RENAL MEDULLARY CIRCULATION BY THE RENIN–ANGIOTENSIN SYSTEM IN GENETICALLY HYPERTENSIVE RATS

1. Renal medullary blood flow (MBF) is believed today to have a potent role in blood pressure control through its influence on sodium and water excretion. The present article reviews: (i) the study of MBF in two experimental models of heritable hypertension, namely spontaneously hypertensive rats (SHR) and Lyon genetically hypertensive (LH) rats selected, respectively, from Wistar and Sprague-Dawley rats; and (ii) the regulation of MBF by the renin-angiotensin system (RAS) in these animals and the interaction between angiotensin (Ang) II and nitric oxide, prostaglandins and reactive oxygen species in the renal medulla. 2. Although numerous renal disorders are observed during or after the development of hypertension, the reduced pressure-natriuresis function is an early apparent and common abnormality found in SHR and LH rats. This abnormality is associated with a blunted increase in MBF in response to elevations in renal perfusion pressure. Moreover, both SHR and LH rats exhibit an exaggerated medullary vasoconstriction and/or a reduced medullary vasodilatation under stimulation with AngII. 3. Chronic RAS blockade prevents the development of hypertension in both SHR and LH rats. This effect involves an improved response of MBF to increasing renal perfusion pressure and to AngII. 4. Medullary blood flow is inappropriately regulated in genetically hypertensive rats; a decreased MBF caused by the disequilibrium of local vasodilator/vasoconstrictor systems may favour the prohypertensive role of the RAS in genetic hypertension.

Disparate effects of chronic AT1 receptor blockade on blood pressure and renal injury in the aging female mRen2.Lewis strain

Salt‐sensitivity, a risk factor for cardiovascular and renal disease, increases with age or in women after menopause. Activation of the renin‐angiotensin system (RAS) may be an important pathogenic component of the salt‐sensitivite phenotype. In this study, we determined whether the angiotensin II receptor 1 (AT1R) antagonist losartan ameliorates blood pressure, proteinuria or vascular reactivity in the aging intact female mRen2.Lewis rats fed a high salt diet (HS, 8% NaCl). HS diet for 8 weeks starting at 60 wks of age increased systolic blood pressure [SBP: 150±7 vs.123±7 mmHg, p<0.05; n=5‐11], proteinuria [275±88 vs. 40±13 mg/kg/day, p<0.05], renal [p<0.05] and left ventricular [p<0.05] hypertrophy, without influencing creatinine clearance. Losartan treatment (20 mg/kg/day; 64 to 68 wks of age) had no effect on SBP and renal or cardiac hypertrophy, but significantly reduced proteinuria [62±28 mg/kg/day, p<0.05; n=8‐11]. Ang II‐dependent vasoconstriction in aortic rings from losartan‐treated animals was abolished, but the phenylephrine response was unchanged. Moreover, losartan treatment had no effect on acetylcholine‐induced relaxation. We conclude that in the aging salt‐sensitive female mRen2.Lewis rat, chronic RAS blockade does not reduce blood pressure, organ hypertrophy, or aortic vascular reactivity; however, AT1R antagonism is renoprotective.

Losartan may prevent the elevation of plasma glucose, corticosterone and catecholamine levels induced by chronic stress

Stress is a stimulus that activates the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Increased activity of the SNS causes to increment or impairment in blood pressure, heart rate, body temperature and plasma glucose and adreno- corticotrophic hormone (ACTH) levels. Angiotensin II (Ang II), which is a product of the renin-angiotensin system (RAS), is an important factor affecting the activity of the SNS and responses to stress. We suggest that the blockade of Ang II may be worthwhile in the prevention and treatment of diabetes mellitus and cardiovascular diseases affected by stress. Therefore, we investigated the effects of immobilisation stress on blood glucose, norepinephrine (NE), epinephrine (E) and corticosterone levels and the effects of an Ang II receptor antagonist, losartan, on these parameters. The rats were kept in small cylindrical cages for 60 min/day for 10 consecutive days to perform chronic immobilisation stress. Losartan (10 mg/kg) was given daily by gavage to Losartan (L) and Losartan + Chronic Stress (L+CS) groups. Control (C) and Chronic Stress (CS) groups received an equal volume of saline daily by gavage for 10 days. After the last stress regimen, blood samples were collected for plasma glucose, NE, E and corticosteroid measurements. Plasma glucose, NE, E and corticosterone levels in the CS Group increased significantly compared with the C group. In Group L+CS, the plasma glucose, NE, E and corticosterone levels decreased significantly vs. Group CS. In Group L there was no significant difference vs. Group C. It can be speculated that chronic blockade of RAS may decrease the excess sympathetic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus.

Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility.

Blockade of the renin-angiotensin system (RAS) by combined angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor (AT(1)) antagonist treatment with reduced dietary sodium intake produces suppression of cardiac growth and regression of cardiac hypertrophy. The purpose of this study was to investigate whether cardiac growth suppression by combined RAS blockade under conditions of dietary sodium restriction is associated with cardiomyocyte atrophy and contractile dysfunction and whether this intervention modifies cardiomyocyte inotropic responsiveness to angiotensin II (Ang II). Rats were fed a high (4% w/w) or low (0.2% w/w) NaCl diet for six days. Both groups were then given a combined intraperitoneal injection of perindopril (6 mg/kg/day) and losartan (10 mg/kg/day) with maintained dietary treatment for another seven days. At the end of the treatment period, animals were anaesthetised and their hearts were removed and weighed. Left ventricular cardiomyocytes were isolated by enzymatic dissociation and cell dimensions were evaluated. A line scan camera and digital imaging technique were used to assess cardiomyocyte contraction and inotropic responses to exogenous Ang II (10 to 10(-8) M). Dietary treatment alone had no effect on body growth, whereas combined RAS blockade suppressed somatic growth in the low sodium (LS) group, compared with the high sodium (HS) group. This growth suppression in the LS group was also evident in the heart at the organ and cellular level. Studies of cardiomyocyte contraction showed that myocytes from the LS group exhibited contractile instability and depression of contractile performance. Compared with the HS group, myocytes from the LS group showed a significant reduction in maximum cell shortening (6.40+0.17 vs. 7.32+0.16% resting length, p<0.05), and maximum rate of shortening (3.85+0.14 vs. 4.29+0.11 cell length/ms, p<0.05). Myocytes of the HS group exhibited negative inotropic responses to Ang II at all concentrations tested, with a significant reduction in maximum cell shortening by 11 16% after 12 minutes peptide exposure (p<0.05 vs. non-treated control). In comparison, Ang II elicited both positive and negative responses in myocytes from the LS group, with a predominant negative inotropic effect. This study provides evidence that combined RAS blockade treatment under restricted sodium intake conditions can impair cardiomyocyte contractile function in association with cardiomyocyte growth suppression. Chronic RAS blockade qualitatively alters the intrinsic inotropic status and responsiveness of ventricular cardiomyocytes, and this shift is further modulated by dietary sodium intake conditions.

Methylprednisolone-induced hypertension. Role for the autonomic and renin angiotensin systems.

The role of the autonomic nervous system (ANS) in the pathogenesis of hypertension induced by methylprednisolone (20 mg/kg/week subcutaneously) was studied in rats before and during chronic renin angiotensin system (RAS) blockade with captopril (20 mg/kg/every 8 hrs by mouth). Sympathetic nervous system (SNS) blockade was accomplished by the intravenous (i.v.) administration of propranolol (0.20 mg/100g) plus phentolamine (1.25 mg/100g/i.v.) and ganglionic (G) blockade by the use of pentolinium tartarate (0.5 mg/100g/i.v.). After 4 weeks, methylprednisolone-treated animals showed significant decreases in mean arterial pressure (MAP) with both SNS (-34 +/- 2 mm Hg) and G (-56 +/- 3 mm Hg) blockades; during chronic RAS blockade, even greater falls in MAP were observed (SNS = -43 +/- 2 mm Hg and G = -75 +/- 3 mm Hg). Nevertheless, for both groups the levels of MAP obtained during SNS and G blockades were higher than those observed in their control groups. At the end of second week, however, in captopril-treated hypertensive rats the values of MAP obtained during ANS blockade were lower than those observed in the control group. An increased responsiveness to exogenous administration of norepinephrine (NE) was observed in animals receiving methylprednisolone and captopril. It is concluded that methylprednisolone hypertension in the rat may be initially explained by activation of RAS and ANS. At later phases, a third mechanism has to be postulated to explain the hypertensive state.