Weight loss and the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system has been causally implicated in obesity-associated hypertension. We studied the influence of obesity and weight reduction on the circulating and adipose tissue renin-angiotensin-aldosterone system in menopausal women. Blood samples were analyzed for angiotensinogen, renin, aldosterone, angiotensin-converting enzyme activity, and angiotensin II. In adipose tissue biopsy samples, we analyzed angiotensinogen, renin, renin-receptor, angiotensin-converting enzyme, and angiotensin II type-1 receptor gene expression. Obese women (n=19) had higher circulating angiotensinogen, renin, aldosterone, and angiotensin-converting enzyme than lean women (n=19), and lower angiotensinogen gene expression in adipose tissue. Seventeen women successfully participated in a weight reduction protocol over 13 weeks to reduce daily caloric intake by 600 kcal. Body weight was reduced by -5%, as were angiotensinogen levels by -27%, renin by -43%, aldosterone by -31%, angiotensin-converting enzyme activity by -12%, and angiotensinogen expression by -20% in adipose tissue (all P<0.05). The plasma angiotensinogen decrease was highly correlated with the waist circumference decline (r=0.74; P<0.001). Weight and renin-angiotensin-aldosterone system reductions were accompanied by a -7-mm Hg reduced systolic ambulatory blood pressure. These data suggest that a 5% reduction in body weight can lead to a meaningfully reduced renin-angiotensin-aldosterone system in plasma and adipose tissue, which may contribute to the reduced blood pressure.     

Current treatment options for CHF management: Focus on the renin-angiotensin-aldosterone system

Optional statement Heart failure (HF) is highly prevalent in our society and its incidence is increasing in concert with the growing aged population. Experimental and clinical studies have consistently shown that HF is ameliorated by inhibition of the reninangiotensin-aldosterone system (RAAS). Acknowledging that heightened activation of the RAAS contributes significantly to HF progression has led to the development of pharmacologic antagonists of RAAS components that have greatly improved both symptoms and prognosis of patients suffering from this syndrome. Angiotensinconverting enzyme (ACE) inhibitors represent the first developed agents that block the production of angiotensin II, and have been shown to be effective across a broad spectrum of patients with HF, including those with asymptomatic left ventricular dysfunction to overt HF. Initiation of ACE inhibitors prior to the onset of symptoms in those with left ventricular systolic dysfunction, and as early as feasible following a myocardial infarction, has been shown to reduce mortality and the development of overt HF in several clinical trials. Clinical data also support the use of angiotensin II receptor antagonists as an alternative to ACE inhibitors in patients who are allergic to, or intolerant of, ACE inhibitors. Agents that antagonize aldosterone via blockade of mineralocorticoid receptors improve clinical outcomes in patients with advanced HF or those with reduced ejection fraction and HF following an acute myocardial infarction. Maximally inhibiting the RAAS, in conjunction with other neurohormonal systems (eg, the sympathetic nervous system by β-adrenergic blockade), leads to improved clinical outcomes in HF, a highly prevalent and costly disease in our society.     

Imaging the renin-angiotensin-aldosterone system in the heart

The influence of the renin-angiotensin system (RAS) is recognized in cardiac and vascular injury. An extrinsic RAS has been known for decades, and an equally important intrinsic RAS has been discovered recently. The latter leads to pathologic tissue alterations in the absence of systemic stimuli and may be the main source of local tissue effects of RAS. A new radiotracer [18F]fluorobenzoyl-lisinopril was synthesized by radiolabeling benzoic acid active ester with 18F and reacting that with the epsilon-amino group of lisinopril. The presence of angiotensin-converting enzyme (ACE) activity and angiotensin II receptors was examined in relation to myocardial fibrosis. This tissue-specific radioligand represents the first study of ACE in the human heart. This article presents preliminary data on imaging the RAS in the human cardiac tissue and discusses the potential for clinical application of these imaging techniques to human patients.     

Insulin influences the renin-angiotensin-aldosterone system in humans

This study investigates whether insulin influences the renin-angiotensin-aldosterone system in humans. Six healthy male volunteers were placed on a 30-minute euglycemic insulin clamp at 160 microU/mL; euglycemia was maintained also in the following 60 minutes by means of appropriate dextrose infusion. Throughout the study, plasma renin activity, angiotensin II, aldosterone, and factors involved in the regulation of the renin-angiotensin-aldosterone system were measured: catecholamines, angiotensin-converting enzyme, sodium, and potassium. A significant increase of plasma renin activity and angiotensin II was observed, and a decrease of aldosterone was also detected. These changes can be ascribed to the effects of the rapid insulin-induced plasma potassium decrease on plasma renin activity and aldosterone secretion because they did not occur in a control clamp study with a potassium infusion.     

Perspectives on the renin-angiotensin-aldosterone system in hypertension

In the syndrome of hyperaldosteronism, the abnormal electrolyte metabolism, secondary to mineralocorticoid excess, seems to play a predominant pathogenetic role in causing elevation of the blood pressure, since the renin-angiotensin system is depressed and unresponsive. The available evidence (results of treatment, consistent failure to cause high blood pressure by administration of excessive salt-remaining steroids to normotensive volunteers, the salt-hypertension model in experimental animals, the higher incidence of adrenal adenomas in hypertensive patients, etc.), however, suggests that other factors participate in the mechanism of hypertension. Angiotensin II stimulates aldosterone secretion, thereby affecting electrolyte balance; in addition, this polypeptide is the most powerful vasoconstrictor known today, the effectiveness of which is greater in a Na-replete condition. In some hypertensive states (renovascular hypertension, end-stage renal disease, malignant phase hypertension, hypertension related to oral-contraceptive medication, and primary reninism) both the renin-angiotensin system and aldosterone production may be elevated. In this group, however, correlation between the latter two variables and hypertension is not sufficiently consistent to implicate them as the sole pathogenetic factors. In the larger group of patients with essential hypertension, the renin-angiotensin-aldosterone system and electrolyte metabolism range from normal to subtle changes (depressed plasma renin, incomplete aldosterone suppression by salt load, decrease in aldosterone metabolism, exaggerated natriuresis, reversal of electrolyte circadian cycle) of difficult interpretation. We suggest that the same factors, clearly abnormal in hypertensive states of more defined etiology, are also at play in causing essential hypertension, perhaps through some as yet undefined abnormal interrelationship.     

Regulation of the renin-angiotensin-aldosterone system in fibromyalgia

OBJECTIVE: To assess the function of the renin-angiotensin-aldosterone (RAA) system in women with fibromyalgia (FM) compared to healthy women. METHODS: Women with FM [n = 14, age 41.0+/-7.2 yrs, body mass index (BMI) 26.4+/-5.4 kg/m2] and healthy women (n = 13, age 40.0+/-7.7 yrs, BMI 25.0+/-5.0 kg/m2) were placed on a low sodium diet (10 mEq sodium/day) for 5 days. After being supine and fasting overnight, subjects received an intravenous infusion of angiotensin II at successive doses of 1, 3, and 10 ng/kg/min for 45 min per dose. Blood pressure (BP), plasma renin activity (PRA), aldosterone, and cortisol were measured at baseline and after each dose of angiotensin II. Prior to sodium restriction, women with FM completed the Hopkins Symptom Checklist-90, which included a question grading the extent of dizziness/faintness on a scale of 0 (none) to 4 (extremely). RESULTS: After dietary sodium restriction, baseline PRA, aldosterone, and supine BP were similar in healthy women and women with FM. Aldosterone and BP rose in response to infused angiotensin II; these responses did not differ significantly between healthy women and women with FM. In women with FM, symptoms of dizziness correlated inversely with BMI (r = -0.81, p < 0.001) and the systolic BP response to 10 ng/kg/min angiotensin II (r = -0.81, p < 0.001). CONCLUSION: The functioning of the RAA system, including the vascular response to angiotensin II, was intact in women with FM compared to healthy women. However, women with FM who complained of dizziness had a blunted vascular response to angiotensin II. This blunted vascular response may indicate intravascular volume depletion in women with symptoms of dizziness.     

Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes

Diabetes (particularly type 2 diabetes) represents a global health problem of epidemic proportions. Individuals with diabetes are not only more likely to develop hypertension, dyslipidemia, and obesity, but are also at a significantly higher risk for coronary heart disease, peripheral vascular disease, and stroke. Angiotensin II plays a key pathophysiological role in the progression of diabetic renal disease, and blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II antagonists has therefore become an important therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. Several studies have demonstrated the effects of angiotensin II antagonists on the reduction of albuminuria and the progression of renal disease from microalbuminuria to macroalbuminuria. More importantly, several endpoint trials have shown that the antiproteinuric effects of losartan and irbesartan translate into cardiovascular and renoprotective benefits beyond blood pressure lowering, thereby delaying the need for dialysis or kidney transplantation by several years. These and other studies indicate that angiotensin II antagonists not only improve survival and quality of life of patients with diabetic nephropathy, but also have the potential to reduce the substantial healthcare burden associated with managing these patients. ACEi also appear to exert similar beneficial effects in diabetic patients, but whether clinically significant differences in renoprotection or mortality exist between angiotensin II antagonists and ACEi in patients with type 2 diabetes remains to be fully investigated in appropriate head-to-head studies.     

Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population.

The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I-converting enzyme (ACE) gene [4656(CT)(2/3)], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B(max) and K(D) values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT)(2/3) variant with plasma ACE levels was observed (P<0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (P=0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (P=0.02). No genotype effect of the AT1R A1166C polymorphism was detected either on the B(max) or the K(D) value of the Ang II receptors on platelets.     

The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease

The renin-angiotensin-aldosterone system regulates renal vasomotor activity, maintains optimal salt and water homeostasis, and controls tissue growth in the kidney. However, pathologic consequences can result from overactivity of this cascade, involving it in the pathophysiology of kidney disease. An activated renin-angiotensin-aldosterone system promotes both systemic and glomerular capillary hypertension, which can induce hemodynamic injury to the vascular endothelium and glomerulus. In addition, direct profibrotic and proinflammatory actions of angiotensin II and aldosterone may also promote kidney damage. The majority of the untoward effects associated with angiotensin II appear to be mediated through its binding to the angiotensin II type 1 receptor. Aldosterone can also induce renal injury by binding to its receptor in the kidney. An understanding of this system is important to appreciate that inhibitors of this cascade can reduce the progression of chronic kidney disease in proteinuric disease states. Pharmacologic agents that can interfere with this cascade include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists. This paper will provide an overview of the renin-angiotensin system, review its role in kidney disease, examine the renal effects of inhibition of this cascade in experimental animal models, and review clinical studies utilizing renin-angiotensin-aldosterone inhibitors in patients with diabetic and nondiabetic nephropathies.     

Change in the renin-angiotensin-aldosterone system in aging. 1

Data are provided that testify to a changed reactivity of the RAAS in old age: Higher sensitivity of this system to the regulatory influences of the sympathico-adrenal and of the hypothalamus-hypophysis system as well as restriction of the functional facilities and reduction of reactivity. The obtained results indicate an aging-dependent reduction of the degree of reliability of the RAAS in stress situations.     

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.