Journal of the Renin-Angiotensin-Aldosterone System

The development of angiotensin II receptor blockers (ARB) as a new class of drugs for the management of hypertension has elicited the attention of many clinicians worldwide with the aim of improving blood pressure (BP) control as well as cardiovascular protection.AmongARB telmisartan has been shown to be characterised by an antihypertensive efficacy fully covering the 24-hour period, thereby allowing to antagonise the adverse effects of early morning BP rise on cardiovascular risk. Other specific effects of the drug are represented by its favourable metabolic profile (particularly on insulin sensitivity) and neutral effects on sympathetic cardiovascular function.These properties are coupled with cardioprotective effects, documented by the evidence that the drug: 1) is effective in favouring the regression of cardiac and vascular organ damage, 2) reduces arterial stiffness and improves vascular distensibility and 3) reverses the endothelial dysfunction typical of the hypertensive state particularly when complicated by renal failure, diabetes, obesity or metabolic syndrome. Several of these properties can account for the results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), documenting the beneficial effects on the drug on cardiovascular morbidity and mortality.

Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise.The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment.The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs inindividuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.

Introduction. We previously reported that acute cigarette smoking can cause a dysfunction of endothelium-dependent vasodilation in cerebral vessels, and that blocking the angiotensin II (Ang II) type 1 (AT1) receptor with valsartan prevented this impairment. Our aim was to investigate the effects of a Rho-kinase inhibitor (fasudil) and a Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase inhibitor (apocynin) on smoking-induced endothelial dysfunction in cerebral arterioles.

Method. In Sprague—Dawley rats, we used a closed cranial window preparation to measure changes in pial vessel diameters following topical acetylcholine (ACh) before smoking. After one-minute smoking, we again examined the arteriolar responses to ACh. Finally, after intravenous fasudil or apocynin pre-treatment we re-examined the vasodilator responses to topical ACh (before and after cigarette smoking).

Results. Under control conditions, cerebral arterioles were dose-dependently dilated by topical ACh (10^-6 M and 10^-5 M). One hour after a one-minute smoking (1 mg-nicotine cigarette), 10^-5 M ACh constricted cerebral arterioles. However, one hour after a one-minute smoking, 10^-5 M ACh dilated cerebral pial arteries both in the fasudil pre-treatment and the apocynin pre-treatment groups, responses that were significantly different from those obtained without fasudil or apocynin pre-treatment.

Conclusion. Thus, inhibition of Rho-kinase and NADPH oxidase activities may prevent the above smoking-induced impairment of endothelium-dependent vasodilation.

Introduction. Our objective was to evaluate the effect of blocking the renin-angiotensin system (RAS) on the expression of transforming growth factor-beta 1 (TGF-β1), platelet derived growth factor-B (PDGF-B), tumour necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) in diabetic kidney glomeruli.

Materials and Method. 1) Uninephrectomised streptozotocin induced diabetic rats were treated during eight months with vehicle (CD) or irbesartan (ID). Uninephrectomised non-diabetic rats were used as control group (ND). Protein urinary excretion and morphological renal damage were analysed. Glomerular expression of TGF-β1, PDGF-B, VEGF and TNF-α were evaluated by Western blot and Immunohistochemistry. 2) Isolated glomeruli of diabetic rats were incubated 24-hours in the presence of different doses of irbesartan. Glomerular expression of TGF-β1, PDGF-B,TNF-α and VEGF were determined by Western blot.

Results. ND and ID presented lower renal injury and proteinuria than CD (p<0.05). Glomerular expression of TGF-β1, PDGF-B,TNF-α and VEGF were similar in ND and ID, but lower than in CD (p<0.05). In addition, in isolated diabetic rat glomeruli, irbesartan reduced the content of all these factors.

Conclusion. Systemic and local administration of irbesartan lowers glomerular expression of TGF-β1, PDGF-B, VEGF and TNF-α.These data suggest that part of the effect of lowering the expression of these growth factors and cytokines is due to a direct blockade of glomerular RAS.

The diagnosis of primary hyperaldosteronism due to microadenoma or unilateral adrenal hyperplasia can be challenging, since hypokalaemic alkalosis, high plasma aldosterone and a definite adenoma on imaging may all be absent.

Method and result. We describe three cases of resistant hypertension (on > 5 antihypertensives) where hyperaldosteronism was suspected because of a suppressed plasma renin level despite treatment with multiple drugs which normally elevate renin. Renin mass was measured by a double-site chemi-immunoluminometric assay. All patients had normal plasma aldosterone levels. Hypokalaemia was present in the first two cases but computed tomography did not show clear cut adenomas.Adrenal vein sampling (AVS) revealed lateralisation (> 4 times higher aldosterone to cortisol ratio (ACR) on the affected than contra-lateral side).The third patient was normokalaemic and AVS showed only minimal lateralisation (ACR 1.3:1).The severe hypertension in all cases was reversed by adrenalectomy, with blood pressure falling to target despite withdrawal of all but one to two drugs.

Conclusions. The robotic assay of renin mass permits rapid detection of patients in whom plasma renin is suppressed below the normal range. A suppressed plasma renin indicates abnormal Na⁺-retention, and — when not overcome by drugs such as angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers — may be the only clue to a curable adrenal adenoma.AVS is required to demonstrate lateralisation of aldosterone secretion, justifying adrenalectomy.

Objectives. The aim of this study was to assess the effects of losartan treatment on exercise tolerance and echocardiographic parameters in patients with mitral regurgitation (MR) secondary to mitral valve prolapse or rheumatic heart disease.

Methods. Twenty-seven patients (14 males, 13 females, mean age 51±11, range 21—76) with moderate MR due to mitral valve prolapse or rheumatic heart disease were examined by means of Doppler echocardiography.The subjects were submitted to treadmill exercise tests using the modified Bruce protocol at baseline, after six hours and after the six-week treatment period to be evaluated based on their exercise tolerance. Mitral Regurgitant Volume (MRV), effective regurgitant orifice diameter, left atrial volume, left ventricle (LV) end-diastolic volume index, LV end-systolic volume index, LV ejection fraction (LVEF), left ventricle mass index were calculated at baseline and after six weeks of treatment with single dose of losartan (50 mg/day).

Results. Total treadmill exercise time increased from 477.7±147.9 to 535.7±149.0 seconds after six hours (p<0.01) and to 559.6±142.8 seconds after six weeks of treatment. Also, metabolic equivalent values increased following six hours of first dose and six weeks of losartan treatment (from 10.9±2.9 to R11.8±3.1, p=0.006 and 12.4±3.1, p=0.002; respectively). However, peak exercise systolic blood pressure (BP) was reduced after six hours and six weeks of treatment, and resting diastolic BP did not change after six hours but reduced at the end of the treatment period. MR volume decreased significantly from 29.3±14.1 ml to 25.1±14.8 ml, (p=0.025) without significant change in regurgitant orifice diameter (0.72±0.37 cm vs. 0.66±0.37 cm, p=NS), left atrium diameter and area while LVEF increased from 51.70±13.37 to 54.11—11.75 (p=0.015) with losartan.

Conclusion. We conclude that the angiotensin II receptor antagonist losartan improves exercise tolerance and echocardiographic parameters in patients with moderate MR.

The influence of intracellular renin plus angiotensinogen (Ao) as well as angiotensin (Ang) II on cell volume was investigated in myocytes isolated from the heart of four-month-old cardiomyopathic hamsters (TO-2) and normal hamsters (F1B). Measurements of cell width and cell length were performed on quiescent cells using a Px-it imaging and computer system.The cell volume was calculated assuming the cells as elliptical cylinders and taking the cell depth equal to one third of cell width. For measurements of sodium pump current, the cells were voltage clamped (holding potential -40 mV) using the whole cell configuration. Cells were exposed to K-free solution to inhibit the pump and then to normal Krebs solution to reactivate the pump. In other experiments the cells were voltage clamped (holding potential -40 mV)and changes in the background current elicited by renin plus Ao or by Ang II were monitored. The results indicated that: a) intracellular dialysis of renin (128 pmol Ang I/ml) plus Ao (110 pmol Ang I generated by renin by exhaustion) decreased the cell volume concurrently with the activation of the sodium pump; b) intracellular losartan (10^-8 M) or extracellular ouabain (10^-8 M) abolished the effect of renin plus Ao on cell volume; c) intracellular Ang II (10^-8 M), by itself, reduced cell volume and increased the pump current density; d) extracellular administration of renin plus Ao, at the same concentration used intracellularly, increased cell volume and inhibited the sodium pump. This increase of cell volume elicited by extracellular renin plus Ao was related to the activation of the Na-K-2Cl cotransporter; e) intracellular Ang II (10-8 M) reversed cell swelling induced by hypotonic solutions. Conclusions. Intracellular and extracellular renin plus Ao have opposite effects on sodium pump and cell volume regulation in the failing heart. Both effects of renin plus Ao are dependent upon the formation of Ang II. Since intracellular Ang II counteracted the cell swelling induced by hypotonic solution, it is reasonable to think that the activation of the intracrine renin-angiotensin system might play a protective role during myocardial ischaemia by reducing cell volume.