Furosemide dynamics in conscious rabbits: Modulation by arginine vasopressin

Summary The aims of this study were to assess the influence of arginine-vasopressin (AVP) on the pharmacodynamics and kinetics of furosemide. To this purpose, the response and the kinetics of furosemide (5 mg/kg i.v.) were studied in two groups of rabbits, one control and one receiving an infusion of AVP (2.5 ng/kg/min). The infusion of AVP generated mean plasma levels of 35 pg/ml, and in these rabbits osmolal clearance was increased, free water clearance was reduced, and renal plasma flow was reduced by 25% (p<0.05). High AVP plasma levels increased the natriuresis (p<0.01) and the urinary excretion of prostaglandin E₂ (U_PgE2V; p<0.01). The increase in U_PgE2V was associated with AVP plasma concentrations (r=0.8248; p<0.001). AVP reduced the increment in natriuresis and diuresis elicited by furosemide from 163±20 to 87±20 µmol/min (p<0.05) and from 1.22±0.11 to 0.83±0.13 ml/min (p<0.05). The infusion of AVP enhanced furosemide metabolic clearance but diminished its renal clearance, resulting in a decrease in the rate of furosemide urinary secretion. It was concluded that high plasma levels of AVP reduce furosemide natriuresis, presumably because of a decrease in furosemide urinary secretion.     

Abnormal Renal Sodium Excretion in the Nephrotic Syndrome after Furosemide: Relation to Glomerular Filtration Rate

ABSTRACT. Danielsen H, Pedersen EB, Madsen M, Jensen T. (Department of Internal Medicine C, Aarhus Kommunehospital, and University of Aarhus, Aarhus, Denmark.) Abnormal renal sodium excretion in the nephrotic syndrome after furosemide: relation to glomerular filtratoni rate. The effect of 40 mg furosemide intravenously on sodium excretion, the renin-aldosterone system and arginine vasopressin (AVP) was studied in 14 patients with the nephrotic syndrome and in 13 control subjects. Creatinine clearance (C_cr) was reduced in all patients but four. Before furosemide, AVP, but not angiotensin II (AII) or aldosterone (Aldo), was increased in the nephrotic patients. After fursoemide, sodium excretion (Na_E) increased less and changes in AVP, AII and Aldo were blunted in the patients. C_cr and Na_E were positively correlated in the nephrotic syndrome. The reduced sodium response after furosemide in the nephrotic syndrome seems to be closely correlated to a reduced glomerular filtration rate but not to an increased activity of the renin-angiotensin-aldosterone system. The reduced response of AVP, AII and Aldo after furosemide is consistent with a lower degree of volume depletion in nephrotic patients.     

Characterization of angiotensin II receptors in the anterior pituitary gland

Specific and high affinity binding sites for angiotensin II were demonstrated in the anterior pituitary gland by binding studies with [¹²⁵I]iodoangiotensin II. The binding properties of the pituitary receptors were similar to those of angiotensin II receptors present in the adrenal gland. The concentration of binding sites in rat anterior pituitary (293 ± 50 fmoles/mg protein) was less than in the adrenal gland, but was much greater than in smooth muscle. Angiotensin II receptors were identified in the anterior pituitary tissue of mature and immature animals of both sexes, and in species including rat, rabbit and dog. No binding of angiotensin II was detected in posterior pituitary homogenates, or in GH₃ pituitary tumor cells. Collagenase-dispersed anterior pituitary cells also contained specific binding sites for angiotensin II, with equilibrium binding constant (K_a) of 3.6 × 10⁹ M^?1. The presence of specific high-affinity angiotensin II receptor in the anterior pituitary gland provides a mechanism by which angiotensin-like peptides could modulate the process of pituitary hormone secretion.     

Clinical update: the role of angiotensin II receptor blockers in patients with left ventricular dysfunction (Part II of II)

Almost 5 million individuals in the United States have chronic heart failure (HF), which is increasing in prevalence. Angiotensin-converting enzyme (ACE) inhibitors are standard therapies for HF, although more than 10% of patients with HF are unable to tolerate these agents. Furthermore, ACE inhibitors may not provide complete blockade of the renin-angiotensin system (RAS) in the long term. Because angiotensin II receptor blockers (ARBs) may block the RAS more completely than ACE inhibitors and are better tolerated, several large-scale ARB trials have been performed exploring their potential role in treating patients with symptomatic HF and left ventricular systolic dysfunction. The Losartan Heart Failure Survival Study (ELITE II) demonstrated no significant differences in morbidity and mortality between the ARB losartan and the ACE inhibitor captopril among elderly patients with HF. The Valsartan Heart Failure Trial (Val-HeFT) demonstrated reductions in hospitalizations for HF with the ARB valsartan when added to standard HF therapy, with no effect on mortality. Both trials suggested a potential negative interaction between ARB and beta-blocker therapy. The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program demonstrated significant reductions in morbidity and mortality with the ARB candesartan in patients with HF due to systolic dysfunction, with or without ACE inhibitors and with or without beta blockers. Thus, the addition of ARBs to the treatment regimen of patients with symptomatic HF should be strongly considered.     

Angiogenesis induced by electrical stimulation is mediated by angiotensin II and VEGF

OBJECTIVE: Physiological angiogenesis in skeletal muscle is an adaptive response to physical training and electrical stimulation. This study investigated the role of angiotensin II (Ang II) in regulating both angiogenesis and vascular endothelial growth factor (VEGF) protein expression induced by electrical stimulation. METHODS: The right tibialis anterior (TA) and extensor digitorum longus (EDL) muscles of Sprague-Dawley rats were stimulated for 8 hours per day for 7 days. The contralateral muscles served as controls. Two days before the surgery and throughout the stimulation protocol, the rats received either lisinopril or losartan in their drinking water. Rats without any drug treatment were used as control. Immunohistochemistry and Western blot analysis were performed to identify the source and quantify the VEGF protein expression in these muscles. The relationship between angiogenesis and VEGF expression was explored using a VEGF-neutralizing antibody. RESULTS: Chronic electrical stimulation of the skeletal muscles led to significant increases in vessel density (14% and 30% for EDL and TA, respectively) within 7 days. In addition, stimulation increased VEGF protein levels in the stimulated muscles. Both lisinopril and losartan blocked elevation in VEGF expression and inhibited the angiogenesis induced by stimulation. VEGF neutralization also inhibited angiogenesis, confirming the relationship between Ang II, VEGF, and vessel growth. CONCLUSION: The current study suggests a pathway involving angiotensin II receptors (AT1) and VEGF in electrically stimulated angiogenesis.     

Functional antagonism of different angiotensin II type I receptor blockers in human arteries

Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type 1 receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary arteries were obtained as excess graft material during coronary bypass surgery. Vessels were prepared as rings and mounted in an organ bath in which vasoconstriction and -dilation can be measured. Concentration-response curves of angiotensin II-mediated vasoconstriction were measured in absence or presence of different concentrations of one of the ARBs. Results. Losartan showed a rightward shift of the angiotensin II-mediated vasoconstriction, whereas addition of its metabolite EXP 3174 caused a decrease of the maximal effect of angiotensin II. Incubation with valsartan and candesartan also resulted in a decrease of the maximal effect. The inhibiting effects on the angiotensin II-mediated vasoconstriction by the highest concentration of EXP 3174, valsartan and candesartan did not differ significantly. Conclusion. In human internal mammary arteries, losartan acts as a surmountable antagonist. On the other hand, EXP 3174, valsartan and candesartan demonstrate an insurmountable type of antagonism. Furthermore, the inhibiting effects of EXP 3174, valsartan and candesartan in our study are equal in the highest concentrations.     

Elevated plasma endothelin concentrations in heart failure; an effect of angiotensin II?

Endothelin is a powerful vasoconstrictor that may be partlyresponsible for the increases in venous and arterial tone characteristicof heart failure. The release of endothelin from endothelialcells in culture is stimulated by angiotensin II. We investigated the relationship between plasma concentrationsof immuno reactive endothelin-1 and angiotensin II in 25 patientswith heart failure and eight with ischaemic heart disease butnormal left ventricular function. Plasma concentrations of endothelinand angiotensin II were correlated (Spearman rank correlationcoefficient of 0.72; P<0.0001) in patients with heart disease.Plasma concentrations of angiotensin II and endothelin werehigher in those patients with heart failure. Angiotensin II was infused over a 3 h period in eight healthyvolunteers. Infusion of angiotensin II increased plasma concentrationsof angiotensin II to levels greater than those usually foundin patients with severe heart failure but induced only a modestrise in plasma concentrations of immunoreactive endothelin-1(0.77 ±0.16 to 1.03 ± 0.03 pmol. I^–1, P<0.02). Increased plasma concentrations of angiotensin II and endothelin-1both appear to reflect the presence and severity of heart failure.Although a significant correlation exists between plasma concentrationsof angiotensin II and endothelin in patients with heart failure,the relationship may not be causal.     

Rationale for the use of angiotensin II receptor blockers in patients with left ventricular dysfunction (part I of II)

Almost 5 million individuals in the United States are diagnosed with chronic heart failure (HF), and the prevalence is increasing. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers, neurohormonal antagonists that block the renin-angiotensin system (RAS) and the sympathetic nervous system, respectively, have been shown in clinical trials to reduce morbidity and mortality in patients with HF, and these therapies are now integral components of standard HF treatment. Yet, morbidity and mortality rates in HF remain unacceptably high, and the limitations of current standard therapies are becoming increasingly apparent. About 10% of patients with HF are unable to tolerate ACE inhibitors, often because of cough. In addition, ACE inhibition may not completely block the RAS because angiotensin II, the main end product of the RAS, can be generated via non-ACE enzymatic pathways. Angiotensin II receptor blockers (ARBs) may exert more complete RAS blockade than ACE inhibitors by interfering with the binding of angiotensin II at the receptor level, regardless of the enzymatic pathway of production. They are also better tolerated than ACE inhibitors and have been shown to improve symptoms and function in clinical trials in patients with HF. These factors provide a strong rationale for the study of the clinical effects of ARBs in patients with HF.     

Does treatment with ACE inhibitors or angiotensin II receptor antagonists prevent atrial fibrillation after dual chamber pacemaker implantation?

AIMS: A retrospective observational study was performed to test the hypothesis that a lower incidence of atrial fibrillation (AF) would be observed in patients treated with either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (AIIRAs) than those without these drugs, 1-year following implantation of a dual chamber pacemaker for all indications. METHODS: One hundred and sixty consecutive patients who underwent implantation of a dual chamber pacemaker between January and August 2002 were identified and their case notes were retrospectively analysed. The primary endpoint was the presence of persistent AF (confirmed by 12-lead ECG recorded from the visit to the pacemaker clinic) at 12-month follow-up. RESULTS: Overall, 8% patients developed new onset persistent AF at 1-year follow-up. The incidence of AF at 1-year was 4% in patients treated with ACE inhibitors, 8% in patients taking AIIRAs or 5% on either drug. Although a trend towards a higher incidence of AF was observed at 1-year (10%) in patients not receiving either of these drugs, this was not statistically significant (P = 0.21, drug vs. no drug). The incidence of AF in patients with a previous history of paroxysmal AF or cardioversion was significantly higher (23%) than those patients without (5%), P < 0.0001. An odds ratio (95% CI) of 7.9 (2.3-27.8) was obtained. CONCLUSION: To confirm these interesting initial results and to investigate this important relationship further, larger prospective randomised controlled studies are required.     

Role of angiotensin II in liver fibrosis-induced portal hypertension and therapeutic implications

Angiotensin II (AT-II) is a peptide that plays an important role in the renin-angiotensin-aldosterone (RAA) system. Traditionally, the RAA system has been related with states of systemic hypertension and hypoperfusion as a counterbalance mechanism. Recently, AT-II has been studied for its properties in the process of fibrosis in several organs, especially in the liver. AT-II is capable to stimulate the activated hepatic stellate cells, which increase expression of profibrogenic molecules like tumor growth factor-β, tissue inhibitor of metalloproteinase-1 and collagen I, among others. At the same time, AT-II is implied in the hemodynamic balance of cirrhosis and portal hypertension. Due to its profibrogenic and vasoactive properties, blockade of AT-II actions constitutes an important therapeutic target to inhibit fibrotic processes and reduction of risk of complications of portal hypertension as well. Some drugs like angiotensin-converting enzyme inhibitors or the angiotensin II receptor blockers have been studied as alternatives for the treatment of patients with cirrhosis with promising results. Nonetheless, additional research is required in order to consider these drugs as a part of the integral treatment of the patient with cirrhosis and portal hypertension.     

Preglomerular and postglomerular basal diameter changes and reactivity to angiotensin II in obese rats

Aim and Methods: Obesity in humans is associated with proteinuria and an increased glomerular filtration, possibly related to an increase in glomerular capillary pressure. We investigated in obese and lean Zucker rats (10–12 weeks old) whether this might be related to alterations in the diameter of preglomerular and postglomerular microvessels and their reactivity to the resistance regulator angiotensin II (AngII), using the hydronephrotic kidney model. Results: The obese rats exhibited a hyperinsulinaemic, euglycaemic state and hypertension. Urinary protein concentration and fluid intake were both increased threefold. Basal diameters of distal interlobular arteries (ILAs) and afferent arterioles (AAs) were larger in the obese rat than in the lean rat (ILA: 25.7 ± 0.3 vs. 23.0 ± 0.4 μm and AA: 18.8 ± 0.3 vs. 16.7 ± 0.5 μm, respectively; p ≤ 0.01), while diameters of efferent arterioles (EAs) were smaller in obese animals (14.2 ± 1.1 vs. 18.2 ± 1.2 μm; p ≤ 0.05). AngII induced a concentration‐dependent constriction in ILA, AA and EA with an augmented response in the obese compared with the lean rats. Thus, at higher concentrations, AngII abolished the diameter difference between obese and lean animals in preglomerular microvessels while exaggerating that in postglomerular arterioles. Conclusions: Our data indicate that in obese rats, a vasodilated state in small preglomerular microvessels and a vasoconstricted state in the postglomerular arterioles exist. Although AngII cancelled the former, the latter remained. Therefore, these data reveal periglomerular vascular changes that may play a role in glomerular dysfunction and renal pathology associated with obesity.     

Evaluation of angiotensin II type‐1 receptor antibodies in primary aldosteronism and further considerations about their possible pathogenetic role

Angiotensin II type‐1 receptor autoantibodies (AT1RAb) have been involved in the genesis of primary aldosteronism (PA), both in aldosterone‐producing adenoma (APA) and in idiopathic hyperaldosteronism (IHA). In this study, we evaluated the titer of AT1RAb in 44 PA patients (15 with APA and 29 with IHA) compared with 18 normotensive healthy controls who were matched for gender and age. In 17 PA patients (6 APA and 11 IHA) the titer was evaluated under mineralocorticoid receptor (MR) antagonist treatment. We found that PA patients had a significantly higher titer of AT1RAb compared with controls (median values 33 [IQR 15.6] IU/mL vs 17.5 [IQR 10.8] IU/mL, respectively; P < 0.0001). No significant difference of the AT1RAb titer was reported among PA patients, subdivided according to the subtypes and the concomitant MR antagonist therapy. No significant correlation was detected between age, gender, BMI, blood pressure values, baseline aldosterone, ARR, and the AT1RAb titer of all patients enrolled. Our data confirm an increased titer of AT1RAb in both subtypes of PA, independently from the concomitant use of MR antagonists and clinical/biochemical characteristics of PA patients. The small sample of patients and the relatively short time of treatment could have influenced these results. Moreover, the ELISA assay fails to evaluate the bioactivity of AT1RAb. Further studies should evaluate if the subtype, the clinical/biochemical recovery of PA, or both, influence the pathogenetic role of AT1RAb. The possible autoimmune pathogenesis and reversal effect with AT1R blocker treatment in PA patients with AT1RAb positivity is intriguing and requires further study.     

Efficacy of combined angiotensin II receptor blocker with tripterygium glycosides on diabetic nephropathy: A protocol for meta-analysis

Background:Several studies have reported good results for angiotensin II receptor blockers (ARB) combined with tripterygium glycosides (TGs) in the treatment of diabetic nephropathy (DN). However, because a small number of cases were included in each study, the statistical power was limited. Therefore, we performed a protocol for meta-analysis to further evaluate the clinical efficacy and safety of combined ARB and TGs in treatment of DN.Methods:The protocol was written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, Science Direct up to April 2021. Outcome measures were 24-h urinary total protein, urinary albumin excretion rate, serum creatinine, blood urea nitrogen, albumin, hemoglobin A1c, β2-microglobulin and serum glutamic pyruvic transaminase. The risk of bias assessment of the included studies was performed by two authors independently using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). We performed meta-analysis using STATA 11.0.Results:The review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings.Conclusion:The findings will provide helpful evidence for the application of combined ARB and TGs in the treatment of DN.OSF registration number:10.17605/OSF.IO/ARGE3     

The role of angiotensin II type 1 receptor blockers in the prevention and management of diabetes mellitus

Angiotensin II Receptor blockers (ARBs) are an important addition to the current range of medications available for treating a wide spectrum of diseases including cardiovascular diseases. Coronary heart disease (CHD) is the most common cause of death in the United Kingdom and worldwide. More importantly, the presence of the metabolic syndrome and the likelihood of diabetes mellitus taking on epidemic proportions in the years to come all threaten to maintain the mortality rate due to CHD. This review article focuses on the clinical studies that have helped define the trends in the usage of these agents in the prevention and treatment of diabetes mellitus and its complications and also explores possible mechanisms of action and future developments.     

Increased vasopressor responsiveness to angiotensin II in Type 1 (insulin-dependent) diabetic patients without complications

Summary The blood pressure response to infused angiotensin II (0.3 to 3 ng · kg^–1 · min ^–1) was investigated in six normotensive patients with Type 1 (insulin-dependent) diabetes free of complications and in six healthy subjects matched for age, sex and weight. Basal blood pressures (111/68 and 114/72 mmHg) and basal plasma angiotensin II levels (18.0±5.2 and 14.1±2.4 pmol/l; mean + SD) were similar in the diabetic and control groups as were 24 h urinary excretions of sodium (157±88 and 154±84 mmol/24h). Equal increments in plasma angiotensin II were produced during the infusions in the two groups. Increases in both diastolic and systolic blood pressure were significantly greater in the diabetic patients throughout the infusion. Mean diastolic increments were: 6.7 versus 1.3 mmHg (0.3 ng dose), 11.0 versus 6.9 mmHg (1 ng dose) and 16.7 versus 12.3 mmHg (3 ng dose) (p<0.001). Corresponding figures for systolic pressure were: 8.7 versus 1.3mmHg, 10.3 versus 3.7mmHg and 15.3 versus 8.7mmHg (p<0.001). Vasopressor responsiveness to angiotensin II is thus increased in Type 1 diabetic patients without complications; it may, therefore, be a consequence of the diabetes rather than of the presence of microvascular disease or hypertension.     

A potential role for angiotensin II in obesity induced cardiac hypertrophy and ischaemic/reperfusion injury

Background The mechanisms for obesity induced myocardial remodelling and subsequent mechanical dysfunction are poorly understood. There is good evidence that angiotensin II and TNFα have strong growth promoting properties and are elevated with obesity. In addition, these two peptides may interact to exacerbate myocardial ischaemic/reperfusion injury.Hypothesis Obesity increases systemic and myocardial renin–angiotensin system (RAS) activity and TNFα levels and contributes to obesity induced cardiac remodelling and ischaemic/reperfusion injury.Methods Male Wistar rats were placed on a standard rat chow diet or cafeteria diet for 16 weeks. Two additional groups of rats received the respective diets and losartan (30 mg/ kg/d) in their drinking water. Hearts were perfused on the isolated working rat heart perfusion system and mechanical function was documented before and after 15 min normothermic total global ischaemia. Blood and myocardial samples were collected for angiotensin II, TNFα and NADPH oxidase activity determinations.Results The rats on the cafeteria diet became obese compared to rats on the standard rat chow (438 ± 5.9 g vs 393 ± 7.3 g for control, p < 0.05). Obesity was associated with elevated serum angiotensin II (0.050 ± 0.015 pmol/ml vs. 0.035 ± 0.003 pmol/ml, p < 0.05) and TNFα levels (42.8 ± 5.93 pg/ml vs. 13.18 ± 2.50 pg/ml, p < 0.05), and increased heart to body weight ratios (3.1 ± 0.04 mg/g vs. 2.8 ± 0.03 mg/g, p < 0.05). Losartan had no effect on body weight but decreased basal myocardial angiotensin II and TNFΑ levels as well as heart to body weight ratio in the obese and lean controls (2.5 ± 0.05 mg/g and 2.6 ± 0.04 mg/g relative to their controls, p < 0.05). Hearts from obese rats had lower reperfusion aortic outputs (AO) than their concurrent controls (18.42 ± 1.17 ml/min vs. 27.8 ± 0.83 ml/min, p < 0.05). Losartan improved aortic output recoveries in obese rats (23.0 ± 1.71 ml/min, p < 0.05).Conclusions Obesity increased serum angiotensin II and TNFα levels, blood pressure, and heart weight to body weight ratios. These changes were associated with decreased basal and post–ischaemic myocardial mechanical function. Chronic AT₁ receptor antagonism prevented the adverse changes in heart weight, mechanical function and susceptibility to ischaemic/reperfusion injury. Although current data do not exclude additional mechanisms for obesity induced cardiac remodelling, they suggest that angiotensin II may contribute to obesity induced cardiac remodelling and ischaemic/reperfusion injury.     

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist

Introduction Blockade of the AT₁ angiotensin II (Ang II) receptor has been shown to provide antihypertensive effects. However, whether AT₁ Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear.Methods and results Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n=13) and guinea pig (n=9) myocardial preparations in the presence of the specific AT₁ Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mol/L of valsartan, resting membrane potential increased from baseline in both rat (–82.3±4.1 vs –76.8±5.8 mV, p<0.05) and guinea pig (–81.6±2.9 vs –76.9±2.0 mV, p<0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7±1.4 vs 80.0±5.6 ms, p<0.05) and ventricular (131.1±8.1 vs 118.7±8.3 ms, p<0.05) myocardium following exposure to 500 mol/L of valsartan. In a separate series of experiments Ang II (1.0 mol/L) had no effect on atrial or ventricular action potential characteristics in either species.Conclusion Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.