Volume 4, Number 3, September 2003

PAPERThe role of Ang (1-7) in mediating the chronic hypotensive effects of losartan in normal rats
John P Collister, Michael D Hendel

Hypothesis: The following studies were designed to test the hypothesis that Ang (1-7) contributes to the chronic hypotensive effects of the angiotensin II AT₁-receptor antagonist, losartan, in normal rats.
Introduction: We have previously shown a chronic, hypotensive response to the AT₁-receptor antagonist, losartan, in normotensive rats. The mechanism of this response is not completely understood. Previous studies by others have demonstrated a role for Ang (1-7) in the beneficial antihypertensive effects of angiotensin-converting enzyme (ACE) inhibition. This is thought to be due to vasodilatory effects of increased levels of Ang (1-7) during ACE inhibition. Since it has now been shown that Ang (1-7) levels are also increased during AT₁ antagonism, we designed experiments to test the hypothesis above.
Materials and methods: Sprague-Dawley rats were instrumented with venous catheters and radiotelemetric pressure transducers and commenced on a normal (0.4%) NaCl diet. Arterial pressure responses were measured in rats treated with losartan (10 mg/kg/day) (LOS rats, n=8) and compared with those treated with losartan and the Ang (1-7) antagonist, A779 (24 µg/kg/hour) (A779/LOS rats, n=11) for 10 days.
Results: By day 7 of treatment, mean arterial pressure had dropped by 27+1 mmHg in LOS rats, in contrast with a decrease of only 21+2 mmHg in A779/LOS rats. This attenuated response in rats treated with A779 became more prominent and continued through day 10 of losartan treatment.
Conclusion: These results support the hypothesis that the chronic hypotensive effects of losartan in normal rats are mediated in part through the actions of Ang (1-7).

JRAAS 2003;4:176-179.

PAPERRamipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction
Wolfgang Linz, Gabi Itter, Lawrence W Dobrucki, Tadeusz Malinski, Gabriele Wiemer

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI).
Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo-treated animals with CHF. Concomitantly, the increased CaI-stimulated O2- production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FU-treatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA.
Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.

JRAAS 2003;4:180-185.

PAPERElevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice
Catherine E Huggins, Andrea A Domenighetti, Thierry Pedrazzini, Salvatore Pepe, Lea MD Delbridge

Introduction: Angiotensin II (Ang II) is known to induce cardiac growth and modulate myocardial contractility. It has been reported that elevated levels of endogenous Ang II contribute to the development of cardiac hypertrophy in hypertensives. However, the long-term functional effects of cardiac exposure to Ang II in normotensives is unclear.
A recently developed transgenic mouse (TG1306/1R), in which cardiac-specific overproduction of Ang II produces primary hypertrophy, provides a new experimental model for investigation of this phenotype. The aim of the present study was to use this model to investigate whether there is a functional deficit in primary hypertrophy that may predispose to cardiac failure and sudden death. We hypothesised that primary cardiac hypertrophy is associated with mechanical dysfunction in the basal state.
Methods: Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene1 were studied at age 30–40 weeks and compared with age-matched wild-type littermates. Left ventricular function was measured ex vivo in bicarbonate buffer-perfused, Langendorff- mounted hearts (at a perfusion pressure of 80 mmHg, 37°C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.
Results: There was no difference in the mean (+SEM) intrinsic heart rate of TG1306/1R and wild-type control mice (357.4+11.8 vs. 367.5+20.9 bpm, n=9 & 7). Under standardised end-diastolic pressure conditions, TG1306/1R hearts exhibited a significant reduction in peak developed pressure (132.2+9.4 vs. 161.5+3.1 mmHg, n=9 & 7, p<0.05) and maximum rate of pressure development (3566.7+323.7 vs. 4486.3+109.4 mmHg, n=9 & 7, p<0.05). TG1306/1R mice show a significant correlation between incidence of arrhythmia and increasing heart size (Spearman’s correlation coefficient 0.61).
Conclusion: These data demonstrate that chronic in vivo exposure to elevated levels of intra-cardiac Ang II is associated with significant contractile abnormalities evident in the ex vivo intact heart. Our findings suggest that endogenous overproduction of cardiac Ang II, independent of changes in blood pressure, is sufficient to induce ventricular remodelling that culminates in impaired cardiac function which may precede failure.

JRAAS 2003;4:186-190.

PAPEREffect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits
Nadine Weckler, Daniela Leitzbach, Leszek Kalinowski, Tadeusz Malinski, Andreas E Busch, Wolfgang Linz

Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis.
This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet.
At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73±2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%.
Six weeks’ feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O2- concentration and bioavailability of NO. In this study, a similar protective effect on endothelial function was shown by ACE-NEP inhibition as already seen with ACE inhibitors in an animal model of atherosclerosis.

JRAAS 2003;4:191-196.

POPULAR
TOPICPAPEREffects of ACE inhibition and AT₁-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients
Dilek Yavuz, Mehmet Koç, Ahmet Toprak, Ihsan Akp?nar, Ayliz Velioglu, Oguzhan Deyneli, Goncagül Haklar, Sema Akal?n

Objective: Disturbed endothelial function is closely associated with hyperinsulinaemia and insulin resistance in essential hypertension. The aims of this study were: 1) to evaluate whether the two alternative drugs, angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II (Ang II) antagonists, had comparable effects on glucose metabolism and endothelial function. 2) to determine whether they improve endothelial dysfunction through modulating insulin resistance and oxidative stress.
Study design and methods: Essential hypertensive patients were randomised into two groups: Twelve (nine patients in final analysis) patients were given enalapril (enalapril group), and twelve (nine patients in final analysis) were given losartan (losartan group). Twelve sex- and age-matched normotensive volunteers were included as controls. Before and after six months of treatment, endothelial function, insulin sensitivity and lipid peroxidation (TBARs) and NO metabolites (NOx) were evaluated.
Results: Endothelial function, measured as flow mediated dilatation (FMD), was improved in both of the treatment groups (p=0.0001). Calculated insulin sensitivity index also improved in the enalapril-treated group (p=0.05) but not in the losartan-treated group, compared with baseline levels. TBARS values decreased significantly in the enalapril group compared with baseline levels (p<0.001). FMD was positively correlated with insulin sensitivity index (r=0.32, p<0.05) and NOx levels (r=0.39, p=0.01) and negatively correlated with TBARS levels (r=-0.53, p=0.0002) in hypertensive patients.
Conclusion: Inhibition of the renin-angiotensin system, either with ACE inhibitors or AT₁-receptor blockers improves endothelial dysfunction. ACE inhibition has prominent effects on improving insulin sensitivity and decreasing oxidative stress in essential hypertensive patients.

JRAAS 2003;4:197-203.

POPULAR
TOPICEDITORIAL REVIEWEpidemiology and clinical aspects of congestive heart failure
Tarita Murray-Thomas, Martin R Cowie

Congestive heart failure (CHF) is an increasing problem for healthcare systems in all developed countries. The prevalence is increasing partly due to ageing of the population, but also due to improved survival from acute cardiac disease such as myocardial infarction. Advances in diagnostic techniques and better understanding of the pathophysiology offer many opportunities for substantial improvement in the management of CHF. This article reviews the current epidemiology of CHF and the related diagnostic issues.

JRAAS 2003;4:131-136.

EDITORIAL REVIEWInteraction of β-blockers and angiotensin receptor blockers/ACE inhibitors in heart failure
Jay N Cohn

The renin-angiotensin-aldosterone system contributes to the progression of heart failure and its inhibition slows ventricular remodelling and favourably affects morbidity and mortality. β-blockers exert a remarkably favourable effect on progression that may be mediated at least in part by renin inhibition. Although earlier trials suggested a possible adverse interaction when an angiotensin receptor blocker was added to an angiotensin-converting enzyme inhibitor and a β-blocker, a recent study and newly analysed mechanistic data indicate that the triple combination provides modest additional inhibition of angiotensin that can further slow progression of disease.

JRAAS 2003;4:137-139.

EDITORIAL REVIEWCombination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure
Kok H Chee, Kadirvelu Amudha, Nik A Hussain, Haron K Haizal, Anna-Maria J Choy, Chim C Lang

Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.

JRAAS 2003;4:140-148.

POPULAR
TOPICEDITORIAL REVIEWInteraction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance
Christophe Meune, Jean-Jacques Mourad, Jean-François Bergmann, Christian Spaulding

Increased understanding of pathophysiological mechanisms of cardiovascular diseases has shown that the renin-angiotensin-aldosterone system (RAAS) is activated in this setting and suggests a central role for the angiotensin-converting enzyme (ACE). ACE transforms angiotensin I (Ang I) to angiotensin II (Ang II), and also promotes the degradation of bradykinin into inactive metabolites. These bradykinins stimulate nitric oxide synthesis and vasodilatator prostaglandin synthesis via a cyclooxygenase (COX) pathway.
COX inhibitors may therefore be deleterious in cardiovascular disease and/or counteract part of ACE inhibitor (ACE-I) efficacy. This has been clearly demonstrated with non-steroidal anti-inflammatory drugs (NSAIDs), including high-dose aspirin, in hypertension, coronary artery disease and chronic heart failure (CHF); most guidelines recommend avoiding their use in such patients.
Theoretically, this effect is dose-mediated and the existence of an identical deleterious effect with low-dose aspirin has been an area of intense debate. In this article, we review studies, most of them conducted in CHF, that pointed out such a possible deleterious effect and a counteraction of ACE-Is with low-dose aspirin, using various criteria of assessment.
However, there are no prospective long-term studies that have validated such an effect, and the role of other anti-aggregating agents has not been evaluated. Until such studies are published, the use of low-dose aspirin (100 mg/day) in such patients can be recommended.

JRAAS 2003;4:149-154.

EDITORIAL REVIEWToward a broader understanding of aldosterone in congestive heart failure
Karl T Weber, Yao Sun, Linus A Wodi, Ahmad Munir, Eiman Jahangir, Robert A Ahokas, Ivan C Gerling, Arnold E Postlethwaite, Kenneth J Warrington

Discovered some 50 years ago, aldosterone (ALDO) has come to be recognised as a mineralocorticoid hormone with well-known endocrine properties in epithelial cells that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in classic target tissues: kidneys, colon, sweat and salivary glands. Though less well known, Mg2+ excretion is likewise enhanced by ALDO, while adrenal ALDO secretion is regulated by extracellular Mg2+ ([Mg2+]o). An emerging body of information has and continues to identify other endocrine actions of ALDO receptor-ligand binding. They include: promoting an efflux of cytosolic free Mg2+, or [Mg2+]i, in exchange for Na+ in such non-epithelial cells as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions that involve regulation of cerebrospinal fluid composition produced by epithelial cells of the choroid plexus, activity of the hypothalamic paraventricular nucleus involved in Na+ appetite, Na+ and H2O excretion and sympathetic nerve activity, and the regulation of TNF-α production from central and/or peripheral sources. Extra-adrenal steroidogenesis and auto/paracrine properties of ALDO generated de novo in the cardiovasculature are now under investigation and preliminary findings suggest they contribute to tissue repair. The past decade has witnessed a revival of interest in this steroid molecule. In years to come, an even broader understanding of ALDO’s contribution to the pathophysiology of congestive heart failure will undoubtedly emerge.

JRAAS 2003;4:155-163.

POPULAR
TOPICEDITORIAL REVIEWMineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease
Bertram Pitt, Charles T Stier Jr., Sanjay Rajagopalan

Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction.
Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis.
While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-Greek small letter kappa κβ and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone.
In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.

JRAAS 2003;4:164-168.

EDITORIAL REVIEWNew-onset diabetes and antihypertensive therapy: comments on ALLHAT trial
Cristina Sierra, Luis M Ruilope

The development of new-onset diabetes is frequent during the follow-up of treated hypertensive patients. The prevalence of such an event seems to differ depending on the type of antihypertensive therapy used to control blood pressure. Diuretics and b-blockers and their association are particularly harmful in this regard. On the contrary, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, alone or in association with diuretics, are associated with a lower prevalence of this metabolic complication. These statements are confirmed by data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study. Long-term studies are required to determine the relevance of development of new-onset diabetes in treated hypertensive patients.

JRAAS 2003;4:169-170.

POPULAR
TOPICEDITORIAL REVIEWAngiotensin receptor blockers in heart failure
Jan Östergren, John JV McMurray

Collectively, a series of large, prospective randomised outcome trials has now shown that angiotensin receptor blockers (ARBs) are of clinical value in a broad spectrum of patients with symptomatic heart failure, regardless of background therapy and ventricular function. There is a clear benefit of ARBs in patients unable to tolerate an angiotensin- converting enzyme (ACE) inhibitor and this benefit is of a similar magnitude to that obtained with an ACE inhibitor (ACE-I). Both Val-HeFT and, particularly, CHARM-Added, also show that symptoms, morbidity and mortality are further reduced if an ARB is added to an ACE-I. This benefit is not only statistically significant but clinically important. CHARM-Preserved showed that candesartan can reduce hospital admission for heart failure in patients with preserved systolic function though more definitive outcome data are needed in this group.

JRAAS 2003;4:171-175.