Volume 1, Number 1, March 2000

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TOPICPAPERMechanical strain-induced human vascular matrix synthesis: The role of angiotensin II
Adrian G Stanley, Hash Patel, Abigail L Knight, Bryan Williams

Introduction: Reduced vascular compliance in patients with hypertension results from an increase in extra-cellular matrix (ECM) protein deposition in blood vessels. At least two key factors, namely mechanical strain and neurohumoral mediators, for example Angiotensin II (Ang II), promote fibrogenesis within vessel walls; however potential interactions between these have not been clearly defined. This work examined the direct effect of mechanical strain on matrix mRNA expression and protein synthesis by human vascular smooth muscle (VSM) cells and identified the importance of renin-angiotensin system (RAS) activation in stretch-induced matrix production.
Methods: Human VSM cells were exposed either to a cyclical mechanical strain regimen or to Ang II in the presence or absence of the Ang II receptor (AT₁ R) antagonist losartan or its more potent metabolite EXP3174. Analysis of matrix mRNA expression (Northerns) and protein synthesis (ELISA) and cellular AT₁-receptor protein expression (Westerns) were determined.
Results: Ang II increased both collagen α1 (92%, SEM +/- 20%) mRNA expression and fibronectin (21% +/- 6%) protein synthesis in static VSM cells compared with unstimulated controls. The effect of Ang II was attenuated by antagonism of the AT₁-receptor (AT₁ R). Similarly, mechanical strain induced an increase in both collagen α1 (102% +/- 30%) mRNA expression and fibronectin (50% +/-21%) protein synthesis. Surprisingly, in the absence of exogenous Ang II, AT₁-receptor blockade attenuated this stretch-induced increase in matrix synthesis. Mechanical strain also induced an increase in total cellular AT₁-receptor protein (30.7% +/- 3.5%) compared with static cells.
Conclusion: Both mechanical strain and Ang II increased matrix gene expression and protein synthesis by human VSM cells. The effect of strain was attenuated by AT₁-receptor antagonism. Our results further suggest that mechanical strain may sensitise human VSM cells to the fibrogenic actions of Ang II, perhaps via upregulation of the AT₁-receptor.

JRAAS 2000;1:32-35.

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TOPICPAPERRat model for investigating ACTH-independent angiotensin-induced aldosterone secretion
Darren M Roesch,Ying Tian, Joseph G Verbalis, Kathryn Sandberg

Study of the acute effects of angiotensin II (Ang II) on aldosterone secretion has been hindered by the confounding influence of Ang II-induced adrenocorticotropic hormone (ACTH) secretion on aldosterone secretion, and by the fact that when laboratory rats are fed standard laboratory chows that are high in sodium, the adrenal is only minimally responsive to Ang II. In this study, we report the development of a model of Ang II-induced aldosterone secretion in NaCl-deprived, dexamethasone (DEX)-treated rats. This model allows the observation of (a) a high magnitude of Ang II-induced aldosterone secretion, (b) a return of plasma aldosterone levels to baseline after stimulation, and (c) aldosterone secretion without the potentially confounding influence of ACTH stimulation.

JRAAS 2000;1:36-39.

PAPERReduction of resistance artery stiffness by treatment with the AT₁-receptor antagonist losartan in essential hypertension
Jeong Bae Park, Hope D Intengan, Ernesto L Schiffrin

In spontaneously hypertensive rats resistance artery structure, endothelial dysfunction and geometry-independent wall stiffness were reduced by an angiotensin AT₁-receptor antagonist. In previous studies of human hypertension, interruption of the renin-angiotensin system corrected small artery structure and endothelial dysfunction, whereas the β-blocker atenolol did not. We hypothesized that the AT₁R antagonist losartan, but not the β-blocker atenolol, would reduce stiffness of gluteal subcutaneous small arteries in essential hypertensive patients. Seventeen untreated mild essential hypertensive patients (47±2years; 75% male) were randomly assigned in double-blind fashion to losartan or atenolol treatment for one year. Small, resistance size arteries were studied on pressurized myographs. Blood pressure (mmHg) was reduced (p<0.01) from 145±4/101±2 and 147±6/98±2 to 128±4/86±2 and 131±3/84±1 by losartan and atenolol, respectively. The media/lumen ratio of small arteries was unaffected by atenolol (8.3±0.3% before and 8.8±0.5% after treatment). In contrast, losartan reduced media/lumen ratio from 8.4±0.4% to 6.7±0.3% (p<0.01). Whereas isobaric elastic modulus was unaffected by either treatment, geometry-independent stiffness (slope of elastic modulus vs. stress) was reduced from 9.7±1.2 to 6.1±0.9 (P<0.05) under losartan treatment, but was unchanged by atenolol (8.2±1.3 to 7.8±0.6). In conclusion, treatment with losartan reduced stiffness and structural alterations of subcutaneous resistance arteries of previously untreated essential hypertensive patients, whereas atenolol failed to do so.

JRAAS 2000;1:40-45.

PAPERLosartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury
Jacinthe Lemay, Pavel Hamet, Denis deBlois

Smooth muscle cell (SMC) apoptosis is transiently increased at the onset of the regression of aortic hypertrophy in spontaneously hypertensive rats (SHR) treated with the angiotensin II AT₁ antagonist losartan. We postulated that losartan induction of SMC apoptosis contributes to suppression of neointimal hyperplasia after vascular injury. Losartan or placebo treatment was initiated two days before balloon injury in the SHR aorta. Compared with time-matched placebo, losartan decreased neointimal cross-sectional area at Days 5 and 10 after injury by 50% and 64% respectively, without affecting medial mass. At Day 10, losartan significantly decreased SMC number (by 56%) in the neointima, but not in the media. DNA synthesis was significantly inhibited at Day 5 but not at Day 10. Losartan significantly increased aortic DNA fragmentation by 2.6- and 4.1-fold, at Days 5 and 10, respectively. In situ labeling of SMC with terminal deoxynucleotidyltransferase revealed significant 61% and 68% increases in apoptotic SMC at Days 5 and 10 with losartan treatment, predominantly in the neointima. Thus, losartan suppressed neointima formation in part by the induction of SMC apoptosis, which may be dissociated from the inhibition of DNA synthesis. Therefore, losartan-induced SMC apoptosis may be a potential therapeutic approach to control occlusive vascular disorders.

JRAAS 2000;1:46-50.

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TOPICEDITORIAL REVIEWThe past, present and future of hypertension management: a potential role for AT₁-receptor antagonists
Norman K Hollenberg, Peter S Sever

The benefits of effective antihypertensive treatment were established at least 40 years ago, but despite the availability of more reliable and better-tolerated antihypertensive drugs, the control of blood pressure remains poor in most patients. Long-term antihypertensive efficacy requires treatment that combines reliable 24-hour reduction of blood pressure with good tolerability to facilitate patient compliance. Treatment should also protect against target-organ damage. As the majority of negative cardiovascular effects of angiotensin II are mediated through the angiotensin II type 1 (AT₁) receptor, specific blockade of this receptor is a rational approach for achieving these ideals. Several AT₁-receptor blockers have been developed that combine antihypertensive efficacy and placebo-like tolerability - the latter being unique in the history of antihypertensive therapy. In experimental animals these drugs prevent or reverse target organ damage in the heart, the vasculature and the kidney. Ongoing large-scale outcome studies are now underway to establish the benefits of AT₁-receptor blockade beyond blood pressure control.

JRAAS 2000;1:5-10.

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TOPICEDITORIAL REVIEWThe HOPE Study (Heart Outcomes Prevention Evaluation)
Peter Sleight

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup.
Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic).
The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint.
This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation.
The HOPE study results show that it is both safe and beneficial to lower BP that is already within the 'normal' range, particularly in patients with known vascular risk factors. This should greatly extend the use of ACE-I to a wider group of patients - not only those with left ventricular dysfunction, hypertension or diabetic microalbuminuria, but to the sort of high-risk patients who are currently given prophylactic treatment with aspirin.

JRAAS 2000;1:18-20.

EDITORIAL REVIEWAngiotensin II receptor blockers in chronic heart failure - Not as ELITE as expected!
Colin AJ Farquharson, Allan D Struthers

As with many large-scale long-term outcome trials, more questions have been posed than answered regarding the potential role of angiotensin II receptor blockers as first-line agents in chronic heart failure. Given the present data, in patients with left ventricular systolic dysfunction, ACE inhibitors must remain the treatment of choice, owing to the large body of data supporting their use in this clinical syndrome. However, ARBs seems a reasonable alternative for renin-angiotensin axis blockade in the significant number of heart failure patients who are genuinely intolerant of ACE inhibitors.
The pendulum has now swung back in favour of ACE inhibition for chronic heart failure, although one can only await with great expectation the results of the ongoing trials comparing not only angiotensin II receptor blockers with ACE inhibitors but a combination of the two with regards tolerability and survival. Whether this potentially useful class of drugs will ultimately become the cornerstone of heart failure therapy in place of, or in addition to, ACE inhibitors is still in debate, but hopefully we should not have to wait too long for the definitive answers.

JRAAS 2000;1:21-22.

EDITORIAL REVIEWRole of chymase on vascular proliferation
Mizuo Miyazaki, Shinji Takai

In the normal state, vascular ACE regulates local angiotensin II formation and plays a crucial role in the regulation of blood pressure, whereas chymase is stored in secretory granules in mast cells and has no enzymatic effects such as angiotensin II-forming activity.⁴⁷ Chymase has a maximal activity immediately upon release into the extracellular matrix in vascular tissues after mast cells have been activated by a strong stimulus such as experienced by catheter-injured and grafted vessels.⁴⁸ Therefore, chymase plays an important role in forming local angiotensin II when vascular tissues are injured, and inhibition of chymase may be useful for preventing vascular proliferation in grafted vessels and after PTCA (Figure 6).

JRAAS 2000;1:23-26.

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TOPICEDITORIAL REVIEWACE inhibitors, angiotensin receptor antagonists and bradykinin
Michael Schachter

Soon after the introduction of angiotensin-converting enzyme inhibitors (ACE-I), it became clear that the drugs were not specific for angiotensin I (Ang I), but also inhibited the breakdown of bradykinin (BK) and substance P. Moreover, the affinity of ACE for BK is much higher than for Ang I at both active sites of the enzyme. There has been great interest in trying to establish whether BK plays an important role in the therapeutic effects of ACE-I. It is now generally believed that BK is probably the major contributor to two of the side-effects characteristic of ACE-I - cough and angioedema.
BK has a variety of biological effects that can be categorised as pro-inflammatory (mostly involving the BK₁ receptor subtype) and vasodilatory (involving predominantly BK₂ receptors). Activation of endothelial BK₂ receptors leads to increased synthesis of nitric oxide (NO) and release of prostacyclin; it is thus plausible that some of the vasodilator response to ACE inhibition may be mediated by increased generation of kinins and NO. There is also evidence that ACE-I may have a direct effect by preventing sequestration and inactivation of the BK₂ receptor and by re-activating the receptor in BK-treated cells.
This paper reviews the currently available published data in both animal and human studies on the interactions of ACE and BK and the potential role of kinins in the response to ACE inhibition.

JRAAS 2000;1:27-29.

EDITORIAL REVIEWBlockade of the renin-angiotensin-aldosterone system and renal protection in diabetes mellitus
Hans-Henrik Parving

A clinical diagnosis of diabetic nephropathy is made in patients with diabetes on the basis of persistent albuminuria (>300 mg/24-hour), the presence of diabetic retinopathy, and the absence of any clinical or laboratory evidence of other kidney or renal tract disease. This definition is valid in patients with either Type 1 or Type 2 diabetes. The clinical syndrome termed diabetic nephropathy is characterised by persistent albuminuria, early arterial blood pressure elevation, a relentless decline in glomerular filtration rate (GFR), and high risk of cardiovascular morbidity and mortality. Previous studies have found a cumulative incidence of diabetic nephropathy of 25–40% after diabetes duration of at least 25 years in both Type 1 and Type 2 diabetes. Diabetic nephropathy has become the leading cause (25–42%) of end-stage renal disease (ESRD) in Europe, Japan, and the United States. Unfortunately, the proportion of ESRD patients suffering from diabetes, particularly Type 2, is expected to rise significantly because the worldwide prevalence of diabetes is expected to double within the next 15 years, and because the individual diabetic patient lives longer and consequently has a greater risk of developing late complications including diabetic nephropathy.
This editorial reviews the evidence for the benefit of blockade of the renin-angiotensin-aldosterone system (RAAS) on the development and the progression of diabetic nephropathy. The renin-angiotensin-system plays an important role in the initiation and progression of diabetic kidney disease. Blockade of the RAAS reduces the progressive rise in albuminuria, diminishes the loss of glomerular filtration power, postpones end-stage renal failure and prolongs survival in patients with diabetic kidney disease.

JRAAS 2000;1:30-31.

EDITORIAL REVIEWNovel mechanisms linking angiotensin II and early atherogenesis
William B Strawn, Richard H Dean, Carlos M Ferrario

We propose that Ang II exerts an as yet uncharacterized immunomodulatory effect on monocyte maturation, differentiation, or extravasation, which may depend on the myelomonocytic phenotype. Since the myelopoietic process originating at stem cells and culminating in release to the blood is at least 6 days, it is conceivable that the observation of reduced monocyte CD11b expression two weeks after completion of losartan treatment indicates a suppression of the CD11b phenotype in newly released CD14⁺/CD45⁺ monocytes. Other studies employing suppression of AT₁-receptors with deoxy-oligonucleotides have reported effects on blood pressure that surpass those predicted by the duration of the treatment.⁸⁷ These data would suggest that it is possible to interrupt a stimulatory signal by Ang II through a gene-related mechanism that in our experiments may reside in the mechanisms that regulate myelopoiesis. While our knowledge of the role of Ang II in the regulation of monocyte formation and function is incomplete, we have taken a first step in attempting to synthesize the data described above into a comprehensive hypothesis for further evaluation of the factors that initiate atherogenesis. Such effects may crucially contribute to the clinical benefit of AT₁-receptor antagonists, independent of depressor effects, and may represent a paradigm for novel, anti-inflammatory actions by this class of drugs.

JRAAS 2000;1:11-17.

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