Volume 2, Number 1, March 2001

POPULAR
TOPICPAPERSalt intake and non-ACE pathways for intrarenal angiotensin II generation in man
Norman K Hollenberg, Suzette Y Osei, M Cecilia Lansang, Deborah A Price, Naomi DL Fisher

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30–40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165±14 mL/min/1.73m²) significantly exceeded the response to captopril (118±12 mL/min/1.73m²; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97±20 mL/min/1.73m²) also significantly exceeded the response to captopril on the same diet (30±15 mL/min/1.73m²; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet, when compared with the response to captopril, suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60–70% range.

JRAAS 2001;2:14-18.

PAPEREffect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade
Tong Chuang Feng, Wang Yui Ying, Ren Jang Hua, Yale Y Ji, Marc de Gasparo

The effects of the specific angiotensin II (Ang II) AT₁-receptor blocker valsartan on events related to restenosis were investigated in rabbits after common carotid balloon injury. Six animals were given valsartan from two days prior to injury until 14 days post-injury. Three control groups (n=6 in each group) were either sham-operated, untreated or treated with the angiotensin-converting enzyme (ACE) inhibitor, captopril. Both ACE inhibition and AT₁-receptor blockade had marked effects on plasma levels of endothelin ET₁, thromboxane TXB₂ and 6-keto-PGF1-alpha. The most dramatic effects on ET₁ levels were seen in rabbits treated with valsartan, where levels were reduced to values close to those for sham-operated animals (96.85 vs. 86.45 pg/ml). Captopril treatment led to a statistically significant (p<0.01) reduction in ET₁ levels compared with untreated animals, but the reduction was only about half that seen with AT₁- receptor blockade. TXB₂ levels doubled (202.58 vs. 413.28 pg/ml) upon arterial injury in control animals but rose by only 20–35% in rabbits treated with captopril (246.45 pg/ml) or valsartan (268.13). In untreated animals, 6-keto-PGF₁-alpha levels decreased slightly after injury, but for both the captopril and valsartan groups, there were significant increases in levels of this prostaglandin derivative, effects attributed to the action of bradykinins. Levels were highest in the captopril-treated animals. Valsartan and captopril treatment led to a significant reduction in neointimal thickness and the extent of lumen stenosis compared with untreated animals. Both treatments were effective in reducing neointimal area and significantly (p<0.05) reduced cell proliferation. The differences between treatments can be attributed to the different actions of the agents, as valsartan leaves the AT₂-receptor unblocked, while captopril, through inhibition of Ang II synthesis, prevents stimulation of both receptors. A combination of both treatments may be a possible way forward in the clinical prevention of restenosis.

JRAAS 2001;2:19-24.

POPULAR
TOPICPAPERDiscordant responses to two classes of drugs acting on the renin-angiotensin system
Peter S Sever, C Limmie Chang

Introduction: Marked heterogeneity characterises blood pressure (BP) responses to antihypertensive drugs. The efficacy of drugs acting on the renin-angiotensin-aldosterone system (RAAS) is predicted (albeit weakly) by plasma renin activity (PRA) and it has been assumed that, within individuals, there would be concordance in efficacy between drugs acting at different sites to block the RAAS.
Design: The present study was a randomised, double-blind, two-way, crossover study designed to evaluate intra-individual BP responses to an angiotensin II AT₁-receptor blocker (ARB), candesartan cilexetil, and an angiotensin-converting enzyme inhibitor (ACE-I), lisinopril, and to identify potential phenotypic characteristics of patients' responses to the drugs.
Methods: 92 patients with essential hypertension, (mean systolic/diastolic BP 160/101 mmHg) entered the trial, of whom 76 patients completed both treatments.
Results: There was marked heterogeneity in response to the two drugs. 50% of patients responded (fall in diastolic BP of >10 mmHg or achieved diastolic pressure <90 mmHg) to both drugs; 16% were non-responders to both drugs; 20% responded to the ACE-I but not the ARB and 15% responded to the ARB but not to the ACE-I. Individual responses to the two drugs were poorly correlated (for diastolic pressure: r=0.19, p=0.11; for systolic pressure: r=-0.01, p=0.92). For the ACE-I, the fall in both systolic and diastolic BP was related to pretreatment PRA (for diastolic pressure: r=0.31, p=0.008; for systolic pressure: r=0.24, p=0.04). In the case of the ARB, no relationship between the fall in BP and PRA was observed.
These observations suggest that more complex mechanisms may be involved in BP reduction with ARBs than with ACE-I.

JRAAS 2001;2:25-30.

PAPERComparative antihypertensive and renoprotective effects of telmisartan and lisinopril after long-term treatment in hypertensive diabetic rats
Wolfgang Wienen, Serge Richard, Pascal Champeroux, Chantal Audeval-Gerard

This study compared the cardiovascular and renal effects of long-term telmisartan (3 and 10 mg/kg/day) and lisinopril (10 mg/kg/day) in an animal model combining hypertension and diabetes mellitus. It was a parallel-group study of diabetic, spontaneously hypertensive rats (SHR), treated with control or active treatment for eight months. A non-diabetic SHR control group was run in parallel. Diabetes was induced by streptozotocin (45 mg/kg i.v.) in SHRs aged 9–10 weeks. Animals were treated with telmisartan (3 or 10 mg/kg/day), lisinopril (10 mg/kg/day) or vehicle. Plasma glucose levels, blood pressure (BP), and urinary protein and albumin excretion were measured monthly. Telmisartan treatment significantly reduced BP of diabetic SHRs in a dose-dependent manner (p<0.05, low-dose, n=18; p<0.01, high-dose, n=15). The BP reduction in the lisinopril group was similar to that in the telmisartan 10 mg/kg/day group. Compared with non-diabetic SHRs, untreated diabetic SHRs developed severe proteinuria and albuminuria over the experimental period (p<0.01). In diabetic SHRs, proteinuria and albuminuria were dose-dependently and significantly attenuated by treatment with telmisartan (p<0.01 with the higher dose) and lisinopril (p<0.01). Compared with the untreated diabetic SHRs, cardiac hypertrophy was significantly reduced after treatment with both doses of telmisartan and with lisinopril. Telmisartan, 10 mg/kg/ day, but not lisinopril, significantly attenuated the diabetes-induced increase in glomerular volume. In conclusion, telmisartan, 10 mg/kg/day, is at least as beneficial as lisinopril, 10 mg/kg/day, in lowering BP, reducing cardiac hypertrophy and attenuating renal excretion of protein and albumin in this model.

JRAAS 2001;2:31-36.

PAPERThe influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits
Wojciech Wojakowski, Jan Gminski, Krzysztof Siemianowicz, Malgorzata Goss, Marek Machalski

Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

JRAAS 2001;2:37-42.

POPULAR
TOPICEDITORIAL REVIEWSignal transduction mechanisms of the angiotensin II type AT₁-receptor: looking beyond the heterotrimeric G protein paradigm
Peter P Sayeski, Kenneth E Bernstein

Angiotensin II (Ang II) is the effector molecule of the renin-angiotensin-aldosterone system (RAAS). This small peptide binds cell surface receptors to maintain a wide variety of haemodynamic responses including salt and water balance, blood pressure and vascular tone. Ang II can also act as a potent growth factor. Under certain conditions however, its growth-promoting effects can be deleterious and lead to vascular disease. The intracellular signalling mechanisms by which the Ang II type 1 (AT₁) receptor converts ligand binding to the appropriate cellular response are the focus of this review. Here, the classical signalling pathway utilising heterotrimeric G proteins is discussed. In addition, more recent work examining the role of tyrosine phosphorylation signalling cascades is also examined. Defining the biochemical signalling pathways by which Ang II mediates its physiological effects will advance our understanding of how such a simple molecule elicits such a wide variety of important cellular responses. Furthermore, it may delineate the mechanisms by which Ang II generates a normal vs. an abnormal cellular response, the results of which lead to vascular disease states that are routinely seen in humans.

JRAAS 2001;2:4-10.

POPULAR
TOPICEDITORIAL REVIEWThe management of the elderly with hypertension
Christopher J Bulpitt

Outcome data from randomised controlled trials in hypertensive patients have shown that, in patients aged 65–79 years, there are clear benefits of antihypertensive treatment in those with a sustained systolic blood pressure (SBP) of >160 mmHg, irrespective of diastolic blood pressure (DBP). Although not definitively proven, it is also probable that treating a sustained DBP of >90 mmHg is beneficial.
However, the information from these trials is limited and leaves several questions unanswered.
For example, to what level should BP be lowered by treatment? Epidemiological data have suggested that DBP should not be lowered below 85 mmHg because of a potential increase in coronary heart disease at lower pressures, the so-called 'J-shaped curve'. However, results from the HOT and SHEP studies do not support this theory; although, in SHEP, a DBP <60 mmHg in the actively treated group was associated with higher cardiovascular events, it is probable that this merely reflects a more pronounced response to antihypertensive treatment in patients who are frail, unwell and therefore already at high risk. Most researchers conclude from these studies that the J-shaped increase in mortality at low pressures reflects the fact that concomitant conditions such as coronary artery disease, cancer and dementia all tend to result in low BP.
Data are less convincing regarding SBP. In the HOT, EWPHE, SHEP and SYST-Eur trials, mean SBP was reduced to between 140 and 150 mmHg. Between 30 and 50% of subjects failed to achieve the target of 140–160 mmHg, and of those who did, a large proportion required treatment with more than one drug. In the elderly, side-effects, particularly postural hypotension, may limit the numbers achieving target BP and will increase non-compliance. The current goals in the elderly should be a standing BP of <140/<80 mmHg.
Another unanswered question is over the choice of antihypertensive drugs in the elderly. In the early MRC trials in the elderly, patients treated with beta-blockers tended to fare badly, leading to the suggestion that these drugs should be avoided in this age group. However, these suggestions were not substantiated by the STOP-hypertension 2 study, in which no disadvantages of beta blockade were demonstrated. Two further trials, ASCOT and ALLHAT are currently underway and will provide further information on the optimal choice of drugs for BP-lowering. It should be noted that, in the ALLHAT studies, one of the treatments, the alpha blocker, doxazosin, has been stopped because of an increase in the relative risk for stroke, heart failure and combined cardiovascular disease. However, with the possible exception of α-blockers, the choice of drugs for BP-lowering in the elderly seems not to be of great importance, and that choice will be largely determined by contra-indications, side-effect profiles and quality of life issues.
Finally, the picture for the very elderly remains confusing. Epidemiological evidence suggests that lower BPs are associated with higher mortality, though this may be a function of the hypotensive effects of co-existing serious illness such as heart disease, cancer and dementia. The only trial specifically designed for the very elderly is the ongoing HYVET trial, though very limited data from over 80 year olds recruited into other trials is also available. The consensus from these studies is that treatment should certainly be given to patients with severe hypertension (SBP >200 mmHg, DBP >110 mmHg) and those with evidence of heart failure, angina, renal failure or accelerated hypertension. In other patients, treatment may prevent a stroke, but will not necessarily prolong life expectancy and may adversely affect quality of life.

JRAAS 2001;2:11-13.

CASE STUDYHypertension due to a giant aldosterone-secreting adenoma
Dirk C Felmeden, Joan G Gearty, Dee M Dawkins, Gareth Beevers

The syndrome of hypertension due to a benign aldosterone-secreting adenoma of the zona glomerulosa of the adrenal cortex was first described by Jerome Conn in 1955.¹ Since then, a great many case series have been published^2-3 and the criteria for the biochemical and histopathological diagnosis have been extensively reported. The tumours are classically canary yellow and rarely more than 1 cm in diameter.⁴ We report the clinical course of a long-standing hypertensive patient with possibly the largest benign adenoma in the Western medical literature.

JRAAS 2001;2:43-44.

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