Volume 3, Number 3, September 2002

PAPERStimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts
Paul Lijnen, Victor Petrov, Kandelaria Rumilla, Robert Fagard

Objective: The aim of the present study was to investigate whether angiotensin II (Ang II), angiotensin III (Ang III) or Ang II (2-8), angiotensin IV (Ang IV) or Ang II (3-8) and Ang II (1-7), Ang II (4-8), Ang II (5-8) and Ang II (1-4) can stimulate collagen gel contraction in cardiac fibroblasts in serum-free conditions.
Methods: Cardiac fibroblasts (from male adult Wistar rats) from passage 2 were cultured to confluency and added to a hydrated collagen gel in a Dulbecco's Modified Eagle's Medium, with or without foetal bovine serum, for one, two or three days. The area of the collagen gels embedded with cardiac fibroblasts was determined by a densitometric analysis. Collagen gel contraction was characterised by a decrease in the gel area.
Results: Ang II dose-dependently stimulated the contraction of collagen mediated by cardiac fibroblasts after one, two or three days of incubation in a serum-free medium. Telmisartan completely blocked the Ang II-induced collagen contraction by cardiac fibroblasts.
PD 123319 and des-Asp¹-Ile⁸-Ang II had no effect on the Ang II-induced collagen contraction by cardiac fibroblasts. Ang III also stimulated the contraction of collagen mediated by cardiac fibroblasts after one, two or three days of incubation in a serum-free medium. des-Asp¹-Ile⁸-Ang II and telmisartan completely blocked the Ang III-induced collagen gel contraction by cardiac fibroblasts. des-Asp¹-Ile⁸-Ang II, however, had no effect on the Ang II-induced collagen gel contraction by cardiac fibroblasts. Ang IV and Ang II (4-8), (5-8), (1-7) and (1-4), however, had no effect on collagen gel contraction by cardiac fibroblasts. Addition of telmisartan, PD 123319 or des-Asp¹-Ile⁸-Ang II alone did not affect collagen gel contraction by cardiac fibroblasts.
Conclusion: Our data demonstrate that the effects of Ang II on the collagen gel contraction by adult rat cardiac fibroblasts in serum-free conditions are Ang II type 1(AT₁)-receptor- mediated, because they are abolished by the specific AT₁-receptor antagonist, telmisartan, and not by the AT₂-receptor antagonist PD 123319 or by the Ang III antagonist des-Asp¹-Ile⁸-angiotensin. The Ang III- stimulated contraction of collagen by cardiac fibroblasts is completely blocked by the Ang III receptor antagonist, des-Asp¹-Ile⁸-angiotensin II, and by telmisartan.

JRAAS 2002;3:160-166.

PAPERAntiproteinuric effect of candesartan cilexetil in patients with chronic glomerulonephritis
Kiyoshi Kurokawa, Keishi Abe, Takao Saruta, Masaaki Arakawa, Ryuichi Kikkawa, Naohiko Ueda, Kaoru Onoyama, Kimio Tomita, Nobuya Ogawa

A prospective, randomised, double-blind, parallel-group, dose-response trial was conducted to investigate the antiproteinuric effect of candesartan cilexetil, the angiotensin II type 1 receptor blocker, in patients with chronic glomerulonephritis. Patients (n=280) were treated for 12 weeks with candesartan cilexetil 2, 4, or 8 mg given orally once-daily (o.d.). The improvement in urinary protein excretion observed at the end of the treatment period was 15.9% in the 2 mg group, 25.6% in the 4 mg group, and 34.6% in the 8 mg group, respectively, showing a clear dose-response (2 mg <4 mg <8 mg; p=0.003). The mean reduction in urinary protein excretion was 11.3% in the 2 mg group, 26.3% in the 4 mg group, and 26.0% in the 8 mg group, showing a dose-response pattern, in that the effect of 4 mg and 8 mg was greater than that of 2 mg (2 mg <4 mg ≈8 mg; p=0.010). As the observed reduction in urinary protein excretion failed to correlate with changes in mean blood pressure, it could not be attributed to the antihypertensive effect of the study drug alone. This suggests that candesartan cilexetil, 4–8 mg o.d., has antiproteinuric effects in patients with chronic glomerulonephritis.

JRAAS 2002;3:167-175.

POPULAR
TOPICPAPEREffects of telmisartan on arterial stiffness in Type 2 diabetes patients with essential hypertension
Roland Asmar, Phillipe Gosse, Jirar Topouchian, Gilbert N’tela, Amanda Dudley, Gillian L Shepherd

Arterial wall stiffness, an important independent risk factor for cardiovascular disease in patients with hypertension, is worsened by the coexistence of diabetes mellitus. This randomised, prospective, double-blind, crossover trial assessed the effects of telmisartan on arterial stiffness in patients with Type 2 diabetes with essential hypertension. After a two-week placebo wash out period, 28 ambulatory patients received telmisartan (40 mg) or placebo for three weeks. Following a second two-week placebo wash out period, patients received the alternate treatment for a further three weeks. Augmentation index and central blood pressure (BP) were determined using the SphygmoCor™ device and pulse wave velocity (PWV) was measured using an automatic device, the Complior™, at the beginning and the end of each period. Telmisartan significantly reduced the carotid–femoral PWV compared with placebo (mean adjusted treatment difference –0.95 m/s; 95% CI: –1.67, –0.23 m/s; p=0.013). Peripheral and central diastolic, systolic and pulse pressures were also significantly reduced with telmisartan compared with placebo. In conclusion, telmisartan reduces arterial stiffness and peripheral and central BPs as assessed by PWV and pulse contour analysis in hypertensive patients with Type 2 diabetes. These properties of telmisartan suggest that it may improve cardiovascular outcome in this patient population.

JRAAS 2002;3:176-180.

PAPERInvolvement of the AT₂-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission
Jippe C Balt, Marie-Jeanne Mathy, Alex Nap, Martin Pfaffendorf, Pieter A van Zwieten

Angiotensin II (Ang II) causes facilitation of sympathetic neurotransmission via prejunctionally-located AT₁-receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang II and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang II is a class effect of all AT₁-receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT₂-receptor is involved in this ‘upturn’ of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1–60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT₂-blocker, PD 123319 (0.5 mg/kg +50 µg/kg/min). Additionally, the effect of the combined (non- selective) AT₁/AT₂-receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model.
The stimulation-induced increase in diastolic blood pressure (DBP) could be dose-dependently reduced by irbesartan. Co-infusion with PD 123319 increased the sympatho-inhibitory potency of irbesartan, possibly through displacement of irbesartan from plasma protein binding sites. The U-shaped dose-response relationship observed with irbesartan, which is illustrative for other ARBs in this model, was not observed when PD 123319 was co-administered with irbesartan, nor with the non-selective AT₁/AT₂-blocker, saralasin. PRA-levels increased from 111.0+17.8 to 198.7+22.2 ng/ml/hour after administration of irbesartan. PRA-levels did not differ when measured after the three highest doses of irbesartan.
Conclusions: The present findings indicate a facilitatory role for the AT₂-receptor, which is unmasked by the highest dose of irbesartan. Different plasma Ang II-levels are unlikely to have caused the less than maximal inhibition after the highest dose of irbesartan.

JRAAS 2002;3:181-187.

POPULAR
TOPICPAPERMortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease
Peter A McCullough, Keisha R Sandberg, Jerry Yee, Michael P Hudson

Hypothesis/introduction: The risks and benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with end-stage renal disease (ESRD) after cardiac events are unknown. We sought to determine the independent effect of ACE inhibitors (ACE-I) on long-term mortality in ESRD patients after cardiac events.
Materials and methods: We analysed a prospective coronary care unit registry and identified 527 ESRD patients, 368 with complete data on medications prescribed, over eight years at a single, tertiary centre.
Results: The overall mean age was 64.4+13.8 years with 54.9% men, and 59.2% African-American. A total of 143/386 (37.0%) were prescribed ACE-I during the hospital stay for cardiac reasons, including congestive heart failure (CHF) 52.8% and acute coronary syndromes (ACS) 47.2%. There were no significant differences in the rates of hypotension or arrhythmias in those who were treated with ACE-I versus those who were not. Survival analysis over three years, adjusted for known confounders, demonstrated a 37% reduction in all-cause mortality in those who received ACE-I, (p=0.0145).
Conclusions: In the setting of coronary care unit admission for CHF and ACS, ESRD patients selected for ACE-I, did not have increased rates of adverse haemodynamic or arrhythmic complications. The use of ACE-I conferred an independent mortality reduction over long-term follow-up.

JRAAS 2002;3:188-191.

POPULAR
TOPICEDITORIAL REVIEWRegression of left ventricular hypertrophy: hoping for a longer life
Andrew Sharp, Jamil Mayet

Left ventricular hypertrophy (LVH) is more than just an adaptive response to hypertension. It predicts a poor prognosis independently of the blood pressure (BP) level. There is increasing evidence from studies such as Heart Outcomes Prevention Evaluation (HOPE) and Losartan Intervention For Endpoint reduction in hypertension (LIFE) that LVH should be a target for treatment, above and beyond BP control. It is likely that drugs blocking the renin-angiotensin-aldosterone system cause greater regression of LVH than other agents and this is probably the mechanism that explains the superiority of losartan over atenolol in the LIFE study. In order to achieve the stringent BP goals suggested by modern guidelines, most patients will require multiple antihypertensive agents and the clinical choices relate more often to which combinations of drugs are most appropriate, rather than which single drug is the best. Tight BP control should be the first priority and this is likely to lead to regression of LVH.

JRAAS 2002;3:141-144.

EDITORIAL REVIEWDevelopments in restenosis
Philip Chan

Restenosis is a major complication leading to the failure of vascular procedures, including surgery, angioplasty and stenting. Major efforts including over 100 clinical trials have been made to overcome this complication, with little success to date. Issues relating to trial rationale, design, measurement and biology are addressed in this review.

JRAAS 2002;3:145-149.

POPULAR
TOPICEDITORIAL REVIEWThe potential benefits of aldosterone antagonism in Type 2 diabetes mellitus
Justine Davies, Allan Struthers

Interest in the renin-angiotensin-aldosterone system (RAAS) has increased since the development of angiotensin-converting enzyme (ACE) inhibitors. It has been discovered that the potential uses of this class of treatment extend far beyond their initial developmental role as antihypertensives, and they are now used routinely in the treatment of heart failure, nephropathy, myocardial infarction and diabetes. However, there is more to RAAS blockade than just inhibition of angiotensin II, and inhibition of aldosterone is becoming recognised as an additional therapeutic manoeuvre in chronic heart failure.
Since inhibition of the RAAS at the level of ACE is now seen to be an important therapy in diabetes; the purpose of this article is to explore the potential benefits of additional aldosterone inhibition in Type 2 diabetes mellitus.

JRAAS 2002;3:150-155.

EDITORIAL REVIEWVasopeptidase inhibitors in heart failure
Adelle Dawson, Allan D Struthers

Considerable attention has recently focused on the vasopeptidase inhibitors (VPI), a new class of drug that combines angiotensin-converting enzyme (ACE) inhibitor activity with inhibition of natriuretic peptide breakdown. In theory, a drug with these properties may be beneficial both in hypertension and in heart failure. Whilst the efficacy of VPIs in hypertension has been consistently demonstrated in pre-clinical and clinical studies, the role of VPIs, if any, in heart failure is less clear, since numerous small studies have produced conflicting results. Furthermore, preliminary results from the recently completed Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE) study have failed to establish the VPI, omapatrilat, as a first line therapy in the treatment of chronic heart failure. We review the literature on VPIs in heart failure and discuss possible reasons for the reported lack of benefit over ACE inhibitors.

JRAAS 2002;3:156-159.