Volume 9, Number 1, March 2008

PAPERChanging dietary sodium alters the chronic cardiovascular effects of losartan in rats
John P Collister, David B Nahey

Introduction: We have previously demonstrated a profound hypotensive response to the angiotensin II type 1 (AT₁)-receptor antagonist losartan in rats consuming a normal salt diet that is not seen in salt-loaded rats, presumably due to a suppression of the renin-angiotensin system (RAS) by high sodium levels. The purpose of the present study was to examine the cardiovascular effects of changing dietary sodium intake during chronic treatment with losartan. We hypothesised that during blockade of AT₁-receptors by chronic losartan infusion, when renin levels would be elevated regardless of dietary sodium, changing diets from high to normal or normal to high salt would have no effect on mean arterial pressure (MAP).
Materials and methods: To test this hypothesis, groups of rats instrumented with radiotelemetry transducers for MAP monitoring and venous catheters for infusion were initially placed on either a 0.4% salt content diet, referred to as Losartan Normal diet – High salt diet (LosN-HI, n = 7), or a 4.0% salt content diet, referred to as Losartan High salt diet – Normal diet (LosHI-N, n = 9). After a thee-day control period, infusion of losartan was begun in all rats (10 mg/kg/day in 7 ml/day isotonic saline i.v.). After 10 days, diets were switched between groups and data were collected for another 10 days, after which losartan infusion was terminated for a 10-day recovery period.
Results: At the start of losartan infusion MAP was observed to be similar between LosN-HI rats (101±2 mmHg) and LosHI-N rats (101±2 mmHg). By day seven of the first 10 day protocol, MAP in LosN-HI rats had fallen to 71±4 mmHg while decreasing to 90±2 mmHg in LosHI-N rats. Five days after switching diets, MAP in LosN-HI rats had risen back to 85±3 mmHg, while MAP in LosHI-N rats had fallen to 75±2 mmHg.
Conclusions: These results do not support our hypothesis, suggesting that changing dietary sodium can alter the chronic hypotensive response to losartan regardless of the initial state of the RAS.

JRAAS 2008;9:10-16.

PAPERAngiotensin type 2 receptor is expressed in human atherosclerotic lesions
Maria E Johansson, Björn Fagerberg, Göran Bergström

Objective: Expression of the angiotensin type 2 receptor (AT₂-receptor) occurs in many animal models of atherosclerosis. However, its expression in human plaques and its functional role remains undetermined. This study examined AT₂-receptor expression in human atherosclerotic plaque and also explored its potentially important functional role in atherosclerosis.
Material and methods: We analysed carotid atherosclerotic plaques obtained from 14 Caucasian patients who had previously undergone endarterectomy for symptomatic carotid artery stenosis. Half of all subjects received treatment with an angiotensin receptor blocker (ARB) (n=7); the remaining subjects received no intervention in the renin-angiotensin system (n=7). Immunohistochemistry measured tissue expression of smooth muscle cells (a-actin), macrophages (CD68 antibody), collagen (picro-sirius), and AT₂-receptor (AT₂-receptor antibody).
Results: AT₂-receptor expression occurred consistently in all specimens. Although cellular localisation varied, AT₂-receptor expression levels correlated with macrophage levels (p<0.01). Compared to conventional treatment, ongoing ARB treatment affected neither AT₂-receptor levels nor plaque composition.
Conclusions: AT₂-receptor is expressed in human atherosclerotic plaque. Furthermore, we detected no functionally important role of AT₂-receptor expression and found no evidence that ARB treatment regulates AT₂-receptor expression.

JRAAS 2008;9:17-21.

POPULAR
TOPICPAPERShort-term effects of angiotensin receptor blockers on blood pressure control, and plasma inflammatory and fibrinolytic parameters in patients taking angiotensin-converting enzyme inhibitors
Mehmet Agirbasli, Altug Cincin, Oytun A Baykan

Introduction: Angiotensin-converting enzyme (ACE) inhibitors reduce cardiovascular events in patients with established vascular disease and heart failure (HF). ACE-inhibitors have important effects on fibrinolytic balance, which may be the underlying mechanism for a reduction in cardiovascular events. Although angiotensin-receptor blockers (ARBs) offer greater tolerability than ACE-inhibitors, the major ARB trials have demonstrated a lack of reduction in myocardial infarction (MI) occurrence and mortality in contrast to ACE-inhibitors. In this study, we investigated the combined effects of ARBs and ACE-inhibitors on fibrinolytic and inflammatory parameters in patients with uncontrolled hypertension.
Methods: Twenty-four patients with uncontrolled hypertension despite taking adequate doses of ACE-inhibitor therapy were selected. Patients were started on Candesartan 16 mg once a day. Plasma plasminogen activator inhibitor (PAI-1) antigen (Ag), tissue plasminogen activator (t-PA) Ag, thrombin-activatable fibrinolysis inhibitor (TAFI) % activity and high sensitivity C-reactive protein (hsCRP) levels, were measured during low salt intake at baseline and two weeks after therapy with an ARB.
Results: Addition of ARB to the regimen reduced systolic (155±17 vs. 139±13, p<0.001), and diastolic (91±9 vs. 81±8, p<0.001) blood pressures (BP). No significant changes were observed in PAI-1 Ag (66±51 vs. 68±52, p=0.9), t-PA Ag (12.6±5.3 vs. 13.3±4.7, p=0.3), TAFI % activity (119±30 vs. 118±32, p=0.9) and hsCRP (3.9±3.4 vs. 3.6±3.6, p=0.7) levels after adding an ARB. Conclusions. Combined ARB and ACE-inhibitor use provide better BP control without any detrimental effect in plasma inflammatory and fibrinolytic parameters.

JRAAS 2008;9:22-26.

PAPERAngiotensinogen gene variants in a Pakistani hypertensive population of Punjab
Farrakh M Alvi, Shahida Hasnain

Background: The renin-angiotensin-aldosterone system (RAAS) plays a key role in blood pressure (BP) regulation. Among the components of the RAAS, the gene for the angiotensinogen (AGT) has been extensively studied. Several studies in different populations link Threonine instead of methionine at position 235 (M235T) and Methinine instead of threonine at position 174 (T174M) polymorphisms with essential hypertension. We were unable to study these polymorphisms in the Punjab population of Pakistan through routine Restriction Fragment Length Polymorphism (RFLP) method. Considering the importance of this region we decided to further investigate the 300 bp region harbouring these two single nucleotide polymorphisms.Methods: Samples were derived from a larger study group. Polymerase chain reaction amplified fragments were subjected to either RFLP or Single Strand Conformation Polymorphism. Single stranded DNA showing mobility shift on denaturing gel were sequenced.
Results: Sequencing confirmed the presence of M235T and T174M polymorphisms in the local population. In addition to these polymorphisms one additional base was found at an identical position in two of the samples. We found a substitution of G with C just adjacent to T174M polymorphism in all seven of our samples studied.
Conclusions: We report two additional bases and one substitution in the angiotensinogen gene of Punjab population. We also suggest that SsmI can be used for the investigation of T174M polymorphism.

JRAAS 2008;9:22-26.

PAPERLack of association between the angiotensin-converting enzyme gene (I/D) polymorphism and diabetic nephropathy in Tunisian type 2 diabetic patients
Imen Arfa, Abdelmajid Abid, Sonia Nouira, Houda Elloumi-Zghal, Dhafer Malouche, Imen Mannai, Mohamed Majdi Zorgati, Nissaf Ben Alaya, Ahmed Rebai, Béchir Zouari, Slim Ben Ammar, Mohamed Chiheb Ben Rayana, Slama Hmida, Samira Blousa-Chabchoub, Sonia Abdelhak

Objective: The aim of the present study was to investigate whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is associated with diabetic nephropathy and type 2 diabetes in the Tunisian population.
Design: A case-control study was conducted among 141 unrelated type 2 diabetic patients with (90 patients) or without nephropathy (51 patients) and 103 non-diabetic controls with normal fasting blood glucose. Genotyping was performed using a nested polymerase chain reaction amplification in order to identify correctly heterozygous individuals.
Results: The distribution of DD, ID and II genotypes did not significantly differ between type 2 diabetic patients with or without nephropathy (DD: 44%; ID: 46%; II: 10% vs. DD: 41%; ID: 47 %; II: 12%, respectively). There was also no significant statistical difference between the genotype distribution and allele frequencies of the (I/D) polymorphism in all type 2 diabetic subjects compared to non-diabetic controls with normal fasting blood glucose (DD: 43%; ID: 46%; II: 11% vs. DD: 37%; ID: 48%; II: 15%, respectively).
Conclusions: In the present preliminary study, the (I/D) polymorphism within the ACE gene is likely not associated with diabetic nephropathy nor with type 2 diabetes in the Tunisian studied population.

JRAAS 2008;9:32-36.

POPULAR
TOPICPAPERAngiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans
Ulrik Pedersen-Bjergaard, Carsten E Thomsen, Hans Høgenhaven, Annelise Smed, Troels W Kjær, Jens J Holst, Flemming Dela, Linda Hilsted, Erik Frandsen, Stig Pramming, Birger Thorsteinsson

Introduction: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia.
Methods: Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests.
Results: Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031). There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups.
Conclusion: Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.

JRAAS 2008;9:37-48.

POPULAR
TOPICPAPEREffect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial
Markus P Schneider, Christian Delles, Arnfried U Klingbeil, Malte Ludwig, Rainer E Kolloch, Michael Krekler, Klaus O Stumpe, Roland E Schmieder

Objective: Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than β-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB).
Methods: One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment.
Results: Peripheral and central systolic and diastolic BP were reduced to a similar extent in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6±10 vs. -4±12% after six months, p<0.001; –4±12 vs. +1±11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol.
Conclusions: Although treatment with irbesartan and atenolol similarly decreased peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave reflection and preserved PP amplification. These haemodynamic effects may at least partly explain the reported differential effects of ARB versus β-blocker treatment on cardiovascular mortality in patients with essential hypertension.

JRAAS 2008;9:49-56.

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TOPICEDITORIAL REVIEWConcomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension
Boris Gojanovic, François Feihl, Lucas Liaudet, Bernard Waeber

Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists (CAs) and blockers of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (ARBs)] are widely used today to initiate antihypertensive treatment but, when given as monotherapy, do not suffice in most patients to normalise blood pressure (BP). Combining a CA and either an ACE-inhibitor or an ARB considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. Several fixed-dose combinations are available (CA + ACE-inhibitors: amlodipine + benazepril, felodipine + ramipril, verapamil + trandolapril; CA + ARB: amlodipine + valsartan). They are expected not only to improve BP control, but also to facilitate long-term adherence with antihypertensive therapy, thereby providing maximal protection against the cardiovascular and renal damage caused by high BP.

JRAAS 2008;9:1-9.

RENIN REPORTThe Bothrops legacy: Vasoactive peptides from Brazil
Friedrich C Luft

JRAAS 2008;9:57-64.