Journal of the Renin-Angiotensin-Aldosterone System

Experimental and clinical evidence is now available that antagonism of angiotensin II (Ang II) with both angiotensin-converting enzyme inhibitors and Ang II receptor antagonists (AIIAs) is effective in slowing the rate of renal functional loss in patients affected by proteinuric kidney diseases.Among AIIAs, telmisartan has been shown to be characterised by a potent and long lasting antihypertensive effect that may be associated with another specific effect of this molecule, the partial agonism of the peroxisome-activated receptor-gamma.Although this action has also been observed with other AIIAs, telmisartan seems to exert a more effective and specific action as in such a way to influence beneficially adipocyte metabolism, diabetes onset and insulin resistance. Recently, we have demonstrated, at the experimental and clinical level, that sustained blockade of Ang II biological activity with this class of compounds can potentially reduce the progression of renal dysfunction and in some circumstances induce the regression of renal functional and structural changes. In this review we analyse available experimental and clinical data that suggest that blocking Ang II with telmisartan may effectively ameliorate renal dysfunction in patients affected by the now frequently observed condition termed metabolic syndrome.

We have evaluated the role of connective tissue growth factor (CTGF) in vascular and renal damage associated with hypertension and possible interactions with angiotensin II (Ang II). Spontaneously hypertensive rats (SHR) were treated with either the Ang II receptor antagonist candesartan (C;2 mg/Kg^-1/day^-1) or antihypertensive triple therapy (TT; in mg/Kg-¹/day^-1 ;20 hydralazine +7 hydrochlorothiazide +0.15 reserpine) for 10 weeks. Wistar Kyoto rats were used as a normotensive control group. Hypertension was associated with an increase in aortic media area, media-to-lumen ratio and collagen density. Kidneys from SHR showed minimum renal alterations. Aorta and renal gene expression and immunostaining of CTGF were higher in SHR. Candesartan decreased arterial pressure, aortic media area, media-to-lumen ratio and collagen density. However, although arterial pressure decrease was comparable for both treatments,TT partially reduced these parameters. Candesartantreated rats showed lower levels of vascular CTGF expression, aortic media area, media-to-lumen ratio and collagen density than TT-treated animals. Treatments improve renal damage and reduce renal gene exp Pression and CTGF immunostaining in SHR in a similar manner.The results show that vascular and renal damage is associated with stimulation of CTGF gene and protein content.These results also might suggest that CTGF could be one downstream mediator of Ang II in hypertension-associated organ damage in SHR.

Introduction. The influence of chronic administration of losartan on gap junction conductance (gj), conduction velocity and interstitial fibrosis was investigated in the failing heart of 4-month-old cardiomyopathic hamsters (TO-2).After two months of administration of losartan (25 mg/kg/day/po) the number of cell pairs showing very low values of gj (2—8 nS) was significantly reduced whereas the group of cell pairs with larger values of gj (18-45 nS) was significantly increased.The conduction velocity measured with intracellular microelectrodes in the wall of the left ventricle was enhanced from 38+2.3 cm/s (n=25) (control) to 49+2 cm/s (n=24) (p<0.05) after losartan administration. Moreover, the number of ventricular fibres showing non-propagated action potentials was significantly decreased (p<0.05) by losartan.The % area of interstitial fibrosis measured in the wall of the left ventricle was reduced from 22+1.4% (n=18) to 14 1.3% (n=18) (p<0.05) after losartan administration.

Conclusion. Chronic blockade of angiotensin II type 1 receptors increased gj in the failing heart. Moreover,the conduction velocity was enhanced remodelling in part by the increase of gj and in part by the decrease of interstitial fibrosis and structural remodelling.

Introduction. Clinical and experimental studies have reported the role of homocysteine in ventricular hypertrophy. Activation of the reninangiotensin system mediated by angiotensin II type 1 (AT1) receptor has also been suggested to contribute to the pathogenesis of ventricular hypertrophy. There are also reports suggesting the affect of angiotensin II (Ang II) on cardiac hypertrophy is mediated by hyperhomocysteinemia. However, there is limited information on the mechanisms of the possible relationship between homocysteine and Ang II in ventricular hypertrophy. In this study we tested the hypothesis that hyperhomocysteinemia induced ventricular hypertrophy and remodelling may be mediated through activation of Ang II AT₁-receptors in rats.

Methods. This study was conducted on control non-treated rats (n=13), methionine-treated rats (1.5 mg/kg/day, n=18) and methionine plus oral AT1 antagonist (valsartan, 30 mg/kg/day, n=13) treated rats for 56 days. Systolic blood pressure (SBP) was determined in rats at baseline, 28 and 56 days. Echocardiography was also performed in all rats after eight weeks, and blood samples were obtained for determination of plasma tHcy. Rats were then sacrificed for histopathological and biochemical assessment of cardiac structure.

Results. The SBP in the methionine-treated rats was significantly higher compared with controls and significantly lower compared with the methionine-valsartan group at 28 and 56 days (p<0.001). In addition, left ventricular wall thickness (LVWT) in the methionine-valsartan group (4.36±0.11 mm) was significantly lower compared with the methionine group (5.0±0.23 mm, p=0.03). Furthermore, cardiac collagen to total protein ratio was significantly lower in the methionine-valsartan group (2.19±0.11%) compared with the methionine group (2.64±0.08%, p=0.026). Fractional shortening (FS) was not significantly different between groups.

Conclusion. Results from this study suggest that hyperhomocysteinemia-induced hypertension and ventricular hypertrophy in rats are mediated, at least partly; by Ang II activation of AT1-receptors.

Apelin (AP), an endogenous ligand of the APJ receptor, is involved in the regulation of cardiovascular homeostasis. Regardless the multiple similarities between AP and angiotensin II (Ang II), their roles seem to be different. We studied both the interactions between Apelin 13 (AP13) and Ang II and to what extent, if any, nitric oxide (NO) is involved.The experiments were performed in endothelium-denuded or endothelium-intact rat portal vein in the presence of 10 µM N(G)-nitro L-arginine methyl ester or 10 µM aminoguanidine. AP13 did not modify the isolated rat portal vein tone by itself, but inhibited the Ang II-induced contractions acting mainly by a NO-dependent mechanism. Our results sustain the hypothesis that AP13 could increase the activity of both constitutive and inducible NO synthase on either endothelium intact or endothelium denuded rat portal vein rings.

Introduction. Vasopressin, mainly through the V_1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure.To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I).

Materials and methods. After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V_1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7).

Results. In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44 7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67 7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30 18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21 20% and 0%, respectively),ACE-I significantly lowered proteinuria (92 2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed.

Conclusion. These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.

Left ventricular (LV) hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors. Here, we determined whether aldosterone modulates hypertrophy in HCM. Cardiac and/or plasma aldosterone were measured in organ donors and HCM patients.The effect of the aldosterone synthase (CYP11B2 ) C-344T polymorphism on LV mass index (LVMI) and interventricular septum thickness (IVS) was determined in 79 genetically independent subjects with HCM. Aldosterone in HCM hearts and plasma was similar to that in normal hearts and plasma. In HCM women, no associations between CYP11B2 genotype and any of the measured parameters were observed, whereas in HCM men, LVMI increased with the presence of the T allele. Similar T allele-related increases were observed for IVS. Multiple regression analysis revealed that the T allele-related effect on IVS occurred independently of renin, the ACE I/D polymorphism, the AT₁-receptor A/C 1166 polymorphism and the AT -receptor A/C 3123 polymorphism. In conclusion, circulating and cardiac aldosterone are normal in HCM, thereby arguing against selectively increased cardiac aldosterone production in HCM.Thus, the association between the CYP11B2 C-344T polymorphism and hypertrophy in HCM most likely relates to the T allele-related increases in circulating aldosterone.This finding raises the need for studies determining the benefit of aldosterone blockade in HCM.

Introduction. The Deletion (D) rather than Insertion (I) variant of the angiotensin-converting enzyme (ACE) gene is associated with higher circulating ACE activity. Meanwhile, coronary risk rises with the menstrual nadir in oestrogen levels, exogenous oestrogen reduces serum ACE activity (with a greater reduction the higher the baseline ACE activity), and pharmacological reduction in ACE activity is cardioprotective. Alterations in coronary risk associated with the menstrual cycle may thus be mediated through (genotype-dependent) changes in ACE activity. We have examined this hypothesis.

Materials and methods. Twenty-three healthy female subjects (12 II, 11 DD genotype) were studied. None were taking oral contraceptive agents. Blood was assayed for oestrogen, follicle stimulating hormone (FSH), luteinising hormone (LH), progesterone and ACE activity every three days throughout their menstrual cycle. Results ACE activity was unrelated to oestrogen, FSH or LH during the menstrual cycle, irrespective of ACE genotype.

Conclusions. The increase in myocardial ischaemia during low oestrogen phases of the menstrual cycle does not appear mediated through a fall in serum ACE activity.

The VIPE study was a prospective, non-comparative, open-label clinical evaluation of 97 hypertensive patients (69.1% female; 68.9±9.5 years; mean blood pressure (BP) 160±12/90±9 mmHg) with echocardiographic evidence of left ventricular hypertrophy (LVH). Patients were treated for six months with a candesartan-based regimen (8 mg/16 mg + HCTZ 12.5 mg + additional drugs to lower BP < 140/90 mmHg). After six months, systolic/diastolic BP was decreased by 19.3±8/9.4±5 mmHg (p<0.001 for both), and left ventricular mass index (LVMI) decreased 17.01 g/m2 (95%CI: -13.2 to -20.99; p<0.001). During treatment with the candesartan-based regimen all echocardiographic parameters related to LVMI were significantly reduced and 28% achieved a target LVMI [< 134 g/m2 (men) and < 110 g/m² (women) ]. No significant changes were observed in ejection fraction, shortening fraction or LV diastolic function. Univariate analysis showed that both age (p=0.03) and diabetes (p=0.029) were predictive of LVH regression.

Thus, a candesartan-based regimen for six months significantly reduced echocardiographic LVH in hypertensive patients in general practice. The drug was very well tolerated and no serious adverse events were reported.

Introduction. Hypertension in type 2 diabetes represents a strong risk factor for cardiovascular events. Either calcium channel blockers or angiotensin receptor blockers (ARBs) may reduce insulin resistance. One of the ARBs, telmisartan (Telm) acting as a PPARγ agonist, significantly reduces HbA1C levels.The aim of this study was the comparison of the effects on glycaemic control of amlodipine (Aml) and Telm in hypertensive type 2 diabetic patients.

Materials and methods. Forty diabetic hypertensive subjects were assigned to two groups. Group A: rosiglitazone (RSG) 4 mg + Telm 80 mg; Group B: RSG 4 mg + Aml 10 mg. All the patients were already treated with metformin, but not with antihypertensive drugs.

Results. After four months treatment, both groups showed a significant reduction of mean blood pressure (Group A: - 13.5%; Group B: - 13.3%) and a positive influence on glycaemic control and insulin resistance. Lower values of glucose, HbA_1C, HOMA index and higher adiponectin levels were observed in Group A compared to Group B.

Conclusions. In type 2 diabetic hypertensive patients, the association of Telm 80 mg and RSG 4 mg seems to display a metabolic advantage compared to Aml 10 mg.The simultaneous beneficial effects on blood pressure and insulin sensitivity may confer make Telm particularly suitable in the treatment of the metabolic syndrome.