Aortic smooth muscle cell phenotypic modulation and fibrillar collagen deposition in angiotensin II-dependent hypertension

BACKGROUND: We investigated the effect of nifedipine, AT-1 and ET-1 receptor blockade on arterial smooth muscle cell phenotypes and collagen deposition in TGRen2 transgenic rat (TGR). METHODS: Four-week-old TGR were blood pressure (BP)-matched and allocated to receive a placebo (n=8), the calcium antagonist nifedipine (n=6), the AT-1 specific receptor antagonist irbesartan (n=6), the ET(A)/ET(B) antagonist bosentan (n=6) or the ET(A)-selective antagonist BMS-182874 (n=5). Sprague-Dawley normotensive rats served as controls (n=6). After 4 weeks of treatment animals were euthanized and the left ventricle (LV) and the structural changes in intracardiac arterioles and aorta were assessed histomorphometrically. Smooth muscle cell phenotypes and fibrillar collagen content of the aortic wall were evaluated by immunostaining, using differentiation markers-specific antibodies and Syrius red staining, respectively. The changes in ET(A) and ET(B) receptor density were also assessed with quantitative autoradiography. RESULTS: Compared to placebo, only irbesartan lowered BP (P<0.001) and prevented LV and small resistance artery hypertrophy. The aorta of placebo-treated TGR showed an increase in foetal-type smooth muscle cell content and fibrillar collagen staining, compared to controls. These changes were blunted by irbesartan, which increased ET(A) receptors in the arterial wall, enhanced by BMS-182874 and unaffected by bosentan. Nifedipine also blunted both the VSMC and collagen changes despite having no effect on BP and ET(A) receptors. CONCLUSIONS: In TGRen2, vascular hypertrophy entails both smooth muscle cell phenotypic modulation and collagen deposition. These alterations do not follow closely the BP changes and seem to imply the dihydropyridine-sensitive calcium channels.     

Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis

OBJECTIVE: Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. METHODS: Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). RESULTS: Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. CONCLUSION: Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.     

Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart

OBJECTIVES: Despite the clinical frequency of diastolic heart failure, its therapeutic strategy has not been established. Our recent study demonstrated activation of the endothelin (ET) system in a diastolic heart failure model with hypertension. Several studies have reported that ET type A (ETA) receptor antagonist improves systolic function and prevents systolic heart failure; however, its effects on diastolic heart failure are unknown. We investigated the effects of chronic administration of ET(A) receptor antagonist in diastolic heart failure. DESIGN AND METHODS: Dahl-Iwai salt-sensitive rats fed on a high-salt diet from 7 weeks of age, in which congestive heart failure develops following hypertension without cardiac chamber dilatation or systolic dysfunction, were divided into groups with and without administration of a subdepressor dose of ET(A) receptor antagonist. RESULTS: Hypertension induced compensatory left ventricular (LV) hypertrophy at 13 weeks in six untreated rats. Persistent pressure overload developed progressive LV hypertrophy and fibrosis from 13 to 19 weeks, resulting in elevated LV filling pressure and increased lung weight. Chronic ET(A) receptor blockade did not restrain compensatory LV hypertrophy at 13 weeks; however, it attenuated LV hypertrophy and fibrosis thereafter (n = 6). These beneficial effects resulted in the maintenance of normal LV filling pressure without changes in LV end-diastolic diameter, indicating prevention of LV stiffening. CONCLUSIONS: Chronic ET(A) receptor blockade is likely to exert beneficial effects in diastolic failure through attenuation of the progression of LV hypertrophy and fibrosis.     

Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ET(A) receptor antagonism

BACKGROUND: To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated. METHODS AND RESULTS: A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202+/-3.2 mm Hg in DOCA-salt rats (P:<0.01 versus Uni-Nx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt rats (P:<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P:<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET(A) antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET(A) antagonist treatment. TGF-beta(1) mRNA and TGF-beta(1) protein increased at 1 week in DOCA-salt rats and were lowered in ET(A) antagonist-treated rats. CONCLUSIONS: ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.     

Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts

OBJECTIVE: Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear. METHODS: Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated. RESULTS: Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats. CONCLUSIONS: RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.     

内皮素受体拮抗剂BMS-182874对高血压大鼠左心室和冠状动脉壁的影响

目的：研究内皮素受体Ａ（ＥＴＡ ）拮抗剂ＢＭＳ－１８２８７４ 对高血压大鼠左心室肥厚和冠状动脉管壁增厚的影响。　　方法：研究于１９９７ 年１月～５ 月完成。４ 周龄大鼠设３组：分别为自发性高血压大鼠（ＳＨＲ组）、ＳＨＲ口服ＢＭＳ－１８２８７４（ＳＨＲ＋ Ｂ组）和正常血压大鼠（ＷＫＹ组），饲养１２周。　　结果：ＳＨＲ＋ Ｂ组与ＳＨＲ组比较，收缩压、左心室重与体重比、冠状动脉外径大于１００ μｍ 的冠状动脉管壁横截面积及横截面积与内径比、平滑肌细胞的宽度及最大冠状动脉流量均无显著差异；冠状动脉外径小于１００ μｍ 的冠状动脉管壁横截面积及横截面积与内径比，ＳＨＲ＋ Ｂ组较ＳＨＲ组显著下降。血浆和心肌的ＥＴ含量：ＳＨＲ组与ＷＫＹ组无显著差异，ＳＨＲ＋ Ｂ组显著下降。　　结论：ＥＴＡ 拮抗剂ＢＭＳ－１８２８７４治疗能部分预防ＳＨＲ外径小于１００ μｍ 冠状动脉管壁的增厚，但对ＳＨＲ大鼠高血压的形成、左心室和外径大于１００ μｍ 冠状动脉管壁的增厚及平滑肌细胞的肥大无明显的影响。     

B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial

OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.     

Endothelin system-dependent cardiac remodeling in renovascular hypertension

The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure-independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (P<0. 01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (P<0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats.     

内皮素在大鼠高血压心肌肥大中的作用

目的研究内皮素（ＥＴ）在一氧化氮合酶（ＮＯＳ）抑制剂亚硝基左旋精氨酸甲酯（Ｌ－ＮＡＭＥ）诱导的高血压心肌肥大中的作用及ＥＴＡ受体阻断剂ＪＫＣ－３０１的保护效应。方法复制大鼠Ｌ－ＮＡＭＥ高血压模型，动物分对照组、高血压组和ＪＫＣ－３０１治疗组，测定心重、血浆及心肌ＥＴ水平和心肌丝裂素活化蛋白激酶（ＭＡＰＫ）活性。结果高血压动物的心重、ＥＴ水平和心肌ＭＡＰＫ活性较对照组都显著升高（Ｐ＜０．０１或０．０５），加用ＪＫＣ－３０１治疗则较高血压组ＥＴ水平不变，但血压、心重和ＭＡＰＫ活性均降低（Ｐ＜０．０１或０．０５），心肌ＭＡＰＫ活性与左心室肥大程度呈正相关（ｒ＝０．８２，Ｐ＜０．０１）。结论一氧化氮缺乏的心肌肥大可能是由ＥＴ所介导的，ＥＴＡ受体阻断剂对此种肥大有防治作用     

Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy

OBJECTIVES: We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). METHODS: Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. RESULTS: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition. CONCLUSION: Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.     

Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.     

The endothelin receptor antagonist decreases ischemia/reperfusion-induced tumor necrosis factor production in isolated rat hearts

Previous studies have shown that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. In the present study, BMS-182874 significantly improved the recovery of cardiac function and reduced the release of CK during reperfusion after ischemia and the content of tumor necrosis factor (TNF-alpha) in myocardial tissues. BMS-182874 also reduced myocardial injury and the increased level of TNF-alpha by exogenous ET-1. These results suggest that the cardioprotective effects of the ET receptor antagonist may be related to inhibition of TNF-alpha production.     

Angiotensin II receptor antagonists in arterial hypertension

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active antihypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was losartan, followed by other agents currently in clinical use, such as: valsartan, eprosartan, irbesartan, telmisartan, candesartan, and many others under investigation. AT-1 receptor antagonists are effective in reducing high blood pressure in hypertensive patients. Monotherapy in mild to moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of a thiazide diuretic is added, 60 to 70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists and beta-blocking agents. Tolerability has been reported to be very good. AT-1 receptor antagonists would be a drug of choice in otherwise well-controlled hypertensive patients treated with angiotensin-converting enzyme inhibitors who developed cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted.     

Pharmacological characterization of 3-azabicyclo[3,2,1] octane-1-yl-l-leucyl-d-tryptophanyl-d-4-Cl-phenylalanine: A novel ET(A) receptor-selective antagonist

BACKGROUND AND OBJECTIVES: Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization. METHODS: Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension. RESULTS: ETP-508 binds to endothelin ET(A) receptor with >10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia. CONCLUSION: These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.     

Beta1-adrenergic receptor gene polymorphisms and response to beta1-adrenergic receptor blockade in patients with essential hypertension

BACKGROUND: Studies suggest that the Ser49Gly and Arg389Gly polymorphisms in the beta1-adrenergic receptor might be of functional importance for the cardiovascular system. Both have been associated with altered receptor activity in vitro, and with hypertension and cardiac failure in vivo. HYPOTHESIS: The aim of this study was to test whether these polymorphisms were associated with the change in heart rate or blood pressure in patients with essential hypertension and left ventricular (LV) hypertrophy treated with the beta1-adrenergic receptor blocker atenolol. METHODS: Blood pressure and heart rate were measured in 101 hypertensive patients with echocardiographically verified LV hypertrophy, randomized in a double-blind study to treatment with either the beta1-adrenergic receptor blocker atenolol or the angiotensin II type I receptor antagonist irbesartan. Changes in blood pressure and heart rate were evaluated after 12 weeks. Beta1-adrenergic receptor genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found no significant associations between the changes in the measured variables and either of the two polymorphisms. However, carriers of the 49Gly allele showed a tendency toward a greater reduction in heart rate compared with patients with the Ser/Ser49 genotype (p = 0.06). CONCLUSIONS: The Ser49Gly and Arg389Gly beta1-adrenergic receptor polymorphisms do not seem to exert a major effect on the changes in heart rate and blood pressure during 12 weeks of treatment with atenolol in patients with essential hypertension and LV hypertrophy.     

Selective endothelin ET(B) receptor antagonist improves left ventricular function but exaggerates degeneration of cardiomyocytes in J2N-k hamsters.

BACKGROUND: Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy. METHODS AND RESULTS: Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters. CONCLUSIONS: Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.     

Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling

Endothelin A (ETA) receptor blockade has prevented vascular remodeling in aldosterone and salt-induced hypertension. To evaluate effects of the ETA receptor antagonist, BMS 182874, compared with the aldosterone antagonist, spironolactone, on vascular remodeling in aldosterone-infused rats not exposed to a high salt diet, Sprague-Dawley rats were infused subcutaneously with aldosterone (0.75 microg/h) and treated with BMS 182874 (40 mg. kg-1. d-1), spironolactone, or hydralazine (both 25 mg. kg-1. d-1) while receiving a normal salt diet for 6 weeks. Aldosterone increased systolic BP (P<0.01), plasma endothelin (3.33+/-0.32 versus 1.85+/-0.40 pmol/L in control, P<0.05), systemic oxidative stress as shown by plasma thiobarbituric acid-reacting substances and vascular nicotinamide adenine dinucleotide phosphate (NADPH) activity. Aldosterone increased small artery media thickness (17.7+/-0.9 versus 13.6+/-0.8 microm in control, P<0.05) and media/lumen ratio (7.6+/-0.4 versus 5.5+/-0.4% in control, P<0.05), with growth index of 21% indicating hypertrophic remodeling. Laser confocal microscopy showed increased collagen and fibronectin deposition and intercellular adhesion molecule-1 (ICAM-1) content in the vessel wall of aldosterone-infused rats. The 3 treatments lowered BP, although hydralazine was slightly less effective. BMS 182874 and spironolactone decreased oxidative stress, normalized the hypertrophic remodeling, decreased collagen and fibronectin deposition, and reduced ICAM-1 abundance in the vascular wall of aldosterone-infused rats, whereas hydralazine only reduced NADPH activity in aorta but did not affect the remaining parameters. Vascular remodeling of small arteries occurs in aldosterone-infused rats exposed to a normal salt diet and may be mediated in part by ET-1 via stimulation of ETA receptors. Endothelin blockade may exert beneficial effects on vascular remodeling, fibrosis, oxidative stress, and adhesion molecule expression in aldosterone-induced hypertension.     

Early intervention with a potent endothelin-A/endothelin-B receptor antagonist aggravates left ventricular remodeling after myocardial infarction in rats

Intervention with selective endothelin (ET)A receptor antagonists within 24 h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ET_A/ET_B receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ET_A/ET_B receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg·kg⁻¹ SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48 h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4 ± 0.5 vs 9.1 ± 0.2 mm; LV end-systolic diameter: 8.5 ± 0.4 vs 7.2 ± 0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ET_A/ET_B receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI. Received: 1 September 2001, Returned for revision: 13 September 2001, Revision received: 6 December 2001, Accepted: 21 December 2001     

Irbesartan reduces common carotid artery intima-media thickness in hypertensive patients when compared with atenolol: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) study

BACKGROUND AND PURPOSE: Angiotensin II promotes cell growth and has been implicated in the development and maintenance of left ventricular (LV) hypertrophy and of structural vascular changes. We wished to examine whether an angiotensin receptor blocker (ARB) would influence structural vascular changes beyond the effects of blood pressure reduction. METHODS: Hypertensive patients with LV hypertrophy (age 55 +/- 9 years, blood pressure 162 +/- 19/104 +/- 8 mmHg, LV mass index 148 +/- 31 g m(-2); mean +/- SD) were randomized double-blind to the ARB irbesartan (n=52) or the beta(1) receptor blocker atenolol (n=56) for 48 weeks. Ultrasonography of the left and right common carotid artery (CCA) and echocardiography were performed at week 0 and 48. RESULTS: With similar reductions in blood pressure, CCA intima-media thickness (IMT) was reduced by irbesartan (from 0.92 +/- 0.14 by 0.01 +/- 0.10 mm, NS), whereas it was increased by atenolol (from 0.94 +/- 0.21 by 0.03 +/- 0.12 mm, P=0.018; P=0.002 between groups). CCA lumen diameter was less reduced by irbesartan than by atenolol. Thus, CCA intima-media area was reduced by irbesartan (from 21.3 +/- 5.0 by 0.90 +/- 2.45 mm(2), P=0.034) but not by atenolol (from 21.3 +/- 6.1 by 0.18 +/- 2.71 mm(2), NS; P=0.037 between groups). Changes in CCA IMT or area did not relate to changes in LV mass. CONCLUSIONS: The favourable effects by irbesartan on CCA IMT with an outward vascular remodelling suggest that angiotensin II mediates structural vascular changes, beyond the effects of blood pressure. This may be important in the prevention of cerebrovascular events.     

Myocardial stiffness is determined by ventricular fibrosis,but not by compensatory or excessive hypertrophy in hypertensive heart

OBJECTIVES: Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart. METHODS: Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks (n=7), rats treated with calcineurin inhibitor from 8 weeks (n=6), and untreated rats (n=7). RESULTS: Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed. CONCLUSIONS: Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.