Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.     

Resveratrol inhibits proliferation of cultured rat cardiac fibroblasts: correlated with NO-cGMP signaling pathway

Rhizoma polygoni cuspidate, used as a traditional Chinese herb, offered the therapeutic potential for cardiovascular diseases. Resveratrol, extracted from root of the rhizoma polygoni cuspidate has sparked increasing interest in therapeutic application. Resveratrol was shown to exert a variety of pharmacological effects including cardioprotective and cancer chemopreventive properties. However, its mechanisms of the action are not completely understood. The aim of this study was to investigate the molecular mechanism of resveratrol on preventing cardiac fibroblasts from proliferative and hypertrophic response induced by angiotensin II. Cell proliferation and cytotoxicity were detected by methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assay, respectively. Hypertrophic response of cardiac fibroblasts was measured by mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Resveratrol (25, 50, 75, and 100 microM) inhibited cardiac fibroblasts proliferation in a dose- and time-dependent manner compared with angiotensin II group (P<0.01), and the inhibitory effects were blocked by pretreatment with N(G)-nitro-l-arginine methyl ester (L-NAME) and 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ). Resveratrol increased nitric oxide (NO) and nitric oxide synthase (NOS) levels in culture medium, increased intracellular cyclic GMP (cGMP) level in cardiac fibroblasts, and decreased ANP and BNP levels in culture medium. The mRNA expression of ANP and BNP was suppressed by resveratrol. These results suggested that resveratrol inhibited cardiac fibroblasts proliferation induced by angiotensin II, and the inhibitory effect might be associated with the activation of NO-cGMP signaling pathway.     

Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats.

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.     

Beneficial effects of the combination of nifedipine and losartan in hypertensive Dahl salt-sensitive rats

BACKGROUND: The antihypertensive and organ-protective effects of the combination of the angiotensin II type 1 receptor blocker losartan and the calcium channel blocker nifedipine were examined in Dahl salt-sensitive rats. METHODS: The rats fed with a high-salt diet developed hypertension accompanied by aorta and heart hypertrophy, and impaired renal function. The animals were treated with losartan (30 mg/kg/day), nifedipine (7.8 mg/kg/day) or with a combination of both drugs for 8 weeks. At the end of the study systolic blood pressure, kidney function, organ weight, and mRNA expression were investigated. RESULTS: Losartan reduced significantly the systolic blood pressure as well as the aorta and left ventricular hypertrophy. Nifedipine and its combination with losartan had similar effects on the systolic blood pressure, aorta and left ventricular hypertrophy but only the combination treatment reduced the expression of transforming growth factor-beta1 in aorta and brain natriuretic peptide in left ventricle significantly. Nifedipine and the combination therapy reduced proteinuria and improved urine creatinine excretion. The expression of collagen III and IV in the kidney was significantly reduced by the combination therapy. CONCLUSION: These results indicate that although losartan and nifedipine were effective in lowering blood pressure and showed moderate organ protection, additional benefits can be expected by combination therapy with both compounds.     

LONG-TERM ANGIOTENSIN II ANTAGONISM IN SPONTANEOUSLY HYPERTENSIVE RATS: EFFECTS ON BLOOD PRESSURE AND CARDIOVASCULAR AMPLIFIERS

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long-term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.     

吡格列酮联合厄贝沙坦对原发性高血压患者左心室肥厚及血清脑钠肽的影响

目的 探讨吡格列酮对原发性高血压患者左心室肥厚及脑钠肽的影响.方法 原发性高血压伴左心室肥厚患者80例完全随机分成2组,各40例.常规治疗组给予厄贝沙坦（150 mg/d）,吡格列酮组给予厄贝沙坦（150 mg/d）＋吡格列酮（15 mg/d）,均治疗6个月.比较2组治疗前后左心室质量指数（LV MI）、血清脑钠肽浓度的变化.结果 治疗后2组患者LVMI、血清脑钠肽浓度均下降（P＜0.05）,2组治疗后比较,吡格列酮组LVMI、血清脑钠肽浓度下降为[（126.2±10.4）g/m2、（113.6±42.9）ng/L,较常规治疗组[分别为（135.5±11.2）g/m2、（138.8±45.8）ng/L]明显（P＜0.05）.结论 吡格列酮能逆转高血压病患者的左心室肥厚,并降低血清脑钠肽浓度.     

Comparison of irbesartan with captopril effects on cardiac hypertrophy and gene expression in heart failure-prone male SHHF/Mcc-fa(cp) rats

Angiotensin-converting enzyme (ACE) inhibitors have proven an effective means to control hypertension and manage cardiac hypertrophy. It is presently unknown if newer specific angiotensin II subtype 1 receptor (AT1R) antagonists are as effective or more effective in treating these conditions compared with ACE inhibitors. There is evidence that these classes of drugs may affect cardiac hypertrophy by different mechanisms. This study compared the effect of irbesartan, an AT1R antagonist, with that of captopril, an ACE inhibitor, on expression of early genetic markers of cardiac hypertrophy in lean male SHHF/Mcc-fa(cp) rats. SHHF/Mcc-fa(cp) rats (n = 10/group) were given captopril (100 mg/kg/day), irbesartan (50 mg/kg/day), or placebo for 16 weeks. Irbesartan and captopril significantly reduced systolic pressure and produced similar rightward shifts in the angiotensin I dose-response curve. Renal renin gene expression was increased 8.6-fold by irbesartan and 17.7-fold by captopril. The only effect on echocardiographic findings was a similar decrease in aortic peak velocity, an index of systolic function, by both treatments. Early markers of cardiac hypertrophy were significantly attenuated by both drugs. Both drugs produced marked and equivalent reductions in left ventricular atrial natriuretic peptide (ANP) messenger RNA (mRNA) levels compared with controls. This decrease in ANP gene expression was accompanied by a decrease in plasma ANP concentration in the treatment groups. The shift from V1 to V3 myosin isozymes was similarly decreased in both treatment groups, compared with controls. These data suggest that captopril and irbesartan are similarly effective in controlling expression of genes associated with ventricular hypertrophy in heart failure-prone SHHF/Mcc-fa(cp) rat.     

DIFFERENTIAL REGULATION OF NATRIURETIC PEPTIDE GENES IN INFARCTED RAT HEARTS

1. We investigated the regulation of the atrial natriuretic peptide and brain natriuretic peptide genes in a rat model of myocardial infarction induced by isoproterenol (IP rat) and in a rat model of cardiac hypertrophy induced by aorto-caval shunt (AC shunt rat). 2. Brain natriuretic peptide (BNP) mRNA levels in atria were significantly higher in IP rats than in controls at 18 h after the administration of isoproterenol, but no significant increases were observed in atrial natriuretic peptide (ANP) mRNA expression levels at any time point examined. In the ventricles, the BNP mRNA levels peaked at 18 h after isoproterenol administration, whereas ANP mRNA levels gradually increased until 3 days after isoproterenol administration. 3. The BNP mRNA levels in both atria and ventricles were significantly increased at 1 day after the introduction of aorto-caval shunt, while the ANP mRNA levels were not. 4. Plasma BNP levels were closely correlated with left ventricular weight per bodyweight, in both IP rats and AC shunt rats. 5. These results suggest the differential regulation of ANP and BNP genes in both the atria and ventricles in these two pathological models.     

Angiotensin type 1 receptor antagonism with irbesartan inhibits ventricular hypertrophy and improves diastolic function in the remodeling post-myocardial infarction ventricle

To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.     

Implications of the LIFE trial

The recent Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study was conducted in patients with essential hypertension with electrocardiogram evidence of left ventricular hypertrophy. This showed that losartan compared to atenolol resulted in a significant reduction in the primary endpoint of cardiovascular morbidity and mortality, as well as a greater reduction in electrocardiographically-defined left ventricular hypertrophy. Importantly, this was despite a mean blood pressure reduction which was similar in both groups. Furthermore, the atenolol arm was associated with higher incidence of newly diagnosed diabetics. The LIFE study has firmly confirmed a place for losartan (and other angiotensin receptor blockers) in the management of hypertension. Losartan has also been shown to be effective in diabetics and in patients with atrial fibrillation, as well as in left ventricular hypertrophy regression. This trial also raises the possibility that beta-blockers should perhaps not be used as first-line monotherapy.     

Effect of pioglitazone on the expression of inflammatory cytokines in attenuating rat cardiomyocyte hypertrophy

Pioglitazone, one of the synthetic peroxisome proliferator-activated receptor (PPARgamma) agonists, has been found to inhibit inflammatory response. However, it is not known yet whether the preventive effect of pioglitazone on cardiac hypertrophy is related to its antiinflammatory function. The objective of this study was to investigate the role of pioglitazone in attenuation of cardiac hypertrophy and its relation to the inhibitory effect on the inflammatory cytokine expression in cultured neonatal rat cardiomyocytes. The mRNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), interleukin (IL)-1beta, IL-6, and PPARgamma was measured by using RT-PCR. Cardiomyocyte hypertrophy was induced by stimulating angiotensin II (Ang II) and evaluated both by measuring surface area of cardiac myocyte and 3H-leucine incorporation. The expressions of IL-1beta, IL-6, ANP, and BNP were significantly enhanced, whereas that of PPARgamma was significantly reduced in Ang II-induced hypertrophic cardiomyocytes. Pioglitazone decreased cardiac myocyte surface area and inhibited 3H-leucine incorporation into cardiomyocytes. Furthermore, pioglitazone upregulated the suppressed expression of PPARgamma and attenuated the increased IL-1beta and IL-6 expression. The effect of pioglitazone might be associated with PPARgamma activation and the consequent antiinflammatory function in prevention and treatment of cardiac hypertrophy.     

洛沙坦抗高血压及左室肥厚的疗效观察

目的 :观察血管紧张素 受体拮抗剂—洛沙坦的降压效果及对高血压病合并左室肥厚的影响。方法 :4 6例合并左室肥厚的 期高血压病患者服用洛沙坦 5 0 mg/ d,观察其血压的变化及治疗前和 6个月后左室质量 (L VM)。结果 :用洛沙坦后 4 d～ 6d血压开始下降 ,2周血压趋向正常 ,4周血压继续缓慢下降 ,6周时达到最大降压效果。 L VM在 12周时无明显变化。 2 4周表现轻度 L VM减少。结论 :洛沙坦是抗高血压的一个有效治疗药物 ,对左心室肥厚有轻度逆转作用     

Increased plasma concentration of natriuretic peptides by selective beta1-blocker bisoprolol

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P < 0.001) by 93 +/- 88% (mean +/- SD) and 148 +/- 117%, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 +/- 45%, and increments in ANP and Nt-ANP were related (r =0.77, P < 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the beta-blocker-induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.     

吡格列酮体外对大鼠心肌肥大的改善作用

目的　探讨噻唑烷二酮 (TZD)类药物吡格列酮在体外对心肌肥大的影响。方法　新生大鼠的原代培养心肌细胞和非心肌细胞 ,以血管紧张素Ⅱ (AngⅡ )刺激建立体外心肌肥大模型 ,并用不同浓度的吡格列酮作用细胞。采用RT PCR法检测心肌肥大特征性基因心钠肽 (ANP)和脑钠肽(BNP)的mRNA表达 ,以MTT比色法和3 H TdR参入实验检测非心肌细胞增殖情况 ,以3 H 亮氨酸参入实验检测心肌细胞蛋白合成速率 ,并用软件分析心肌细胞表面积。结果　肥大模型出现后 ,心肌细胞表面积、ANP和BNP的mRNA表达以及蛋白合成速率增加 ;非心肌细胞增殖活跃 ,但ANP和BNP的mRNA表达没有变化。吡格列酮可以逆转这些变化 ,同时下调非心肌细胞的ANP和BNP的mRNA表达 ,并呈一定的剂量依赖性。结论　吡格列酮体外对大鼠心肌肥大有改善作用 ,预示着TZD类药物具有防治心肌肥大等心血管疾病的药理作用     

The role of the renin-angiotensin and natriuretic peptide systems in the pulmonary vasculature.

1. The role of vasoactive peptide systems in the pulmonary vasculature has been studied much less extensively than systemic vascular and endocrine effects. The current understanding of the role of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) in the pulmonary circulation is therefore reviewed. 2. Plasma concentrations of angiotensin II, the main vasoactive component of the RAS, are elevated in pulmonary hypertension and may interact with hypoxaemia to cause further pulmonary vasoconstriction. Pharmacological manipulation of angiotensin II can attenuate hypoxic pulmonary vasoconstriction but larger studies are needed to establish the efficacy of this therapeutic strategy in established pulmonary hypertension. 3. Although all the known natriuretic peptides, ANP, BNP and CNP are elevated in cor pulmonale, only ANP and BNP appear to have pulmonary vasorelaxant activity in humans. ANP and BNP can also attenuate hypoxic pulmonary vasoconstriction, suggesting a possible counter-regulatory role for these peptides. Inhibition of ANP/BNP metabolism by neutral endopeptidase has been shown to attenuate development of hypoxic pulmonary hypertension but this property has not been tested in humans. 4. It is also well established that there are potentially important endocrine and systemic circulatory interactions between the RAS and NPS. This also occurs in the pulmonary circulation and in humans, where at least BNP acts to attenuate angiotensin II induced pulmonary vasoconstriction. This interaction may be particularly relevant as a mechanism to counter-regulate overactivity of the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)     

阿托伐他汀对体外心肌细胞肥大的抑制作用

目的探讨阿托伐他汀体外抑制心肌肥厚的药理作用。方法体外培养新生大鼠的心室肌细胞,用血管紧张素Ⅱ(AngⅡ)诱导心肌细胞肥厚模型,以不同浓度的阿托伐他汀作用于心肌细胞,用软件分析测量心肌细胞表面积,3H-亮氨酸参入法检测心肌细胞蛋白合成速率及使用RT-PCR半定量测定心钠素(ANP),脑钠素(BNP)和特异分布于心脏的丝氨酸蛋白酶(Corin)的表达变化。结果AngⅡ可成功诱导体外培养的新生大鼠心室肌细胞肥大,表现为心肌细胞面积和3H-亮氨酸的参入增加,ANP、BNP、Corin表达升高等特征性改变,从而分析阿托伐他汀对心肌肥厚的作用。阿托伐他汀可逆转上述变化并呈剂量依赖性,而作为溶剂的DM-SO对肥大的心肌细胞差异无显著性。结论阿托伐他汀抑制AngⅡ介导的体外心肌细胞肥大,预示其具有降脂以外的其他重要药理作用。