Role of polyamines in isoproterenol-induced cardiac hypertrophy: effects of alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase

DFMO is a selective irreversible inhibitor of ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway. DFMO was utilized to determine the role of polyamines in isoproterenol (ISO)-induced cardiac hypertrophy. Daily subcutaneous administration of 200 mg/kg of DFMO reduced cardiac putrescine levels but did not significantly alter the basal levels of spermidine or spermine, nor was normal cardiac growth affected. ISO-induced cardiac hypertrophy was accompanied by increased putrescine and spermidine levels but spermine was not significantly altered. DFMO reversed the ISO-induced increases in putrescine and inhibited or attenuated both the increases in spermidine content and the cardiac hypertrophy. Although normal ODC activity appears not to be necessary for the maintenance of basal levels of polyamines or for normal cardiac growth, sustained inhibition of ODC interferes with ISO-induced elevations of putrescine, spermidine and heart weight.     

Regulation of cardiac beta-adrenergic receptors by captopril. Implications for congestive heart failure

The interaction of the renin-angiotensin system and the sympathetic nervous system in patients with congestive heart failure is not well understood. We tested the hypothesis that angiotensin-converting enzyme inhibitors can resensitize the beta-adrenergic receptor system. Guinea pigs were given captopril, isoproterenol, or both for 2 weeks. At death, cardiac sarcolemmal and light vesicle fractions and intact mononuclear leukocytes were prepared. Captopril treatment led to an up-regulation of cardiac beta 1- but not mononuclear leukocyte beta 2-adrenergic receptors and an increase in isoproterenol-stimulated adenylate cyclase activity in the heart. Animals treated with isoproterenol developed cardiac hypertrophy, had increased plasma norepinephrine levels, and had a decreased number and responsiveness of both cardiac and mononuclear leukocyte beta-adrenergic receptors. Concomitant treatment with captopril attenuated alterations of heart weight, plasma norepinephrine levels, and cardiac beta-receptor density and function. In contrast to its cardiac effects, captopril treatment did not diminish the down-regulation of mononuclear leukocyte beta 2-adrenergic receptors by isoproterenol. Our data suggest that captopril may resensitize the cardiac but not the mononuclear leukocyte beta-adrenergic receptor-adenylate cyclase system after long-term catecholamine exposure.     

Comparison of cardiac lesions induced in rats by isoproterenol and by repeated stress of restraint and water immersion with special reference to etiology of cardiomyopathy

Cardiac lesions induced in rats by isoproterenol, a potent beta-agonist, and by repeated stress of restraint and water immersion, in which sensitization of beta-adrenergic receptors would be expected to be induced, were investigated morphologically and following facts were revealed. 1) Cardiac lesions induced by isoproterenol, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were more analogous to cardiomyopathy than myocardial infarction or cardiac hypertrophy. 2) Cardiac lesions induced by repeated stress of restraint and water immersion, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were similar to those induced by isoproterenol. These results suggest that the endogenously induced dominant beta-adrenergic stimulating action during stress may play an important role in the pathogenesis of cardiomyopathy, the specific etiology of which is not yet known.     

Renin-angiotensin inhibition reverses advanced cardiac remodeling in aging spontaneously hypertensive rats

BACKGROUND: Many experiments using young hypertensive animal models support the evidence that angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 blocker attenuates the progression of cardiac hypertrophy. However, it is still unclear whether inhibiting the renin-angiotensin system can reverse age-related cardiac hypertrophy. To clarify the role of renin-angiotensin system inhibition in naturally advanced myocardial hypertrophy we treated spontaneously hypertensive, aging rats with an angiotensin-converting enzyme inhibitor or an angiotensin receptor type 1 blocker. METHODS: We used osmotic pumps to deliver the blood-pressure reducers temocaprilat, olmesartan, hydralazine, or saline for 4 weeks. RESULTS: Heart and body weights were significantly reduced in animals treated with temocaprilat or olmesartan compared with animals treated with hydralazine or saline. Histologic myocyte size and cardiac fibrosis were significantly attenuated by temocaprilat or olmesartan. Real-time polymerase chain reaction (PCR) revealed that temocaprilat or olmesartan suppressed expression of cardiac transforming growth factor-beta1 and fibroblast growth factor-2 mRNA, a marker of cardiac fibrosis. Cardiac and systemic oxidative stress assessed by 8-isoprostane levels was significantly reduced in animals treated with temocaprilat or olmesartan compared with hydralazine-treated or saline-treated rats. Renin-angiotensin system inhibition reduced cardiac expression of NAD(P)H oxidative components p22phox, p47phox, and gp91phox. CONCLUSIONS: Renin-angiotensin system inhibition can reverse age-related, advanced cardiac hypertrophy. The mechanism of reversal is partly due to suppression of cardiac oxidative stress.     

Significance of the hexose monophosphate shunt in experimentally induced cardiac hypertrophy

1. In three models of cardiac hypertrophy in rats (aortic constriction, application of a single dose of isoproterenol and daily injections of triiodothyronine) the biosynthesis of myocardial adenine nucleotides was enhanced. 2. In hypertrophying hearts due to aortic constriction and isoproterenol application, the activity of glucose-6-phosphate dehydrogenase and the available pool of 5-phosphoribosyl-1-pyrophosphate were increased indicating a stimulation of the hexose monophosphate shunt. In triiodothyronine-treated animals only the cardiac pool of 5-phosphoribosyl-1-pyrophosphate turned out to be elevated. 3. In all three models of cardiac hypertrophy, the enhancement of myocardial adenine nucleotide biosynthesis was exaggerated by ribose. It thus appears that the 5-phosphoribosyl-1-pyrophosphate pool is the limiting factor for the increase of adenine nucleotide biosynthesis under these conditions. 4. Long-term i.v. infusion of ribose (200 mg/kg/h) in isoproterenol-treated rats prevented the decrease of the cardiac ATP concentration induced by isoproterenol. However, the isoproterenol-induced stimulation of total cardiac protein synthesis was not altered, suggesting that the ATP decline may not be the trigger for stimulating protein synthesis in this model of myocardial hypertrophy.     

Prevention, diagnosis, and treatment of hypertensive heart disease

Hypertensive heart disease (HHD), a result of long-standing hypertension, is characterized by changes in the myocardial structure and function in the absence of other primary cardiovascular abnormalities. Although increased blood pressure is the initiating stimulus, neurohormonal factors, particularly the renin-angiotensin system, play a key role in remodeling of cardiac chamber geometry and walls. Optimal antihypertensive therapy in the setting of therapeutic lifestyle changes is crucial in the prevention and control of HHD. Regression of left ventricular hypertrophy (LVH) is achievable and associated with improved prognosis. However, prevention of myocardial remodeling before LVH establishes would further increase the benefits to cardiac function and prognosis. Antihypertensive agents exhibit variable effectiveness in inducing LVH regression. Currently, renin-angiotensin system blocking agents seem to be the most effective approach for LVH regression and reverse remodeling in these patients.     

In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy

Cardiac angiotensin-converting enzyme (ACE) may play an important role in regulating cardiac hypertrophy. Angiotensin II (Ang II) stimulates cardiac hypertrophy as well as the production of extracellular matrix. However, it is still unclear whether Ang II exerts a direct effect on cardiac hypertrophy independent of its effect on blood pressure or the circulating renin-angiotensin system. Although ACE inhibitors and/or Ang II receptor antagonists have regressed cardiac hypertrophy, classic pharmacological experiments cannot exclude the contribution of hemodynamics and the circulating renin-angiotensin system. In vivo gene transfer provides the opportunity of assessing the effects of increased cardiac angiotensin in the intact animal without circulating angiotensin or blood pressure. Therefore, we used a "gain of function" approach to obtain local overexpression of cardiac ACE. Transfection of the human ACE vector into rat myocardium resulted in a significant increase in cardiac ACE activity (P<0.01). More interestingly, morphometry at 2 weeks after transfection revealed a significant increase in the thickness and areas of cardiac myocytes in hearts transfected with the ACE vector (P<0.01). In addition, transfection of the ACE vector also resulted in a significant increase in collagen content (P<0.01). This increase in cardiac hypertrophy was abolished by the administration of perindopril. Local transfection of the ACE vector into the heart did not result in systemic effects such as increased blood pressure, heart rate, or serum ACE activity. In summary, we have demonstrated that increased autocrine/paracrine angiotensin can directly cause cardiac hypertrophy independent of systemic factors and hemodynamic effects. This approach has important potentials for defining the role of autocrine/paracrine substances in cardiovascular disease.     

腺苷A1受体激动剂2-氯化腺苷抑制异丙肾上腺素诱导大鼠心肌肥厚的作用及机制

目的通过观察腺苷A1受体激动剂2-氯化腺苷(2-CADO)对异丙肾上腺素所致大鼠心肌肥厚的抑制作用及能量代谢的改变,探讨腺苷A1受体激动剂对肥厚心肌能量代谢的调节作用及其可能的作用机制。方法大剂量异丙肾上腺素皮下注射建立大鼠心肌肥厚模型。SD大鼠40只,雌雄不限,分为空白对照组、肥厚模型组、2-CADO组[2-氯化腺苷0.6 mg/(kg.d)腹腔注射]、普萘洛尔组[28 mg/(kg.d)普萘洛尔灌胃],每组10只。造模完毕第2天给药,连续8周。检测大鼠全心质量指数(HMI)、左心质量指数(LVMI);取左心室组织进行Masson染色,观察细胞横径(TDM)改变;碱水解法进行羟脯氨酸(Hyp)含量测定;紫外分光光度法检测心肌组织乳酸(LA)和游离脂肪酸(FFA)含量;激光共聚焦显微镜定量检测线粒体膜电位(MMP)。结果与空白对照组相比,肥厚模型组HMI、LVMI显著上升,心肌组织形态发生肥厚样改变;Hyp、LA和FFA含量显著升高,MMP下降了44%。与肥厚模型组相比,2-CADO组HMI、LVMI下降,TDM明显降低,Hyp、LA和FFA含量显著降低,MMP上升了50%。结论 2-CADO可以抑制异丙肾上腺素导致的心肌肥厚,其机制可能与改善肥厚心肌的能量代谢有关。     

Regulation of angiotensinogen gene expression and protein in neonatal rat cardiac fibroblasts by glucocorticoid and beta-adrenergic stimulation

We previously demonstrated the presence of components for a renin-angiotensin system in fibroblasts cultured from neonatal rat ventricles, the regulation of expression of which has not been studied. Since glucocorticoids and beta-adrenergic stimuli have been implicated in cardiac hypertrophy, and function as regulators of the circulating renin-angiotensin system, we examined the effects of dexamethasone and isoproterenol on angiotensinogen mRNA levels and protein secretion in cultured neonatal rat cardiac fibroblasts. Treatment of cardiac fibroblasts for 8 h with 10 micromol/l isoproterenol or 100 nmol/l dexamethasone increased angiotensinogen mRNA levels by 246 +/- 7% and 1406 +/- 207%, respectively. Over 24 h, dexamethasone and isoproterenol increased angiotensinogen secretion by 148 +/- 32% and 123 +/- 26%, respectively. Angiotensin II, which has been reported to be a positive regulator of angiotensinogen synthesis and secretion in liver, markedly attenuated the effects of dexamethasone and isoproterenol on angiotensinogen mRNA expression and secretion. In the presence of 1 micromol/l angiotensin II, the stimulation in angiotensinogen secretion observed with dexamethasone and isoproterenol was decreased by 62% and 76%, respectively. The negative feedback of angiotensin II on angiotensinogen expression was primarily mediated through the type one angiotensin II (AT1) receptor (IC50 = 0.30 +/- 0.02 nmol/l). In summary, results from this study demonstrate that angiotensinogen mRNA levels and protein secretion in cardiac fibroblasts are positively regulated by glucocorticoid and beta-adrenergic stimulation. In addition, angiotensinogen production by cardiac fibroblasts is under negative feedback control of angiotensin II.     

Effects of sulfinpyrazone, aspirin and propranolol on the isoproterenol-induced myocardial necrosis

Prophylactic effects of sulfinpyrazone (100 mg/Kg), aspirin (5 mg/Kg, 50 mg/Kg), and propranolol (2 mg/Kg, 10 mg/Kg) on myocardial necrosis and hypertrophy induced by isoproterenol were examined. Drugs were administered to rats daily by gavage for a period of 2 weeks and after that isoproterenol (40 mg/Kg) was injected subcutaneously. The control group received gavage of water and isoproterenol injection. The "no infarct" group received gavage of water and saline injection. Premedication of sulfinpyrazone and propranolol significantly preserved myocardial CK activity and decreased cardiac hypertrophy compared with control group (24 hours after isoproterenol injection) while aspirin did not have such effects. Myocardial cyclic AMP concentration significantly increased 30 min after isoproterenol injection in control and all the premedicated rats compared with the "no infarct" rats. The increment of cyclic AMP was not suppressed by sulfinpyrazone and propranolol during this period. Plasma levels of prostaglandins were significantly suppressed by the administration of sulfinpyrazone and 50 mg/Kg of aspirin, and were not suppressed by 5 mg/Kg of aspirin. It was concluded that premedication of sulfinpyrazone and propranolol reduce cardiac necrosis and hypertrophy induced by isoproterenol, but aspirin did not have such cardioprotective effects.     

Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model

Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dtmax were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A1 agonist N6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A1 receptor-mediated mechanisms.     

Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7)

Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin-angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart.     

Cardiac consequences of primary hyperaldosteronism

The activation of the renin-angiotensin system is associated with vascular and cardiac hypertrophy. But there are few data on the renal and cardiac consequences of the hypersecretion of aldosterone. In the experimental setting, hyperaldosteronism leads to an excess of fibrous interstitial tissue and cardiac hypertrophy. In man, these consequences are those of hyperaldosteronism. The aim of this study was to assess the cardiac consequences of hyperaldosteronism in a series of 31 patients with a documented Conn adenoma, in comparison with a matched population of 31 patients with primary hypertension. For the same level of blood pressure, cardiac hypertrophy is more prominent in hyperaldosteronism and there is a positive correlation between the level of plasma aldosterone and left ventricular wall thickness. Left ventricular hypertrophy is of the concentric type. In addition, an increase in myocardial fibrosis (that can now be quantified by echocardiography) is observed, with a positive correlation between plasma aldosterone and reflected ultrasound which might correspond to increased myocardial collagen. These anatomic modifications of myocardial structure result in diastolic dysfunction. Overall, Conn adenoma is associated in accelerated disease, which is partly independent of the level of blood pressure.     

Hypertrophy and function of the left heart ventricle in hypertension]

Left ventricular hypertrophy in arterial hypertension occurs in over 50% of patients. The detection of such high incidence has been facilitated by the introduction of echocardiography into diagnostic studies. Both earlier electrocardiographic findings and later echocardiographic results show that cardiac hypertrophy leads to an increased mortality and predisposes to cardiac arrhythmias, ischemic heart disease including myocardial infarction and heart failure. The development of hypertrophy is mediated by hemodynamic factors such as elevated blood pressure due to increased peripheral vascular resistance, ejection fraction, increased cardiac output, blood viscosity, as well as by non-hemodynamic factors. Of the latter ones the contribution of a genetic factor is discussed, whereas the role of para- and autocrine cardiac function manifested by local production and action of catecholamines as well as the renin-angiotensin system has been proved. Blockade of these systems makes possible prevention of the development of cardiac hypertrophy or its regression. Such results have been obtained both in experimental studies and in humans with hypertension treated with selected drugs. Regression of hypertrophy is accompanied by an improvement in systolic and especially diastolic cardiac function, the impairment of which is usually diagnosed prior to the detection of hypertrophy. The improvement in cardiac function and possibility of preventing consequences of hypertrophy help us to evaluate the efficacy of hypotensive drugs and their preferential use in this regard. There are also changes in recently recommended models of pharmacological treatment in arterial hypertension.     

The renin-angiotensin system in left ventricular remodeling

Left ventricular remodeling is a dynamic process that occurs in reaction to an insult to the myocardium. The response to either loss of cells, as may occur following myocardial infarction, or to hemodynamic overload, as may occur in aortic stenosis, is an attempt to maintain cardiac output and normalize wall tension. This is accomplished through the activation of the renin-angiotensin system and hypertrophy of noninfarcted segments of the myocardium. In the case of moderate or large infarctions these mechanisms fail to normalize wall stress. The stimulus to further remodeling remains, viable myocytes hypertrophy (with greater increases in cell length than width), the mass-to-volume ratio increases, and an exponential increase in wall stress results. This increase in myocyte tension has been associated with premature myocyte cell death. Thus, a vicious cycle is established wherein overstretch of the myocardium while sustaining cardiac output leads to progressive myocyte loss and left ventricular dilation. The renin-angiotensin system plays an integral role in this process. Its inhibition by angiotensin-converting enzyme (ACE) inhibitors both chronically and immediately after myocardial infarction has been shown to decrease left ventricular volumes and reduce mortality. Controversy exists regarding the mechanism through which ACE inhibitors exert their effects. ACE inhibitors reduce after-load/preload, circulating angiotensin II levels, and raise circulating levels of bradykinin. It is not yet clear which mechanism is responsible for the greatest impact on left ventricular dilation and mortality. Inhibition of the renin-angiotensin system is clearly beneficial to cardiac performance as well as morbidity and mortality when myocardium is lost and heart failure ensues. Specific modes of action require further definition, including local and systemic effects. Possible benefits of angiotensin receptor blockade versus augmentation of bradykinin requires definition, setting the stage for further study, while the beneficial therapeutic use of these agents continues.     

Altered myocardial contractility and energetics in hypertrophied myocardium

Alterations of myocardial contractility and energetics were examined in cardiac hypertrophy induced by different types of cardiac overload. Myocardial contractility was estimated by isometric contraction of isolated left ventricular papillary muscles. Myocardial energetics were assessed from ventricular myosin isoenzyme patterns obtained by pyrophosphate gel electrophoresis. Cardiac hypertrophy was induced by endurance swim-training and sustained pressure-overload by abdominal aortic constriction or volume-overload created by an arteriovenous shunt. In swim-trained hypertrophied myocardium, isometric developed tension (T) and dT/dtmax showed a tendency to increase and response of dT/dtmax to isoproterenol increased significantly as compared with sedentary rats. Training shifted the left ventricular myosin isoenzyme pattern toward VM-1, which has the highest ATPase activity. In pressure- or volume-overloaded myocardium, dT/dtmax decreased significantly and mechanical response to isoproterenol also decreased (or tended to decrease in volume-overloaded hearts) as compared with the respective sham-operated controls. In pressure- or volume-overloaded hearts, left ventricular myosin isoenzyme pattern shifted toward VM-3, which has the lowest ATPase activity. These results indicate that alterations in myocardial contractility, mechanical catecholamine responsiveness and myocardial energetics in hypertrophied myocardium do not always display the same trend, but are greatly influenced by the causes or duration of cardiac overload.     

Myocardial enzymatic activity of renin and cathepsin D before and after bilateral nephrectomy

A local renin-angiotensin system is present within the myocardium and can play a role in the initiation and maintenance of cardiac hypertrophy. The source of myocardial renin may be direct cardiac renin gene expression, or plasma renin of renal origin. A primary indication that myocardial renin is derived from plasma renin of renal origin was from work showing that cardiac renin activity was no longer detected 30 hours after bilateral nephrectomy (BNX). However, more recent studies have been able to detect myocardial renin after BNX. We measured normal rat cardiac renin before and after 48-hour BNX using a myocardial renin assay with improved sensitivity. The myocardial renin assay was also used to assess normal rat cardiac myocyte renin levels. Since cardiac tissue contains cathepsin D, a lysosomal enzyme capable of renin-like activity, a rat cathepsin D assay was also developed to assess cathepsin D contribution to renin-like activity. Several artifacts were shown to contribute to myocardial renin-like enzymatic activity levels after BNX, including initial plasma renin stimulation during BNX surgery, assay pH, and cardiac cathepsin D activity. Myocardial renin concentration after 48-BNX was found to be only ∼1 % of normal control levels, and renin concentration in normal cardiac myocytes was only 2-fold greater than assay blanks. Both results were probably overestimated due to cathepsin D contamination. In conclusion, no evidence was found for myocardial renin synthesis in the normal adult rat heart, and myocardial renin decays to near zero levels after 48-hour BNX. Received: 5 March 2001, Returned for revision: 12 March 2001, Revision received: 9 April 2001, Accepted: 10 April 2001     

Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice

Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout (KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-beta1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.     

Left ventricular adaptation to hypertension and plasma renin activity

Chronic pressure and volume overload result in morphologically and functionally distinct forms of myocardial hypertrophy. In essential hypertension, the respective effect of these factors on the morphology of the left ventricle remains unknown. In the present study, we hypothesised that activity of the renin angiotensin system (assessed by plasma renin activity) may be associated to the variability of the left ventricular adaptation to essential hypertension. To assess this relation, we categorised by echocardiography 333 never-treated hypertensive patients, according to values of left ventricular mass and relative wall thickness. Higher systolic and pulse arterial pressure was strongly associated with concentric left ventricular hypertrophy (27% of hypertensives). When compared to the normal left ventricle group, patients with eccentric left ventricular hypertrophy (15% of hypertensives) had a high cardiac index (5 +/- 1 vs 4 +/- 0.8 L/min/m2; P = 0.0001), a lower basal plasma renin activity (0.81 +/- 0.63 vs 1.45 +/- 1.3 ng/ml/h; P = 0.02) and similar mean values of left ventricular performance and glomerular filtration rate. A tendency for depressed myocardial contractility assessed by the midwall shortening/end-systolic stress was associated with concentric left ventricular remodelling and hypertrophy when compared to hypertensive with a normal left ventricle. In conclusion, at the early phase of essential hypertension, in patients without renal dysfunction, each anatomic pattern of cardiac adaptation to hypertension was associated with a distinct profile of haemodynamics, myocardial function and activity of the renin-angiotensin system. Journal of Human Hypertension (2000) 14, 181-188.