Cardiac hypertrophy and cardiac renin-angiotensin system in Dahl rats on high salt intake

OBJECTIVE: On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). METHODS: Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. RESULTS: In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. CONCLUSIONS: These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.     

Network integration of the adrenergic system in cardiac hypertrophy

Adrenergic receptors play a pivotal role in regulating cardiac function in response to a constantly changing environment. Altered alpha and beta adrenergic receptor signaling in vivo is associated with cardiac hypertrophy and failure. This review focuses on the different roles of adrenergic receptors in regulating cardiac function under normal and pathological conditions. Understanding the signaling mechanisms of these receptors in the context of the heart is likely to provide a better therapeutic approach towards treatment of heart failure.     

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.     

Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure

One of the major conceptual advances in our understanding of the pathogenesis of heart failure has been the insight that heart failure may progress as the result of the sustained overexpression of biologically active "neurohormones", such as norepinephrine and angiotensin II, which by virtue of their deleterious effects are sufficient to contribute to disease progression by provoking worsening left ventricular (LV) remodeling and progressive LV dysfunction. Recently, a second class of biologically active molecules, termed cytokines, has also been identified in the setting of heart failure. Analogous to the situation with neurohormones, the overexpression of cytokines is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between proinflammatory cytokines and the adrenergic system have been recognized in the heart for over a decade, the nature of the important interactions between proinflammatory cytokines and the renin-angiotensin system has become apparent only recently. Accordingly, in the present review, we will discuss the evidence which suggests that there is a functionally significant cross-talk between neurohormonal and inflammatory cytokine signaling in cardiac hypertrophy and failure.     

Left ventricular hypertrophy and renin-angiotensin system blockade

The renin-angiotensin system (RAS), an important control system for blood pressure and intravascular volume, also causes left ventricular hypertrophy (LVH) and fibrosis. The main causal mechanism is the increase in blood pressure, which leads to increased left ventricular wall stress; however, aldosterone release from the adrenals and (more controversially) the direct action of angiotensin II on the cardiomyocytes also play a role. Large clinical trials evaluating the blockade of the RAS with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated an ability to prevent progression and induce regression of left ventricular mass, thereby reducing the significant and independent cardiovascular risk conferred by LVH. Regression of left ventricular mass is also achieved by other medication classes, but the RAS blockers have an additional beneficial effect for the same blood pressure reduction, for which the mechanism is not entirely clear. Studies comparing the efficacy of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers to achieve LVH regression have not demonstrated any clear benefit of one class over the other.     

肾上腺素受体在心肌细胞肥大中的作用

目的 :观察 α受体阻滞剂酚妥拉明和 β受体阻滞剂心得安对肾上腺素诱导的心肌细胞肥大的作用。方法 :用培养的新生大鼠心肌细胞 ,测量其表面积和 [3H]-亮氨酸 （[3H]- L eu）的掺入量来判断心肌细胞肥大。结果 :肾上腺素可明显增加心肌细胞表面积和 [3H]- L eu的掺入量 ,α,β受体阻滞剂能阻断肾上腺素增加心肌细胞表面积和 [3H]-L eu掺入量。结论 :α,β受体阻滞剂有减轻肾上腺素诱导心肌细胞肥大的作用。     

Local cardiac renin-angiotensin system: hypertension and cardiac failure

In addition to the effect on arterial pressure, angiotensin II, the effector peptide of the renin-angiotensin system (RAS), exerts mitogenic and growth promoting effects on cardiac myocytes and non-myocytic elements; and both of these effects significantly contribute to the development and progression of hypertensive heart disease (HHD). The traditional concept of the RAS as a systemic, endocrine system has been expanded and the identification of its components in many organs and tissue has been amassed. This paper reviews evidence that supports the concept that the cardiac RAS participate importantly in the development and risk of HHD.     

Reactive oxygen and nitrogen species balance in the determination of thyroid hormones-induced cardiac hypertrophy mediated by renin-angiotensin system

Role of reactive oxygen species (ROS)/nitric oxide (NO) balance and renin-angiotensin system in mediating cardiac hypertrophy in hyperthyroidism was evaluated in an in vivo and in vitro experimental model. Male Wistar rats were divided into four groups: control, thyroid hormone, vitamin E (or Trolox, its hydrosoluble analogue), thyroid hormone+vitamin E. Angiotensin II receptor (AT1/AT2) gene expression, immunocontent of AT1/AT2 receptors, angiotensinogen, NADPH oxidase (Nox2), and nitric oxide synthase isoforms, as well as ROS concentration (hydrogen peroxide and superoxide anion) were quantified in myocardium. Thyroid hormone increased ROS and NO metabolites, iNOS, nNOS and eNOS isoforms and it was accompanied by cardiac hypertrophy. AT1/AT2 expression and the immunocontent of angiotensinogen and Nox2 were enhanced by thyroid hormone. Antioxidants reduced ROS levels, Nox2, AT1/AT2, NOS isoforms and cardiac hypertrophy. In conclusion, ROS/NO balance may play a role in the control of thyroid hormone-induced cardiac hypertrophy mediated by renin-angiotensin system.     

The relationship of the sympathetic nervous system and the renin-angiotensin system in congestive heart failure

Congestive heart failure is a complex clinical syndrome characterized by circulatory and metabolic abnormalities. It has been apparent for more than 25 years that the sympathetic nervous system and the renin-angiotensin-aldosterone system are markedly activated in the late stages of heart failure. These two systems interact to facilitate sympathetic drive and promote salt and water retention. Circumstantial evidence is now accumulating to indicate that excessive sympathetic drive and angiotensin II activity may contribute to the pathophysiology of heart failure. These observations suggest that a dual strategy of modulating sympathetic nervous system activity to the heart while blocking angiotensin II activity may provide a rational therapeutic approach to the treatment of heart failure. Xamoterol, a beta 1 partial agonist, may enhance myocardial contractile force in the steady state, while acting to inhibit excessive sympathetic drive during exercise or severe heart failure. The concomitant use of a converting-enzyme inhibitor would be expected to blunt the detrimental effects of excessive angiotensin II activity. Modulation of adrenergic drive coupled with inhibition of marked angiotensin II activity may be potentially more effective in the treatment of congestive heart failure than either strategy used alone.     

Lack of association among five genetic polymorphisms of the renin-angiotensin system and cardiac hypertrophy in patients with aortic stenosis

BACKGROUND: Patients with aortic stenosis (AS) have left ventricular hypertrophy (LVH). It is thought that LVH in these patients is a consequence of chronic left ventricular pressure overload. However, there is only a poor correlation between the degree of AS and the degree of LVH. Genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) have been considered to trigger the response of the left ventricle to chronic pressure overload and determine the degree of LVH in patients with AS. METHODS: One hundred five consecutive patients with symptomatic AS were examined by echocardiography and left heart catheterization to determine the severity of AS and LVH. Five genetic polymorphisms of the RAAS (ACE, AGTR1, AGT, CMA, CYP11B2) were analyzed in all patients and the results of genetic analysis were correlated to severity of AS and LVH to determine the importance of the polymorphisms for LVH. RESULTS: All tested genotypes were in Hardy-Weinberg equilibrium and allele frequencies were similar to other study populations. There was no correlation between the severity of AS and the severity of LVH. There was no association between the five tested genotypes of the RAAS and the severity of AS (mean gradient and area of the aortic valve) or LVH (LV muscle mass). CONCLUSION: We conclude that LVH in patients with AS is not determined by the tested genetic polymorphisms of the RAAS.     

The intrinsic cardiac nervous system and atrial fibrillation

PURPOSE OF REVIEW: Radiofrequency ablation techniques to cure cardiac arrhythmias have focused on destroying myocardial tissue involved in abnormal excitation or conduction. This review will address recent basic and clinical studies which suggest that targeting autonomic nerves and ganglia on the large vessels and the heart, within the pericardium, can result in cardiac arrhythmia suppression with little, if any, damage to healthy myocardium. RECENT FINDINGS: Basic reports have shown that electrical stimulation of autonomic nerves on the heart itself can facilitate the induction of atrial fibrillation. The initial investigations found that the lowest threshold for inducing atrial fibrillation was at the entrances of the pulmonary veins. Moreover, beta-blockade blunted this response whereas atropine abolished atrial fibrillation inducibility. Subsequent studies found that ganglionated plexi clustered at the pulmonary vein entrances (within fat pads) could be stimulated without atrial excitation. Now, premature beats induced in the pulmonary veins could be converted to atrial fibrillation with a significantly greater propensity than without ganglionated plexi stimulation. Furthermore, ablation of these ganglionated plexi abolished atrial fibrillation inducibility. Clinical studies have been forthcoming clearly implicating these intrinsic cardiac ganglia in clinical atrial fibrillation. SUMMARY: Previous ablation procedures have focused on destroying myocardial sites that participated in the initiation and perpetuation of various tachyarrhythmias. New basic and clinical findings may allow targeting autonomic elements at a few specific sites on the heart that are directly related to arrhythmia formation, thereby reducing extensive damage to healthy myocardium.     

Role of adrenergic receptor system in canine left ventricular hypertrophy

Although sympathetic nervous system and catecholamines have been postulated to play an important role in the development of myocardial hypertrophy, the precise mechanism is still ill-defined. We then developed two experimental canine models; 12 dogs with surgical cardiac denervation by the method of Geis et al, inducing up-regulation of myocardial adrenergic receptors, and 12 dogs with chronic infusion of subhypertensive dose of norepinephrine (NE) at a rate of 0.04 mg/kg/day. After two months, both models induced myocardial hypertrophy, as indicated by significant increases in left ventricular (LV) wall thickness and cell diameter as compared with 14 sham-operated control dogs. Cardiac denervation remarkably depleted myocardial NE contents, while plasma NE remained unchanged. Both alpha-1 and beta receptors were unregulated, Bmax increasing by 90% and 50% respectively. Decrease in myocardial cyclic-AMP content was relatively small as compared with the marked reduction in myocardial NE, probably by the compensatory augmentation of beta receptor system activity. Chronic NE infusion also reduced myocardial NE content possibly due to stimulation of presynaptic alpha-2 receptor inhibiting NE synthesis and release. Number of alpha-1 and beta receptors also increased by 90% and 30% respectively, while myocardial cyclic-AMP content remained unchanged. These observations indicate that neither direct stimulation of NE on the myocardial cell nor increased in cyclic-AMP is the mechanism for cardiac hypertrophy in both models.(ABSTRACT TRUNCATED AT 250 WORDS)