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Angiotensinogen mRNA expression in human tissues was detected not only in the liver, but also in both atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Angiotensinogen was present in the endocardial layer of the human left ventricle, rather than in the epicardial layer, and in the conduction system and right atrium. Furthermore, we found angiotensinogen to be widespread in the left ventricle of diseased hearts. We examined the involvement of collagen in the occurrence and progression of cardiomyopathy. In the early phase of cardiomyopathy, the extracellular matrix of the myocardium is rich in type III collagen, which is similar to immature tissues. In the later phase, the matrix resembles that of hard tissues in which collagen is mainly of type I and is insoluble. We also examined the relationship between angiotensin II and collagen synthesis. Previous studies have demonstrated that myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction in hypertensive cardiac hypertrophy. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats (SHR) was 1.6 fold greater than that in Wistar-Kyoto rats. The responsiveness of collagen production to angiotensin II was significantly enhanced in SHR. This effect was angiotensin receptor specific because it was blocked by the competitive inhibitor. These results indicate angiotensin II may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.

The renin-angiotensin system acts to constrict vessels and enhance renal retention of sodium and water to raise the blood pressure. Angiotensinogen (ang-n) is synthesized in the liver and released into the blood. It is cut by renin, which is produced by the kidneys, and becomes angiotensin I. Angiotensin I is cleaved by angiotensin converting enzyme (ACE) into angiotensin II, which is an active pressor substance. Recently, the presence of cardiac renin-angiotensin system has been reported in some animals [1,2,3] but it has not been investigated fully in the human heart. Angiotensin II appears to be a stimulus for cardiac hypertrophy [4]. In clinical studies, ACE inhibitor has been reported to cause regression of cardiac hypertrophy [5]. Bearing these findings in mind, we studied the presence of ang-n, renin mRNAs and ang-n protein in human autopsy hearts and discussed its relation to cardiac hypertrophy.

Various diseases and clinical settings can induce congestive heart failure (CHF). As such, it is unlikely that a single mechanism can explain the cardiac dysfunction observed in CHF. However, CHF patients (or animals) share several similar features: reduced cardiac contractility, increased sympathetic nerve activity, and activation of several hormonal systems (e.g., renin-angiotensin system, vasopressin, and atrial natriuretic factor) to compensate for the impaired cardiac function. In this setting, cardiac receptor, GTP-binding proteins, and their effector molecules (adenylyl cyclase, phospholipase C, several ion channels) are inevitably exposed to chronically elevated neurohormonal stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and post-receptor signal transducing pathways (1). It is therefore likely that in CHF one or more types of desensitization contributes to a reduction in signal transducing efficiency in order to maintain intracellular homeostasis. To date, several laboratories have reported a decrease in β-adrenergic receptor (βAR) density in CHF patients and model animals (2–4, 5 for review). Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients (6,7) and animal models (8). Although direct evidence for a change in the catalytic protein of adenylyl cyclase has not been available, limited information have suggested a reduced catalytic activity in terminally failing hearts (9). In this study, we have suggested changes of βAR, GTP-binding protein and catalytic protein using two different animal models with an emphasis on defining the kinetics for the desensitization process of adenylyl cyclase system.

In cardiac hypertrophy,collagen accumulation in the myocardial interstitium is associated with hypertrophy of cardiomyocytes [1]. Collagen remodeling causes impaired ventricular compliance,abnormal electrical conduction and impaired oxygenation of the cardio-myocytes [2].At present,factors that regulate cardiac collagen metabolism are not elucidated.Eghbali et al [3] found that cardiac fibroblasts are mainly responsible for the synthesis of fibrillar type I and III co11agen.Recent studies have demonstrated that angiotensin II (A II),in addition to its inotropic and chronotropic actions,may exert effects by acting as a growth factor in the car¬diovascular system and that there may be local autocrine or paracrine renin-angiotensin system in several tissues [4].There are no data concerning the effects of A II on cardiac nonmyocytes.In this study we examined the effects of A II on collagen synthesis by cardiac fibroblasts in normotensive and hypertensive rats.

Plasma membrane inositol phospholipids were breakdown by hormones and neurotransmitters through the mediation of the specific receptors (1–4). This phosphatidylinositol (PI) turnover pathway generates two second messengers, inositol-(l,4,5)-trisphosphate (IP3) and sn-1,2-diacylglycerol (DAG) (5,6). DAG stimulates membrane-bound phospholipid-dependent, Ca2+- dependent protein kinase C (7), while IP3 releases Ca2+ from stores in the sarcoplasmic reticulum (8,9). The physiological significance of this Pi–turnover pathway is not still clear in any mammalian cell system. It is controversial whether IP3 stimulates Ca2+ release from SR in cardiac myocytes.

It has been demonstrated that components of the renin-angiotensin system such as renin, angiotensinogen (ATN), angiotensin-converting enzyme (ACE) and angiotensin II receptor exist within the heart and function independently from circulating renin-angiotensin system [1–4]. The potent myotropic actions of angiotensin II, as well as its effects on positive inotropism and chronotropism, make it likely that the heart is the site of a locally active renin-angiotensin system. It is suggested that angiotensin II is one of the contributing factors to regulation of cell growth, moreover, ACE inhibitors regress left ventricular hypertrophy. The purpose of this study is to determine whether intrinsic renin-angiotensin system play a role for the development and the regression of left ventricular hypertrophy in spontaneously hypertensive rats (SHR).