Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats

Nagano, Masahiro; Higaki, Jitsuo; Mikami, Hiroshi; Nakamaru, Mitsuaki; Higashimori, Koichi; Katahira, Katsutoshi; Tabuchi, Yoshikatsu; Moriguchi, Atsushi; Nakamura, Fumiaki; Ogihara, Toshio

doi:10.1097/00004872-199107000-00003

Cited by 97 publications

(48 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly, plasma Ang II concentrations were previously reported to be significantly increased by enalapril 28,29 and imidapril, 30 despite reductions in systolic blood pressure, left ventricular weight and left ventricular Ang II concentration. 31 The mechanism underlying these findings remains unclear, but one possible explanation is the presence of an ACE-independent pathway for Ang II production, which may be activated during pharmacological ACE inhibition; for example, chymase is reportedly activated by captopril treatment. 27 Another mechanism that could be involved in the imidapril-induced reduction in blood pressure is ACE inhibitor-mediated activation of ACE2, leading to increases in Ang (1-7) levels.…”

Section: Discussionmentioning

confidence: 99%

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

et al. 2011

View full text Add to dashboard Cite

It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg À1 per day losartan, an angiotensin receptor blocker, or with 20 mg kg À1 per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

et al. 2011

View full text Add to dashboard Cite

show abstract

“…10 In particular, the effect of ACE inhibitors in reducing cardiac hypertrophy in some rat models of hypertension correlates better with the reduction of local angiotensin II levels than the reduction of systemic pressure or plasma angiotensin II. 24 Also, in vitro studies have suggested that angiotensin II stimulates cardiomyocyte growth and proliferation of cardiac fibroblasts. 25,26 To investigate the functional role of angiotensin II produced within the heart, transgenic mice models were made that overexpressed components of the RAS within this organ.…”

Section: Discussionmentioning

confidence: 99%

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

232

191

View full text Add to dashboard Cite

To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

show abstract

“…23 In fact, a close correlation has been reported in experimental animals between LVH and myocardial levels of A II. 24 In addition to its direct action of stimulating protein synthesis and cell proliferation, A II has also been shown to release other growth factors from smooth-muscle cells and blood cells, such as the platelet-derived growth factor. Furthermore, it enhances peripheral sympathetic activity and exerts a permissive action on the release of noradrenaline, 25 which possesses trophic properties of its own and promotes myocardial cell growth and hypertrophy.…”

Section: Left-ventricular Hypertrophymentioning

confidence: 99%

Angiotensin II as a cardiovascular risk factor

Gavras

2002

J Hum Hypertens

View full text Add to dashboard Cite

A renin-angiotensin level that is inappropriately high for the systemic blood pressure and the state of sodium balance is now recognized to be one of the modifiable cardiovascular risk factors. Angiotensin acts both as a circulating hormone and as a locally acting paracrine/autocrine/intracrine factor. The adverse effects of angiotensin on the heart include the mechanical results of elevated resistance to the pumping function of the myocardium, as well as the effects of neurohumoral abnormalities on various cardiac structures. In addition, cardiac damage follows acute ischaemic injury or chronic energy starvation due to coronary artery disease, attributable to either mechanical obstruction Keywords: angiotensin II; renin-angiotensin system; cardiovascular disease; myocardial infarction Myocardial ischaemiaAngiotensin II (A II) is one of the major systemic pressor hormones (others include noradrenaline, vasopressin and endothelin). The idea that excessive levels of circulating A II can cause myocardial infarctions originated from an early experiment in which exogenous infusion of A II produced widespread areas of myocardial necrosis in rabbits. 1 Clinical observations in patients subjected to extreme stimulation of the renin-angiotensin system during haemodialysis revealed that these patients were prone to coronary death. This was attributed to intense coronary vasoconstriction, because focal myocardial necrosis was described in areas with no detectable coronary obstructive lesions. 2 These experiments were later replicated and amplified by other investigators. 3,4 It was found that an excess of endogenous or exogenous A II can damage the myocardium via several additional mechanisms, such as increased sarcolemmic permeability and death of cardiac myocytes, or increased permeability and destruction of coronary microvascular endothelial cells. All these eventually lead to the replacement of contractile myocardium by fibrotic tissue.Angiotensin II exerts a preferential pressor action on the coronary, renal, cerebral and adrenal vasculaCorrespondence: H Gavras, Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. E-mail: hgavrasȰbu.edu (atherosclerotic and/or thrombotic) or functional stenosis (vasospasm). Activation of the renin-angiotensin system has several haemodynamic and humoral consequences, all of which may damage the myocardium. These include acute myocardial ischaemia, left-ventricular hypertrophy, arrhythmias, alterations in the coagulation-fibrinolysis equilibrium, increased oxidative stress, and pro-inflammatory activity. A brief review of some of the mechanisms by which activation of the renin-angiotensin system can inflict damage on the heart is presented.

show abstract

Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats

Cited by 97 publications

References 0 publications

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Angiotensin II as a cardiovascular risk factor

Contact Info

Product

Resources

About