Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats.

Abstract

The long-term administration of N -nitro-L -arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, produces coronary vascular remodeling and myocardial hypertrophy in animals. This study used a rat model to investigate the role of angiotensin I converting enzyme (ACE) in the pathogenesis of such changes. We studied the following groups, all of which received drug treatment in their drinking water: untreated controls, and those administered L-NAME, L-NAME, and an ACE inhibitor (ACEI), and L-NAME and hydralazine. Cardiovascular structural changes and tissue ACE activities were evaluated after the first, fourth, and eighth week of treatment. In rats treated with L-NAME alone, vascular remodeling was evident at the fourth and eighth week, and myocardial hypertrophy was present at the eighth week of treatment. The vascular and myocardial remodeling were characterized by increased tissue ACE activities and immunodetectable ACE in those tissues. These changes were markedly reduced by ACEI, but not by hydralazine treatment.

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

“…4,5 The structural changes consistently observed after long-term NOS inhibition include vascular hypertrophy and adventitial collagen deposition. 6 A number of factors may contribute to this pathology, including increased local vascular expression of ACE, 6 endothelin production, 7 and the induction of type I collagen expression. 8 Conversely, ACE inhibition and endothelin antagonists have been shown to prevent hypertension and perivascular fibrosis in L-NAMEtreated animals.…”

“…8 Conversely, ACE inhibition and endothelin antagonists have been shown to prevent hypertension and perivascular fibrosis in L-NAMEtreated animals. 6,8 Aside from the well-defined roles that endothelial NO plays in regulating vascular tone and structure, it has also been reported that NO suppresses plasminogen activator inhibitor-1 (PAI-1) expression in vascular tissue. 9 It was recently reported that long-term NOS inhibition induced vascular PAI-1 expression in rat models.…”

Effects of taxifolin on the activity of angiotensin-converting enzyme and reactive oxygen and nitrogen species in the aorta of aging rats and rats treated with the nitric oxide synthase inhibitor and dexamethasone

“…These data on the ability of taxifolin to bring the ACE activity to the normal level have been obtained for the first time; however, it is possible to compare them with the influence of flavonoids on other manifestations of age-related vessel pathology or pathology caused by the NO synthase inhibitor or glucocorticoid hormones. As known, vessel remodeling in rats enhances with aging (Basso et al 2007) and as a result of the effect of the NO synthase inhibitor (Takemoto et al 1997;Katoh et al 2001). In these cases, pathological changes in vessels are caused by enhanced ACE activity because ACE inhibitors prevent vessel remodeling (Takemoto et al 1997;Katoh et al 2001;Basso et al 2007).…”

“…As known, vessel remodeling in rats enhances with aging (Basso et al 2007) and as a result of the effect of the NO synthase inhibitor (Takemoto et al 1997;Katoh et al 2001). In these cases, pathological changes in vessels are caused by enhanced ACE activity because ACE inhibitors prevent vessel remodeling (Takemoto et al 1997;Katoh et al 2001;Basso et al 2007). Glucocorticoid hormones also increase the ACE activity in the aorta ), blood pressure (Saruta 1996), and the risk of CVD (Nashel 1986;Souverein et al 2004).…”

“…Both types of cells contain a significant amount of active (intranuclear) 5-lipoxygenase (Mehrabian and Allayee 2003). The increase in the contribution of NADPH oxidase is caused by its activation by angiotensin II (Griendling et al 1994;Rajagopalan et al 1996;Landmesser et al 2002), the concentration of which rises upon treatment of rats with L-NAME because of the increase in the ACE activity (Takemoto et al 1997;Korystova et al 2012). There are data showing that the activation of NADPH oxidase with angiotensin II depends on 5-lipoxygenase: angiotensin II activates 5-lipoxygenase and LTB4, a product of 5-lipoxygenase, activates NADPH oxidase (Luchtefeld et al 2003).…”