ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

Abstract

Rakusan K, Chvojkova Z, Oliviero P, Ostadalova I, Kolar F, Chassagne C, Samuel JL, Ostadal B. ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats. Am J Physiol Heart Circ Physiol 292: H1237-H1244, 2007. First published December 1, 2006; doi:10.1152/ajpheart.00965.2006.-Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT1) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT1 receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT1 but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1␣ markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT1 receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.angiotensin II receptors; ischemia-reperfusion; caveolin-1 ADAPTATION TO CHRONIC HYPOXIA increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation in both adult and immature heart. In addition to the protective effect, chronic hypoxia may also induce other adaptive responses, including hypoxic pulmonary hypertension and right ventricular (RV) hypertrophy (22). This is a beneficial adaptation, allowing the RV to cope with an increased afterload and to maintain cardiac output. Although many potential factors have been proposed to play a role in the mechanisms of cardiac adaptation to chronic hypoxia, the available data are not sufficiently conclusive. Moreover, a substantial amount of information concerning the adaptive response was obtained from the adult myocardium, whereas much less is known about this process in the immature heart. However, clinical relevance of the developmental approach is obvious: chronic hypoxia is the main pathophysiological feature of hypoxemic congenital heart disease. Understanding the mechanisms by which these malformations modify the myocardium and how they impact on the adaptive mechanisms during ischemia may provide ins...

Effect of intermittent hypoxia on the cardiac HIF-1/VEGF pathway in experimental type 1 diabetes mellitus

“…Instead, the PI3K/Akt pathway was suggested to be involved in IH-induced cardioprotection in this study. Similarly, Rakusan et al (48) reported VEGF-independent vascularization and cardioprotection induced by IH with the involvement of caveolin-1 and a receptor of angiotensin.…”

Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1–7)

“…It has been previously reported that the high oxidative stress produced in EAC model causing chronic hypoxia and tissue injury [18], [33]. This chronic hypoxia increased the density of angiotensin II type 1receptors [34]. Therefore, EAC model can be considered as a good target for angiotensin II type 1 receptor blockers.…”

“…Therefore, EAC model can be considered as a good target for angiotensin II type 1 receptor blockers. Angiotensin II type 1 receptor blockade is reported to have inhibitory effects on many models of angiogenesis 34–37 and on the growth of microvessels induced by angiotensin II[38].Therefore, angiotensin II type 1 receptor blockers have been considered as an anti-angiogenic therapeutic option [39].…”

Developmental determinants of cardiac sensitivity to hypoxia

“…Moreover, Sasaki et al (2000) demonstrated that exposure of myocytes to an NO donor directly activates mitochondrial K ATP channels. Furthermore, Rakusan et al (2007) have observed that angiotensin II is also involved in the mechanisms of adaptation of the immature heart to CH: the chronic blockade of angiotensin II type 1 receptors by irbesartan surprisingly, in contrast to adults, completely abolished the cardioprotective effect of CH. These observations should be taken into consideration in the treatment of children suffering from cyanotic congenital heart disease.…”