Celiprolol reduces oxidative stress and attenuates left ventricular remodeling induced by hypoxic stress in mice

Abstract

We have previously reported that intermittent hypoxic stress, which is relevant to sleep apnea syndrome (SAS), increases oxidative stress and induces left ventricular (LV) remodeling. Celiprolol, a β1-selective adrenoreceptor blocker, is known to have not only an antihypertensive effect but also an antioxidant effect through releasing nitric oxide. The aim of this study was to examine the hypothesis that celiprolol might ameliorate the LV remodeling induced by intermittent hypoxia through its antioxidant effect. Male C57BL/6J mice (8 weeks old) were exposed to intermittent hypoxia (30 s of 5% oxygen followed by 30 s of 21% oxygen) for 8 h day(-1) during the daytime for 10 consecutive days or were maintained under normoxic conditions. Animals were treated with either celiprolol (100 mg kg(-1) day(-1) by gavage) or vehicle. Hypoxic stress caused fluctuations in blood pressure (BP), an increase in the mean cardiomyocyte diameter, perivascular fibrosis and a decrease in endothelial nitric oxide synthase (eNOS) expression. These changes were associated with increased levels of 4-hydroxy-2-nonenal protein, superoxide, tumor necrosis factor-α mRNA and brain natriuretic peptide mRNA in the LV myocardium. Celiprolol significantly suppressed BP fluctuation, restored eNOS expression and reduced oxidative stress and superoxide production, thus ameliorating hypoxia-induced LV remodeling in mice. These findings suggest that treatment with celiprolol might prevent cardiovascular events in borderline hypertensive patients with SAS.

Cardiovascular protection by ezetimibe and influence on oxidative stress in mice exposed to intermittent hypoxia

“…It has been known that IH increases the levels of various inflammatory factors (Li et al, 2011) and we have reported that the serum levels of TNF-α and IL-6, as well as the phosphorylation of NF-κB were increased (Nishioka et al, 2013;Matsumoto et al, 2009;Yamashita et al, 2007). Increased levels of TNF-α and oxidative stress might promote the activation of NF-κB and the development of cardiac hypertrophy.…”

“…It is known that the prevalence of sleep-related breathing disorders is high in patients with cardiovascular disease and obstructive sleep apnea is common in obese patients with atherosclerosis (Gottlieb et al, 2010). Recently, sleep apnea syndrome has been recognized as an independent risk factor of cardiovascular events, and it has been reported that intermittent hypoxia due to sleep apnea might accelerate cardiac remodeling (Nishioka et al, 2013;Kato R et al, 2014). Although reducing the LDL-cholesterol level may decrease cardiovascular events, there are still residual risks including the complication of sleep apnea syndrome (Kubo et al, 2003;Baigent et al, 2005;Gottlieb et al, 2010).…”

Augmented cardiovascular responses to episodes of repetitive compared with isolated respiratory events in preschool children with sleep-disordered breathing

“…Rodent models of long-term intermittent hypoxia have demonstrated hypertension and increased sympathetic activity (22), increased right ventricular systolic pressure, right ventricular mass, neovascularization of distal pulmonary vessels (23), systemic and pulmonary vascular pressure (24,25), cardiac hypertrophy, and cardiac and perivascular fibrosis (26). Previous studies in children have however not found a strong link between arterial desaturation and elevated HR and BP (27).…”

The polymorphic and contradictory aspects of intermittent hypoxia

“…The outcomes observed by different authors are highly varied and likely depend on the particular IH parameters employed, such as duration, frequency, and severity of hypoxia. With consideration of these factors, long-term IH exposures in murine models showed increased right ventricular systolic pressure, right ventricular mass, neovascularization of distal pulmonary vessels (54), cardiomyocyte diameter (133), systemic and pulmonary vascular pressures (24, 132), interstitial space (33), cardiac hypertrophy, cardiac and perivascular fibrosis (133), inflammation and dysfunction (198), and a decrease in endothelial nitric oxide synthase (eNOS) expression in ventricular and aortic tissues (133,192).…”