Postnatal Intermittent Hypoxia and Developmental Programming of Hypertension in Spontaneously Hypertensive Rats

Abstract

Abstract-Obstructive and central apneas during sleep are associated with chronic intermittent hypoxia (CIH) and increased cardiovascular morbidity. Spontaneously hypertensive rats exposed to CIH during postnatal days 4 to 30 develop exaggerated hypertension as adults. We hypothesized that reactive oxygen species and altered L-Ca 2ϩ channel activity may underlie the postnatal programming of exaggerated blood pressure and cardiac remodeling. Newborn male spontaneously hypertensive rats were exposed to CIH (10% and 21% O 2 alternating every 90 seconds, 12 h/d, for postnatal days 4 to 30) or normoxia (room air). In each condition, spontaneously hypertensive rats received daily (SC) 1 of 3 treatments: L-calcium channel blocker nifedipine (5 mg/kg), superoxide dismutase mimetic MnTMPyP pentachloride (10 mg/kg), or vehicle (polyethylene glycol). Blood pressure was evaluated monthly for 6 months after birth, and echocardiographic assessments were conducted at 6 months of age. CIH vehicle-treated rats presented higher systolic blood pressure (187Ϯ5 mm Hg) as compared with normoxic vehicle treated controls (163Ϯ2 mm Hg; PϽ0.001). Postnatal CIH elicited marked increases in left ventricular wall thickness in a pattern of concentric hypertrophy with augmented systolic contractility. The treatment with nifedipine in the CIH group attenuated blood pressure (159Ϯ2 mm Hg; PϽ0.001) and normalized left ventricular wall thickness and systolic function, whereas the treatment with SOD mimetic decreased blood pressure (165Ϯ2 mm Hg; PϽ0.001) and reduced left ventricular wall thickness without changes in the systolic function. We conclude that Ca 2ϩ and reactive oxygen species-mediated signaling during intermittent hypoxia are critical mechanisms underlying postnatal programming of an increased severity of hypertension and hypertrophic cardiac remodeling in a genetically susceptible rodent model. Key Words: intermittent hypoxia Ⅲ calcium channels Ⅲ oxidative stress Ⅲ sleep apnea Ⅲ hypertension I ntermittent hypoxia (IH) during sleep is one of the characteristics of sleep apnea that is associated with substantial cardiovascular (CV) morbidity, such as hypertension and heart failure. Sleep-disordered breathing with apneic episodes and intermittent hypoxemia are frequently encountered in young children 1 ; however, the potential consequences of postnatal IH on adult CV dysfunction are not clear. There is accumulating evidence that IH is associated with an increased oxidative stress [2][3][4][5][6] and that redox signaling during this condition has been extensively implicated in CV pathophysiology, including some forms of hypertension and cardiac function. 2,7-9 Perinatal L-arginine and antioxidant supplements were shown to reduce blood pressure (BP) in adult spontaneously hypertensive rats (SHRs), suggesting a critical role of oxidative status during perinatal development in programming BP later in life. 10 In previous work from our laboratory, we demonstrated that SHRs exposed for the first 30 days of postnatal life to a chronic intermitt...

Differences in left ventricular cardiomyocyte loss induced by chronic intermittent hypoxia between spontaneously hypertensive and Wistar–Kyoto rats

“…Moreover, our findings show that when MnTMPyP was injected daily beforehand into SHR exposed to IH for 30 consecutive days, the cardiomyocyte necrosis and loss caused by CIH were significantly reduced. This phenomenon is similar to those found in the other studies that showed treatment with MnTMPyP reduced ROS-triggered cell death [21,27]. Therefore, our findings suggest that cardiomyocyte death due to CIH is mainly caused by an increase in free radicals and a decrease in antioxidant capacity, allowing excess free radicals to cause oxidative damage to cardiomyocytes.…”

“…In each group, WKY and SHR were randomly assigned to two subgroups (n=5 in each subgroup), perfusion with propidium iodide (PI, Sigma, USA) and phosphate-buffered saline (PBS), except the group of IH30 combined with MnTMPyP, which was assigned to perfusion with PI. Rats were given daily intraperitoneal injections of 10 mg/kg MnTMPyP (Sigma; St. Louis, MO, USA) 10 min before daily IH exposure initiation [21]. All surgical and experimental procedures were approved by the Institutional Animal Care and Use Committee of Tzu Chi University.…”

Hypoxia. 4. Hypoxia and ion channel function

“…The mechanisms underlying these responses are unclear, and whether IH alters the activity or function of vascular ion channels has not been rigorously studied. The involvement of L-type VGCCs in IH-induced outcomes in the systemic circulation is indirectly supported by data demonstrating aggravated hypertension in spontaneously hypertensive rats following postnatal exposure to IH and prevention of this result by the L-type VGCC blocker, nifedipine (208). Moreover, indirect and uncomprehensive evidence suggests that exposure of a brain endothelial cell line to IH leads to activation of NSCCs with subsequent involvement of store-operated Ca 2ϩ release mediated by IP 3 R and RyR (232).…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…1). Cyclic polyamine (aza crown ethers)-based SOD mimics were characterized in details in vitro and in vivo (295). Mn salen derivatives were investigated as well (88).…”