Postnatal intermittent hypoxia and developmental programming of hypertension in spontaneously hypertensive rats: the role of reactive oxygen species and L-Ca2+ channels.
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(2+) 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 (187+/-5 mm Hg) as compared with normoxic vehicle treated controls (163+/-2 mm Hg; P<0.001). 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 (159+/-2 mm Hg; P<0.001) and normalized left ventricular wall thickness and systolic function, whereas the treatment with SOD mimetic decreased blood pressure (165+/-2 mm Hg; P<0.001) and reduced left ventricular wall thickness without changes in the systolic function. We conclude that Ca(2+) 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.
Soukhova-O'Hare
Galia K
GK
Kosair Children's Hospital Research Institute, University of Louisville, KY 40202, USA.
Ortines
Roger V
RV
Gu
Yan
Y
Nozdrachev
Alexander D
AD
Prabhu
Sumanth D
SD
Gozal
David
D
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D004452:Echocardiography; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications*; D008054:Lipid Peroxides / Q000032:analysis; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
D000975:Antioxidants; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D008054:Lipid Peroxides; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D017382:Reactive Oxygen Species; D009543:Nifedipine