This Article Full Text Full Text (PDF) All Versions of this Article: 52/1/156    most recent HYPERTENSIONAHA.108.110296v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Soukhova-O'Hare, G. K. Articles by Gozal, D. PubMed PubMed Citation Articles by Soukhova-O'Hare, G. K. Articles by Gozal, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Related Collections Other etiology Animal models of human disease

(Hypertension. 2008;52:156.)
© 2008 American Heart Association, Inc.

Original Articles

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

The Role of Reactive Oxygen Species and L-Ca²⁺ Channels

Galia K. Soukhova-O'Hare; Roger V. Ortines; Yan Gu; Alexander D. Nozdrachev; Sumanth D. Prabhu; David Gozal

From the Kosair Children’s Hospital Research Institute (G.K.S-O., D.G.), Department of Pediatrics, Institute of Molecular Cardiology (R.V.O., Y.G., S.D.P.), Department of Medicine, and Department of Pharmacology and Toxicology (D.G.), University of Louisville, Ky; Department of General Physiology (G.K.S-O., A.D.N.), St Petersburg State University, St Petersburg, Russia; Medical Service (S.D.P.), and the Louisville Veterans’ Affairs Medical Center, Louisville, Ky.

Correspondence to David Gozal, University of Louisville, Department of Pediatrics, KCHRI, 570 S Preston St, Ste 204, Louisville, KY 40202. E-mail david.gozal{at}louisville.edu

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-Ca²⁺ 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% O₂ 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 Ca²⁺ 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 • calcium channels • oxidative stress • sleep apnea • hypertension