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Influence of Intermittent Hypoxia on Myocardial and Hepatic P‐glycoprotein Expression in a Rodent Model
Author(s) -
Dopp John M.,
Moran John J.,
Abel Nicole J.,
Wiegert Nicholas A.,
Cowgill John B.,
Olson E. Burt,
Sims J. Jason
Publication year - 2009
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.29.4.365
Subject(s) - hypoxia (environmental) , intermittent hypoxia , medicine , endocrinology , real time polymerase chain reaction , apnea , obstructive sleep apnea , gene expression , ventricle , reverse transcription polymerase chain reaction , messenger rna , biology , chemistry , gene , biochemistry , organic chemistry , oxygen
Study Objective. Patients with obstructive sleep apnea who receive drug therapy for cardiovascular disease may experience resistant hypertension, arrhythmias, or more severe heart failure, and many of the drugs used to treat these conditions are substrates for P‐glycoprotein (P‐gp) transporters. Therefore, we sought to determine if intermittent hypoxia, which mimics obstructive sleep apnea, would upregulate myocardial and hepatic P‐gp expression and Abcb1a and Abcb1b messenger RNA (mRNA) expression (genes that encode for P‐gp) in an animal model. Design. Prospective, randomized, blinded, parallel‐design animal study. Setting. University research laboratory. Animals. Thirty adult, male Sprague‐Dawley rats. Intervention. Rats were assigned to either 2 weeks of intermittent hypoxia exposure similar to sleep apnea (12 rats) or no hypoxia exposure (controls, 18 rats). Measurements and Main Results. After intermittent hypoxia or normoxia exposure, the rats were anesthetized. Heart and liver were harvested, and small samples were taken from the left ventricle (heart) and the liver for analysis. Expression of P‐gp was measured by Western blotting, whereas Abcb1a and Abcb1b mRNA expression was assessed by real‐time polymerase chain reaction. Band density of myocardial (but not hepatic) P‐gp expression (standardized by β‐actin) was significantly higher in hypoxic rats than in control rats (p=0.03). Quantitative polymerase chain reaction revealed that myocardial and hepatic Abcb1a and myocardial Abcb1b mRNA expression were significantly increased in hypoxic rats compared with controls (p<0.05). Conclusion. Myocardial P‐gp expression and myocardial and hepatic Abcb1a mRNA expression were significantly increased after 2 weeks of intermittent hypoxia. Hypoxia‐induced increases in P‐gp expression may partially explain drug‐resistant cardiovascular disease in patients with obstructive sleep apnea.