Influence of intermittent hypoxia on myocardial and hepatic P-glycoprotein expression in a rodent model.
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.


METHODS
Prospective, randomized, blinded, parallel-design animal study.


METHODS
University research laboratory.


METHODS
Thirty adult, male Sprague-Dawley rats.


METHODS
Rats were assigned to either 2 weeks of intermittent hypoxia exposure similar to sleep apnea (12 rats) or no hypoxia exposure (controls, 18 rats).


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 beta-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).


CONCLUSIONS
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.
Dopp
John M
JM
Schools of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA. jmdopp@pharmacy.wisc.edu
Moran
John J
JJ
Abel
Nicole J
NJ
Wiegert
Nicholas A
NA
Cowgill
John B
JB
Olson
E Burt
EB
Sims
J Jason
JJ