Influence of Intermittent Hypoxia on Myocardial and Hepatic P‐glycoprotein Expression in a Rodent Model

Abstract

Study Objective-The purpose of this study was to determine if intermittent hypoxia that mimics obstructive sleep apnea would upregulate myocardial and hepatic p-glycoprotein protein and Abcb1a/ Abcb1b mRNA expression.Design-Prospective, randomized, blinded, parallel designed animal study Setting-University Research LaboratoryParticipants-Thirty adult, male Sprague-Dawley rats Intervention-We assigned rats to either two weeks of intermittent hypoxia similar to sleep apnea (N=12) or control treatment (N=18) (no hypoxia).Measurements and Main Results-After intermittent hypoxia or normoxia exposure, rats were anesthetized and the heart and liver were harvested and small samples were taken from the left ventricle (heart) and the liver for analysis. P-glycoprotein protein expression was measured by Western blotting, while Abcb1a/Abcb1b mRNA expression (genes that code for P-glycoprotein) was assessed by real-time polymerase chain reaction. Band density of myocardial (but not hepatic) pglycoprotein protein expression (standardized by β-actin) was higher in hypoxic compared to control rats (p=0.03). Quantitative polymerase chain reaction revealed that myocardial and hepatic Abcb1a and myocardial Abcb1b mRNA expression were increased in hypoxic rats compared to controls.Conclusions-Myocardial P-glycoprotein expression and myocardial and hepatic Abcb1a mRNA expression are significantly increased by two weeks of intermittent hypoxia. Hypoxia-induced increases in p-glycoprotein expression may partially explain drug resistant cardiovascular disease in OSA.

Obstructive sleep apnea and cognitive impairment: Addressing the blood–brain barrier

“…Dopp et al demonstrated an increase in Abcb1a mRNA ( Abcb1 is the gene that codes for p-glycoprotein) expression in the heart and liver of mice exposed to 2 wks of cyclical intermittent hypoxia. 119 Gong et al showed cerebral ischemic preconditioning with intermittent hypobaric hypoxia increases glutamate transporter 1 in neurons of the hippocampus of rats. 120 But expression of other transporters is decreased.…”

Influence of different hypoxia types on p-glycoprotein functional activity and expression

“…В эксперименте на 30 половозрелых крысах (две группы из 12 опытных и 18 контрольных животных) с использованием методов Western blotting и ПЦР показано повышение экспрессии Pgp в миокарде, а также увеличение количества миокардиальной и печеночной иРНК гена mdr1a и миокардиальной иРНК гена mdr1b в результате воздействия на жи-вотных интермиттирующей дыхательной гипоксии в течение двух недель [14].…”

“…Данная область представляет собой последовательность нуклеотидов 5'-GCGTG-3', расположенную на рас-стоянии от -49 до -45 пар нуклеотидов от сайта старта транскрипции [12,14].…”

MDR1 will play a key role in pharmacokinetic changes under hypoxia at high altitude and its potential regulatory networks

“…So the expression of MDR1 under hypoxia at high altitude will make a major contribution to absorption, distribution, metabolism, excretion of its substrates. Many previous studies have introduced the changes of the mRNA and protein expression of MDR1 in different tissues under hypoxia (see Table 2; Bush & Li, 2002;Comerford et al, 2002;Ding et al, 2010;Dopp et al, 2009;Fradette et al, 2007;Ho et al, 2003;Lazarowski et al, 2007;Lotz et al, 2007;Maillefert et al, 1996;Marie et al, 1991;Musto et al, 1991;Pirker et al, 1991;Schaich et al, 2005;Wartenberg et al, 2003;Xia et al, 2004;Yamada et al, 2000). But most of the experimental samples are tumor tissues or tumor cells that are pathological anoxia; what we should do in future is to do the research by use normal tissues or cells under hypoxia conditions.…”