P-glycoprotein modulates aldosterone plasma disposition and tissue uptake

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Abstract

Aldosterone plays an important role in the pathophysiology of numerous cardiovascular disorders including heart failure and hypertension. Because aldosterone's actions are primarily mediated by its interaction with an intracellular mineralocorticoid receptor, factors affecting the cellular uptake and distribution of aldosterone may be important determinants of the hormone's activity. P-glycoprotein (P-gp) is an ATP-binding cassette efflux transporter encoded by the ABCB1 (also known as MDR1) gene in humans. P-gp is expressed on the luminal membrane of the capillary endothelial cells of tissues that are targets for aldosterone, including the brain and heart, where it attenuates cellular uptake of substrates. Recent in vitro evidence indicates P-gp transports aldosterone. Therefore, in this study we tested the hypothesis that P-gp modulates the uptake of aldosterone into the brain and heart by comparing the plasma and tissue distribution of [H]-aldosterone in wild-type and P-gp-deficient [mdr1a/1b (-/-)] mice. Compared with wild-type mice, [H]-aldosterone activity in the plasma, brain, and heart was significantly (P < 0.05) higher in the mdr1a/1b (-/-) animals. The area under the plasma or tissue concentration-time curves in the mdr1a/1b (-/-) mice was 2.0, 1.6, and 1.6-fold higher in the brain, heart, and plasma, respectively, than in wild-type controls. Our results demonstrate that P-gp plays an important role in aldosterone plasma disposition and modestly limits its uptake into the brain. The increased exposure of the brain and heart to aldosterone in the absence of P-gp suggests P-gp may play a key role in modulating aldosterone's effects in these organs.

Original languageEnglish (US)
Pages (from-to)55-59
Number of pages5
JournalJournal of Cardiovascular Pharmacology
Volume47
Issue number1
DOIs
StatePublished - Jan 1 2006

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P-Glycoprotein
Aldosterone
Brain
Mineralocorticoid Receptors
ATP-Binding Cassette Transporters
Vascular Endothelium
Tissue Distribution
Endothelial Cells
Heart Failure
Hormones
Hypertension

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

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abstract = "Aldosterone plays an important role in the pathophysiology of numerous cardiovascular disorders including heart failure and hypertension. Because aldosterone's actions are primarily mediated by its interaction with an intracellular mineralocorticoid receptor, factors affecting the cellular uptake and distribution of aldosterone may be important determinants of the hormone's activity. P-glycoprotein (P-gp) is an ATP-binding cassette efflux transporter encoded by the ABCB1 (also known as MDR1) gene in humans. P-gp is expressed on the luminal membrane of the capillary endothelial cells of tissues that are targets for aldosterone, including the brain and heart, where it attenuates cellular uptake of substrates. Recent in vitro evidence indicates P-gp transports aldosterone. Therefore, in this study we tested the hypothesis that P-gp modulates the uptake of aldosterone into the brain and heart by comparing the plasma and tissue distribution of [H]-aldosterone in wild-type and P-gp-deficient [mdr1a/1b (-/-)] mice. Compared with wild-type mice, [H]-aldosterone activity in the plasma, brain, and heart was significantly (P < 0.05) higher in the mdr1a/1b (-/-) animals. The area under the plasma or tissue concentration-time curves in the mdr1a/1b (-/-) mice was 2.0, 1.6, and 1.6-fold higher in the brain, heart, and plasma, respectively, than in wild-type controls. Our results demonstrate that P-gp plays an important role in aldosterone plasma disposition and modestly limits its uptake into the brain. The increased exposure of the brain and heart to aldosterone in the absence of P-gp suggests P-gp may play a key role in modulating aldosterone's effects in these organs.",
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N2 - Aldosterone plays an important role in the pathophysiology of numerous cardiovascular disorders including heart failure and hypertension. Because aldosterone's actions are primarily mediated by its interaction with an intracellular mineralocorticoid receptor, factors affecting the cellular uptake and distribution of aldosterone may be important determinants of the hormone's activity. P-glycoprotein (P-gp) is an ATP-binding cassette efflux transporter encoded by the ABCB1 (also known as MDR1) gene in humans. P-gp is expressed on the luminal membrane of the capillary endothelial cells of tissues that are targets for aldosterone, including the brain and heart, where it attenuates cellular uptake of substrates. Recent in vitro evidence indicates P-gp transports aldosterone. Therefore, in this study we tested the hypothesis that P-gp modulates the uptake of aldosterone into the brain and heart by comparing the plasma and tissue distribution of [H]-aldosterone in wild-type and P-gp-deficient [mdr1a/1b (-/-)] mice. Compared with wild-type mice, [H]-aldosterone activity in the plasma, brain, and heart was significantly (P < 0.05) higher in the mdr1a/1b (-/-) animals. The area under the plasma or tissue concentration-time curves in the mdr1a/1b (-/-) mice was 2.0, 1.6, and 1.6-fold higher in the brain, heart, and plasma, respectively, than in wild-type controls. Our results demonstrate that P-gp plays an important role in aldosterone plasma disposition and modestly limits its uptake into the brain. The increased exposure of the brain and heart to aldosterone in the absence of P-gp suggests P-gp may play a key role in modulating aldosterone's effects in these organs.

AB - Aldosterone plays an important role in the pathophysiology of numerous cardiovascular disorders including heart failure and hypertension. Because aldosterone's actions are primarily mediated by its interaction with an intracellular mineralocorticoid receptor, factors affecting the cellular uptake and distribution of aldosterone may be important determinants of the hormone's activity. P-glycoprotein (P-gp) is an ATP-binding cassette efflux transporter encoded by the ABCB1 (also known as MDR1) gene in humans. P-gp is expressed on the luminal membrane of the capillary endothelial cells of tissues that are targets for aldosterone, including the brain and heart, where it attenuates cellular uptake of substrates. Recent in vitro evidence indicates P-gp transports aldosterone. Therefore, in this study we tested the hypothesis that P-gp modulates the uptake of aldosterone into the brain and heart by comparing the plasma and tissue distribution of [H]-aldosterone in wild-type and P-gp-deficient [mdr1a/1b (-/-)] mice. Compared with wild-type mice, [H]-aldosterone activity in the plasma, brain, and heart was significantly (P < 0.05) higher in the mdr1a/1b (-/-) animals. The area under the plasma or tissue concentration-time curves in the mdr1a/1b (-/-) mice was 2.0, 1.6, and 1.6-fold higher in the brain, heart, and plasma, respectively, than in wild-type controls. Our results demonstrate that P-gp plays an important role in aldosterone plasma disposition and modestly limits its uptake into the brain. The increased exposure of the brain and heart to aldosterone in the absence of P-gp suggests P-gp may play a key role in modulating aldosterone's effects in these organs.

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