Efficacy of carvedilol in reversing hypertension induced by chronic intermittent hypoxia in rats

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Abstract

Animal models of chronic intermittent hypoxia (CIH) mimic the hypertension observed in patients with obstructive sleep apnoea. Antihypertensive drugs were applied to these animal models to address the physiological mechanism but not to revert established hypertension. We aimed to investigate the efficacy of carvedilol (CVDL), an unselective beta-blocker that exhibits intrinsic anti-alpha 1-adrenergic and antioxidant activities in a rat model of CIH-induced hypertension. The variability of CVDL enantiomers in plasma concentrations was also evaluated. Wistar rats with indwelling blood pressure telemeters were exposed during their sleep period to 5.6 CIH cycles/h, 10.5 h/day, for 60 days. CVDL was administered by gavage beginning on Day 36 of the CIH period and was continued for 25 days. R-(+)-CVDL and S-(-)-CVDL plasma concentrations were monitored by HPLC. CIH significantly increased diastolic and systolic blood pressure by 25.7 and 21.6 mm Hg respectively, while no effect was observed on the heart rate (HR). CVDL administration at 10, 30 and 50 mg/kg/day promoted a significant reduction in HR but did not affect arterial pressure. The S/(R+S) ratio of CVDL enantiomers was lower in rats exposed to CIH. The blockade of the sympathetic nervous system together with the putative pleiotropic effects of CVDL did not alter the CIH-induced hypertension. Although OH induced pharmacokinetic changes in the R/(R+S) ratio, these effects do not appear to be responsible for the inability of CVDL to reverse this particular type of hypertension. (C) 2015 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)58-67
JournalEuropean Journal Of Pharmacology
Volume765
Issue numberNA
DOIs
Publication statusPublished - 15 Oct 2015

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Hypertension
Blood Pressure
Animal Models
Heart Rate
carvedilol
Hypoxia
Sympathetic Nervous System
Obstructive Sleep Apnea
Adrenergic Agents
Antihypertensive Agents
Wistar Rats
Arterial Pressure
Sleep
Pharmacokinetics
Antioxidants
High Pressure Liquid Chromatography

Keywords

  • Antihypertensive drugs
  • Beta-blockers
  • Carvedilol
  • Chronic intermittent hypoxia
  • Telemetry

Cite this

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title = "Efficacy of carvedilol in reversing hypertension induced by chronic intermittent hypoxia in rats",
abstract = "Animal models of chronic intermittent hypoxia (CIH) mimic the hypertension observed in patients with obstructive sleep apnoea. Antihypertensive drugs were applied to these animal models to address the physiological mechanism but not to revert established hypertension. We aimed to investigate the efficacy of carvedilol (CVDL), an unselective beta-blocker that exhibits intrinsic anti-alpha 1-adrenergic and antioxidant activities in a rat model of CIH-induced hypertension. The variability of CVDL enantiomers in plasma concentrations was also evaluated. Wistar rats with indwelling blood pressure telemeters were exposed during their sleep period to 5.6 CIH cycles/h, 10.5 h/day, for 60 days. CVDL was administered by gavage beginning on Day 36 of the CIH period and was continued for 25 days. R-(+)-CVDL and S-(-)-CVDL plasma concentrations were monitored by HPLC. CIH significantly increased diastolic and systolic blood pressure by 25.7 and 21.6 mm Hg respectively, while no effect was observed on the heart rate (HR). CVDL administration at 10, 30 and 50 mg/kg/day promoted a significant reduction in HR but did not affect arterial pressure. The S/(R+S) ratio of CVDL enantiomers was lower in rats exposed to CIH. The blockade of the sympathetic nervous system together with the putative pleiotropic effects of CVDL did not alter the CIH-induced hypertension. Although OH induced pharmacokinetic changes in the R/(R+S) ratio, these effects do not appear to be responsible for the inability of CVDL to reverse this particular type of hypertension. (C) 2015 Elsevier B.V. All rights reserved.",
keywords = "Beta-blockers, BAROREFLEX, NITRIC-OXIDE, FOSB/DELTA-FOSB, Carvedilol, RECOMMENDATIONS, ENDOTHELIN, OBSTRUCTIVE SLEEP-APNEA, HEART-RATE, DYSFUNCTION, Antihypertensive drugs, Telemetry, BLOOD-PRESSURE, Chronic intermittent hypoxia, MECHANISMS, Antihypertensive drugs, Beta-blockers, Carvedilol, Chronic intermittent hypoxia, Telemetry",
author = "Diogo, {Luc{\'i}lia N} and Pereira, {Sofia A.} and Nunes, {Ana R.} and Afonso, {Ricardo A.} and Santos, {Ana I.} and Monteiro, {Maria Em{\'i}lia Carreira Saraiva}",
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TY - JOUR

T1 - Efficacy of carvedilol in reversing hypertension induced by chronic intermittent hypoxia in rats

AU - Diogo, Lucília N

AU - Pereira, Sofia A.

AU - Nunes, Ana R.

AU - Afonso, Ricardo A.

AU - Santos, Ana I.

AU - Monteiro, Maria Emília Carreira Saraiva

N1 - PMID: 26291659 WOS:000364249100008

PY - 2015/10/15

Y1 - 2015/10/15

N2 - Animal models of chronic intermittent hypoxia (CIH) mimic the hypertension observed in patients with obstructive sleep apnoea. Antihypertensive drugs were applied to these animal models to address the physiological mechanism but not to revert established hypertension. We aimed to investigate the efficacy of carvedilol (CVDL), an unselective beta-blocker that exhibits intrinsic anti-alpha 1-adrenergic and antioxidant activities in a rat model of CIH-induced hypertension. The variability of CVDL enantiomers in plasma concentrations was also evaluated. Wistar rats with indwelling blood pressure telemeters were exposed during their sleep period to 5.6 CIH cycles/h, 10.5 h/day, for 60 days. CVDL was administered by gavage beginning on Day 36 of the CIH period and was continued for 25 days. R-(+)-CVDL and S-(-)-CVDL plasma concentrations were monitored by HPLC. CIH significantly increased diastolic and systolic blood pressure by 25.7 and 21.6 mm Hg respectively, while no effect was observed on the heart rate (HR). CVDL administration at 10, 30 and 50 mg/kg/day promoted a significant reduction in HR but did not affect arterial pressure. The S/(R+S) ratio of CVDL enantiomers was lower in rats exposed to CIH. The blockade of the sympathetic nervous system together with the putative pleiotropic effects of CVDL did not alter the CIH-induced hypertension. Although OH induced pharmacokinetic changes in the R/(R+S) ratio, these effects do not appear to be responsible for the inability of CVDL to reverse this particular type of hypertension. (C) 2015 Elsevier B.V. All rights reserved.

AB - Animal models of chronic intermittent hypoxia (CIH) mimic the hypertension observed in patients with obstructive sleep apnoea. Antihypertensive drugs were applied to these animal models to address the physiological mechanism but not to revert established hypertension. We aimed to investigate the efficacy of carvedilol (CVDL), an unselective beta-blocker that exhibits intrinsic anti-alpha 1-adrenergic and antioxidant activities in a rat model of CIH-induced hypertension. The variability of CVDL enantiomers in plasma concentrations was also evaluated. Wistar rats with indwelling blood pressure telemeters were exposed during their sleep period to 5.6 CIH cycles/h, 10.5 h/day, for 60 days. CVDL was administered by gavage beginning on Day 36 of the CIH period and was continued for 25 days. R-(+)-CVDL and S-(-)-CVDL plasma concentrations were monitored by HPLC. CIH significantly increased diastolic and systolic blood pressure by 25.7 and 21.6 mm Hg respectively, while no effect was observed on the heart rate (HR). CVDL administration at 10, 30 and 50 mg/kg/day promoted a significant reduction in HR but did not affect arterial pressure. The S/(R+S) ratio of CVDL enantiomers was lower in rats exposed to CIH. The blockade of the sympathetic nervous system together with the putative pleiotropic effects of CVDL did not alter the CIH-induced hypertension. Although OH induced pharmacokinetic changes in the R/(R+S) ratio, these effects do not appear to be responsible for the inability of CVDL to reverse this particular type of hypertension. (C) 2015 Elsevier B.V. All rights reserved.

KW - Beta-blockers

KW - BAROREFLEX

KW - NITRIC-OXIDE

KW - FOSB/DELTA-FOSB

KW - Carvedilol

KW - RECOMMENDATIONS

KW - ENDOTHELIN

KW - OBSTRUCTIVE SLEEP-APNEA

KW - HEART-RATE

KW - DYSFUNCTION

KW - Antihypertensive drugs

KW - Telemetry

KW - BLOOD-PRESSURE

KW - Chronic intermittent hypoxia

KW - MECHANISMS

KW - Antihypertensive drugs

KW - Beta-blockers

KW - Carvedilol

KW - Chronic intermittent hypoxia

KW - Telemetry

U2 - 10.1016/j.ejphar.2015.08.019

DO - 10.1016/j.ejphar.2015.08.019

M3 - Article

VL - 765

SP - 58

EP - 67

JO - European Journal Of Pharmacology

JF - European Journal Of Pharmacology

SN - 0014-2999

IS - NA

ER -