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Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration
07:59

Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration

Published on: April 4, 2022

Coadministration of carvedilol attenuates nitrate tolerance by preventing cytochrome p450 depletion

Atsushi Nakahira1, Yukiko Minamiyama, Shigekazu Takemura

  • 1Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Circulation Journal : Official Journal of the Japanese Circulation Society
|June 25, 2010
PubMed
Abstract

Insights

Carvedilol prevents nitroglycerin tolerance by reducing oxidative stress and maintaining NO/cGMP pathway activity. This antioxidant effect, particularly at higher doses, preserves vascular function during long-term nitroglycerin administration.

Area of Science:

  • Pharmacology
  • Cardiovascular Research
  • Biochemistry

Background:

  • Long-term nitroglycerin (NTG) use leads to tolerance, associated with increased reactive oxygen species (ROS) in vasculature.
  • Carvedilol, an adrenergic blocker with antioxidant properties, is known to prevent nitrate tolerance via an unknown mechanism.
  • This study investigates carvedilol's role in attenuating NTG tolerance, focusing on cytochrome P450 (CYP) enzymes.

Purpose of the Study:

  • To elucidate the mechanism by which carvedilol attenuates nitroglycerin (NTG)-induced tolerance.
  • To investigate the role of cytochrome P450 (CYP) enzymes and oxidative stress in carvedilol's protective effects against NTG tolerance.

Main Methods:

  • Male Wistar rats received continuous infusions of NTG alone or with carvedilol (20 or 100 microg/h) for 48 hours.
  • Nitrate tolerance was assessed hemodynamically via NTG bolus injections.
  • Levels of CYP1A1/1A2, superoxide production, and phosphorylated vasodilator-stimulated phosphoprotein (P-VASP) were measured in aortic and cardiac tissues.

Main Results:

  • Coadministration of carvedilol hemodynamically prevented NTG-induced tolerance.
  • NTG alone increased vascular superoxide production, decreased cardiac CYP1A1/1A2 levels, and depleted P-VASP.
  • Carvedilol significantly attenuated these NTG-induced changes, with greater effect at the higher dose (100 microg/h).

Conclusions:

  • Coadministration of carvedilol effectively attenuates nitrate tolerance.
  • Carvedilol maintains NO/cGMP pathway activity by preventing free radical generation and CYP depletion.
  • These findings highlight carvedilol's potential in managing nitrate tolerance.

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