Injury to the Ca2+ ATPase of the sarcoplasmic reticulum in anesthetized dogs contributes to myocardial reperfusion injury

Steven C. Smart, Kiran B. Sagar, Jo El Schultz, David C. Warltier, Larry R. Jones

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objective: Sarcoplasmic reticulum dysfunction may contribute to calcium (Ca2+) overload during myocardial reperfusion. The aim of this study was to investigate its role in reperfusion injury. Methods: Open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion were randomized to intracoronary infusions of 0.9% saline, vehicle, or the Ca2+ channel antagonist, nifedipine (50 μg/min from 2 minutes before to 5 minutes after reperfusion). After each experiment, transmural myocardial biopsies were removed from ischemic/reperfused and nonischemic myocardium in the beating state and analyzed for (i) sarcoplasmic reticulum protein content (Ca2+ ATPase, phospholamban, and calsequestrin) by immunoblotting and (ii) Ca2+ uptake by sarcoplasmic reticulum vesicles with and without 300 micromolar ryanodine or the Ca2+ ATPase activator, antiphospholamban (2D12) antibody. Results: Contractile function did not recover in controls and vehicle-treated dogs after ischemia and reperfusion (mean systolic shortening, -2 ± 2%), but completely recovered in nifedipine- treated dogs (17 ± 2%, p = NS vs. baseline, p < 0.01 vs. control). Ventricular fibrillation occurred in 50% of controls and vehicle dogs and 0% of nifedipine-treated dogs (p < 0.01). Ca2+ uptake by the sarcoplasmic reticulum vesicles was severely reduced in ischemic/reperfused myocardium of controls and vehicle dogs (p < 0.01 vs. nonischemic). Ryanodine and the 2D12 antibody improved, but did not reverse the low Ca2+ uptake. Protein content was similar in ischemic/reperfused and nonischemic myocardium. In contrast, Ca2+ uptake and the responses to ryanodine and 2D12 antibody were normal in ischemic/reperfused myocardium from nifedipine-treated dogs. Conclusion: Dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump correlates with reperfusion injury. Reactivation of Ca2+ channels at reperfusion contributed to Ca2+ pump dysfunction. Ca2+ pump injury may be a critical event in myocardial reperfusion injury.

Original languageEnglish (US)
Pages (from-to)174-184
Number of pages11
JournalCardiovascular research
Volume36
Issue number2
DOIs
StatePublished - Nov 1 1997

Fingerprint

Myocardial Reperfusion Injury
Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Dogs
Nifedipine
Wounds and Injuries
Ryanodine
Reperfusion
Myocardium
Reperfusion Injury
Antibodies
Calsequestrin
Myocardial Reperfusion
Coronary Occlusion
Ventricular Fibrillation
Immunoblotting
Coronary Vessels
Proteins
Thorax
Ischemia

Keywords

  • Anesthetized
  • Calcium
  • Calcium channel antagonist
  • Dog
  • Intracellular concentration
  • Myocardial ischemia
  • Nifedipine
  • Protein analysis
  • Reperfusion
  • Stunning arrhythmias
  • Ventricular fibrillation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Injury to the Ca2+ ATPase of the sarcoplasmic reticulum in anesthetized dogs contributes to myocardial reperfusion injury. / Smart, Steven C.; Sagar, Kiran B.; Schultz, Jo El; Warltier, David C.; Jones, Larry R.

In: Cardiovascular research, Vol. 36, No. 2, 01.11.1997, p. 174-184.

Research output: Contribution to journalArticle

Smart, Steven C. ; Sagar, Kiran B. ; Schultz, Jo El ; Warltier, David C. ; Jones, Larry R. / Injury to the Ca2+ ATPase of the sarcoplasmic reticulum in anesthetized dogs contributes to myocardial reperfusion injury. In: Cardiovascular research. 1997 ; Vol. 36, No. 2. pp. 174-184.
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abstract = "Objective: Sarcoplasmic reticulum dysfunction may contribute to calcium (Ca2+) overload during myocardial reperfusion. The aim of this study was to investigate its role in reperfusion injury. Methods: Open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion were randomized to intracoronary infusions of 0.9{\%} saline, vehicle, or the Ca2+ channel antagonist, nifedipine (50 μg/min from 2 minutes before to 5 minutes after reperfusion). After each experiment, transmural myocardial biopsies were removed from ischemic/reperfused and nonischemic myocardium in the beating state and analyzed for (i) sarcoplasmic reticulum protein content (Ca2+ ATPase, phospholamban, and calsequestrin) by immunoblotting and (ii) Ca2+ uptake by sarcoplasmic reticulum vesicles with and without 300 micromolar ryanodine or the Ca2+ ATPase activator, antiphospholamban (2D12) antibody. Results: Contractile function did not recover in controls and vehicle-treated dogs after ischemia and reperfusion (mean systolic shortening, -2 ± 2{\%}), but completely recovered in nifedipine- treated dogs (17 ± 2{\%}, p = NS vs. baseline, p < 0.01 vs. control). Ventricular fibrillation occurred in 50{\%} of controls and vehicle dogs and 0{\%} of nifedipine-treated dogs (p < 0.01). Ca2+ uptake by the sarcoplasmic reticulum vesicles was severely reduced in ischemic/reperfused myocardium of controls and vehicle dogs (p < 0.01 vs. nonischemic). Ryanodine and the 2D12 antibody improved, but did not reverse the low Ca2+ uptake. Protein content was similar in ischemic/reperfused and nonischemic myocardium. In contrast, Ca2+ uptake and the responses to ryanodine and 2D12 antibody were normal in ischemic/reperfused myocardium from nifedipine-treated dogs. Conclusion: Dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump correlates with reperfusion injury. Reactivation of Ca2+ channels at reperfusion contributed to Ca2+ pump dysfunction. Ca2+ pump injury may be a critical event in myocardial reperfusion injury.",
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AU - Sagar, Kiran B.

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AU - Warltier, David C.

AU - Jones, Larry R.

PY - 1997/11/1

Y1 - 1997/11/1

N2 - Objective: Sarcoplasmic reticulum dysfunction may contribute to calcium (Ca2+) overload during myocardial reperfusion. The aim of this study was to investigate its role in reperfusion injury. Methods: Open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion were randomized to intracoronary infusions of 0.9% saline, vehicle, or the Ca2+ channel antagonist, nifedipine (50 μg/min from 2 minutes before to 5 minutes after reperfusion). After each experiment, transmural myocardial biopsies were removed from ischemic/reperfused and nonischemic myocardium in the beating state and analyzed for (i) sarcoplasmic reticulum protein content (Ca2+ ATPase, phospholamban, and calsequestrin) by immunoblotting and (ii) Ca2+ uptake by sarcoplasmic reticulum vesicles with and without 300 micromolar ryanodine or the Ca2+ ATPase activator, antiphospholamban (2D12) antibody. Results: Contractile function did not recover in controls and vehicle-treated dogs after ischemia and reperfusion (mean systolic shortening, -2 ± 2%), but completely recovered in nifedipine- treated dogs (17 ± 2%, p = NS vs. baseline, p < 0.01 vs. control). Ventricular fibrillation occurred in 50% of controls and vehicle dogs and 0% of nifedipine-treated dogs (p < 0.01). Ca2+ uptake by the sarcoplasmic reticulum vesicles was severely reduced in ischemic/reperfused myocardium of controls and vehicle dogs (p < 0.01 vs. nonischemic). Ryanodine and the 2D12 antibody improved, but did not reverse the low Ca2+ uptake. Protein content was similar in ischemic/reperfused and nonischemic myocardium. In contrast, Ca2+ uptake and the responses to ryanodine and 2D12 antibody were normal in ischemic/reperfused myocardium from nifedipine-treated dogs. Conclusion: Dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump correlates with reperfusion injury. Reactivation of Ca2+ channels at reperfusion contributed to Ca2+ pump dysfunction. Ca2+ pump injury may be a critical event in myocardial reperfusion injury.

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KW - Stunning arrhythmias

KW - Ventricular fibrillation

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