What is the clinical evidence from this study?

Study design: RCT. Population: Myocardial reperfusion injury. Intervention: Nifedipine vs. 0.9% saline or vehicle. Primary outcome: Mean systolic shortening (p=<0.01).

What does this research mean for the field?

Intracoronary administration of the calcium channel antagonist nifedipine improves contractile function recovery and prevents ventricular fibrillation in dogs with myocardial reperfusion injury by preventing dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

November 1, 1997Open Access

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

Q: What are the key findings of this study?

Intracoronary nifedipine improved contractile function recovery (17% vs -2%, p<0.01) and prevented ventricular fibrillation (0% vs 50%, p<0.01) in dogs with myocardial reperfusion injury.

Q: What does this research mean for the field?

Intracoronary administration of the calcium channel antagonist nifedipine improves contractile function recovery and prevents ventricular fibrillation in dogs with myocardial reperfusion injury by preventing dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Intracoronary nifedipine improved contractile function recovery (17% vs -2%, p<0.01) and prevented ventricular fibrillation (0% vs 50%, p<0.01) in dogs with myocardial reperfusion injury.

Study Design

Type

RCT

Randomization

randomized

Structured PICO

Does intracoronary nifedipine improve sarcoplasmic reticulum function and contractile recovery in dogs undergoing myocardial ischemia and reperfusion?

Population

Open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion

Intervention

Intracoronary infusion of nifedipine (50 micrograms/min from 2 minutes before to 5 minutes after reperfusion)

Comparator

Intracoronary infusions of 0.9% saline or vehicle

Outcome

Sarcoplasmic reticulum protein content (Ca2+ ATPase, phospholamban, and calsequestrin) and Ca2+ uptake by sarcoplasmic reticulum vesiclessurrogate

In a canine model of ischemia-reperfusion, nifedipine prevented sarcoplasmic reticulum Ca2+ ATPase pump dysfunction and improved contractile recovery.

Main Result

Absolute Event Rate: 17% vs -2%

p-value: p=<0.01

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 micrograms/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.