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Positive inotropic effect of acetylcysteine in cardiomyopathic Syrian hamsters
M S Finkel1, L Shen, C V Oddis
1Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania.
Insights
Acetylcysteine improved heart muscle function in cardiomyopathic hamsters by acting on the sarcoplasmic reticulum calcium release channel (SRCRC). This suggests a potential mechanism for hibernating myocardium due to chronic ischemia.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- The cardiomyopathic Syrian hamster (CMH) model exhibits chronic myocardial ischemia, potentially linked to sarcoplasmic reticulum calcium release channel (SRCRC) defects.
- Redox state alterations affecting thiol groups may influence SRCRC function and contribute to ischemia.
Purpose of the Study:
- To investigate the inotropic effects of sulfhydryl donors, specifically acetylcysteine (AC), cysteine, and cystine, in CMH.
- To explore the relationship between SRCRC function and chronic ischemia in the CMH model.
Main Methods:
- Isolated papillary muscles from CMH and control (F1B) hamsters were used to assess inotropic responses.
- The effects of AC, cysteine, and cystine on muscle tension and response to stimulation frequency were measured.
- The impact of AC, ryanodine, and verapamil on CMH muscle tension was evaluated.
Main Results:
- Acetylcysteine demonstrated a positive inotropic effect in CMH papillary muscles, unlike cysteine and cystine.
- AC normalized the tension response to stimulation frequency in CMH compared to controls.
- AC, ryanodine, and verapamil abolished the difference in tension between CMH and control muscles.
Conclusions:
- Findings support a defect in the SRCRC in CMH, potentially explaining the observed chronic ischemia.
- This SRCRC defect could be primary or represent a novel mechanism for hibernating myocardium in the context of chronic ischemia.
Abstract:
Several laboratories have provided indirect evidence that the myocardium of the cardiomyopathic Syrian hamster (CMH) is chronically ischemic on the basis of microvascular spasm. We previously reported evidence supporting a defect in the ryanodine-sensitive sarcoplasmic reticulum calcium release channel (SRCRC) in CMH. A relation between alterations in SRCRC and chronic ischemia has not yet been explored. A potential mechanism could be the effects of changes in redox state on thiol groups. Thiol reagents have previously been shown to regulate calcium release from SRCRC. Accordingly, we studied the inotropic effects of the sulfhydryl donors, acetylcysteine (AC), cysteine, and cystine in CMH. AC was a positive inotrope in isolated papillary muscles prepared from CMH, but not F1B controls (F1B) (p < 0.01). No significant differences were noted in inotropic responses to cysteine or cystine. AC blunted the response of CMH > F1B control papillary muscle preparations to stimulation frequency (p < 0.01). The actual tension generated (in mg/mm2) by CMH was no longer different than F1B with addition of AC (10(-3) M), ryanodine (10(-8) M), or verapamil (5 x 10(-7) M). These findings are consistent with a defect in SRCRC in CMH. This defect may be primary or may provide a novel mechanism for hibernating myocardium owing to chronic ischemia.