Protection of ischemic rat heart by dantrolene, an antagonist of the sarcoplasmic reticulum calcium release channel
| Autor: | Riccardo Zucchi, Gongyuan Yu, Giovanni Ronca, Simonetta Ronca-Testoni |
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| Rok vydání: | 2000 |
| Předmět: |
Inotrope
Male Physiology Ischemia Myocardial Ischemia Hemodynamics Pharmacology Dantrolene Physiology (medical) medicine Animals Rats Wistar Calcium metabolism Chemistry Ryanodine Endoplasmic reticulum Antagonist Heart Ryanodine Receptor Calcium Release Channel medicine.disease Rats Sarcoplasmic Reticulum Verapamil Anesthesia Calcium Cardiology and Cardiovascular Medicine Perfusion medicine.drug |
| Zdroj: | Basic research in cardiology. 95(2) |
| ISSN: | 0300-8428 |
| Popis: | Cytosolic Ca2+ overload plays a major role in the development of irreversible injury during myocardial ischemia. Such overload is due at least in part to the release of Ca2+ from the sarcoplasmic reticulum. Therefore, we investigated whether dantrolene, a blocker of the sarcoplasmic reticulum Ca2+ release channel, may protect from ischemic injury. In binding experiments, we determined the effect of dantrolene on [3H]-ryanodine binding in rat cardiac tissue. In perfusion experiments, isolated rat hearts were perfused for 20 min in the working mode, in the presence of 0-45 microM dantrolene. The hearts were then subjected to 30 min of global ischemia and 120 min of retrograde reperfusion. Tissue injury was evaluated on the basis of triphenyltetrazolium chloride (TTC) staining and LDH release. The binding experiments showed that dantrolene displaced 4 nM [3H]-ryanodine with IC50 of 34 microM. In the perfusion experiments, tissue necrosis (i.e., TTC-negative tissue) averaged 28.3 +/- 1.6% of the ventricular mass under control conditions. Dantrolene was protective at micromolar concentrations: tissue necrosis decreased to 21.4 +/- 1.0% and 8.4 +/- 1.4% with 1 microM and 45 microM dantrolene, respectively (P0.05 and P0.01). Similar results were obtained with regard to LDH release. At low concentrations (up to 4 microM), dantrolene did not produce any significant hemodynamic effect, except for a slight increase in coronary flow, whereas at higher concentration a negative inotropic effect was apparent. In conclusion, dantrolene reduced ischemic injury even at concentrations that did not affect contractile performance. Modulation of sarcoplasmic reticulum Ca2+ release might represent a new cardioprotective strategy. |
| Databáze: | OpenAIRE |
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