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Cardioprotection by ouabain and digoxin in perfused rat hearts
Giuseppina D'Urso1, Sabina Frascarelli, Riccardo Zucchi
1Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Italy.
Abstract:
This work was aimed at determining the cardioprotective effect of digitalis glycosides in rat heart, and to relate it with Na, K-ATPase inhibition and ERK1/2 activation. Isolated working rat hearts were perfused in the presence of ouabain or digoxin, which were used at concentrations ranging from 10 to 10 M. The hearts were then subjected to 30 minutes of global normothermic ischemia followed by 120 minutes of retrograde reperfusion; irreversible tissue injury was determined on the basis of triphenyltetrazolium chloride staining. Significant cardioprotection was observed with 10 M and 10 M ouabain (ischemic injury averaged 7.0 +/- 3.5% and 8.3 +/- 0.6% versus 37.3 +/- 2.0% in controls, P < 0.01 in each case). Hearts treated with digoxin showed decreased ischemic injury at 10 M and 10 M (18.0 +/- 1.5% and 14.2 +/- 1.0%, P < 0.01 versus control in both cases). In parallel experiments, ERK2 phosphorylation was increased by 10 to 10 M ouabain, while ERK1 and ERK2 phosphorylation was increased by 10 to 10 M digoxin. The cardioprotective effect was not related to Na, K-ATPase inhibition, since Rbuptake was not significantly different between control and treated hearts.
Insights
Digitalis glycosides like ouabain and digoxin show cardioprotective effects in rat hearts, reducing injury during ischemia. This protection is linked to ERK1/2 activation, not Na, K-ATPase inhibition.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Biochemistry
Background:
- Digitalis glycosides are known for their effects on cardiac function.
- Their precise mechanisms, particularly regarding cardioprotection and signaling pathways, require further elucidation.
- Investigating the role of Na, K-ATPase and ERK1/2 activation is crucial for understanding their therapeutic potential.
Purpose of the Study:
- To determine the cardioprotective effects of digitalis glycosides (ouabain and digoxin) in an isolated working rat heart model.
- To investigate the relationship between these cardioprotective effects and the inhibition of Na, K-ATPase.
- To examine the activation of extracellular signal-regulated kinases (ERK1/2) by digitalis glycosides.
Main Methods:
- Isolated working rat hearts were perfused with varying concentrations of ouabain or digoxin.
- Hearts underwent global normothermic ischemia followed by reperfusion.
- Irreversible tissue injury was assessed using triphenyltetrazolium chloride staining.
- Na, K-ATPase activity was measured via Rubidium uptake.
- ERK1/2 phosphorylation levels were analyzed.
Main Results:
- Both ouabain and digoxin demonstrated significant cardioprotection, reducing ischemic injury in a dose-dependent manner.
- Ouabain (10-10 M) and digoxin (10-10 M) significantly decreased irreversible tissue injury compared to controls.
- Ouabain increased ERK2 phosphorylation, while digoxin increased both ERK1 and ERK2 phosphorylation.
- No significant difference in Na, K-ATPase inhibition (Rubidium uptake) was observed between control and treated groups.
Conclusions:
- Digitalis glycosides exhibit significant cardioprotective effects against ischemia-reperfusion injury in rat hearts.
- The cardioprotection is associated with ERK1/2 pathway activation.
- The observed cardioprotective effects are independent of Na, K-ATPase inhibition.
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