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Adenosine prevents hyperkalemia-induced calcium loading in cardiac cells: relevance for cardioplegia
A Jovanović1, A E Alekseev, J R López
1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
Insights
Adenosine prevents harmful intracellular calcium (Ca2+) loading in heart cells caused by hyperkalemic solutions. This cardioprotective effect, mediated by protein kinase C, may enhance the use of adenosine in cardiac surgery.
Area of Science:
- Cardiology
- Cell Physiology
- Pharmacology
Background:
- Hyperkalemic cardioplegic solutions arrest the heart but can cause intracellular Ca2+ loading, leading to ventricular dysfunction.
- Adenosine is a potential cardioprotective adjunct to cardioplegia, but its effect on hyperkalemia-induced Ca2+ loading is unknown.
Purpose of the Study:
- To investigate whether adenosine supplementation protects cardiac cells from hyperkalemia-induced Ca2+ loading.
- To elucidate the cellular mechanisms underlying adenosine's potential cardioprotective effects.
Main Methods:
- Isolated guinea pig ventricular cardiomyocytes were loaded with a Ca2+-sensitive fluorescent probe.
- Intracellular Ca2+ concentration was measured using digital epifluorescent microscopy during hyperkalemic challenges with and without adenosine.
Main Results:
- Hyperkalemia significantly increased intracellular Ca2+ concentration (88 to 1,825 nmol/L).
- Adenosine (1 mmol/L) completely prevented this K+-induced Ca2+ loading (remaining at 86 nmol/L).
- Adenosine's effect was abolished by protein kinase C inhibitors but not by an ATP-sensitive K+ channel antagonist.
Conclusions:
- Adenosine effectively prevents hyperkalemia-induced Ca2+ loading in cardiomyocytes.
- This protective effect is cell-autonomous and mediated via a protein kinase C-dependent pathway.
- Adenosine's ability to prevent Ca2+ loading may enhance its efficacy as an adjunct to cardioplegic solutions.
Background:
Hyperkalemic cardioplegic solutions effectively arrest the heart but also induce membrane depolarization, which could lead to intracellular Ca2+ loading and contribute to ventricular dysfunction associated with cardiac operations. Adenosine, which possesses cardioprotective properties, has been proposed as an adjunct to conventional cardioplegic solutions. However, it is not known whether adenosine supplementation enables cardiac cells to withstand hyperkalemia-induced Ca2+ loading.
Methods:
Single ventricular cardiomyocytes were isolated from guinea pig hearts, loaded with a Ca(2+)-sensitive fluorescent probe, and imaged by digital epifluorescent microscopy. The emitted fluorescence of the probe, a measure of the intracellular Ca2+ concentration, was recorded from single myocytes during hyperkalemic challenges in the absence and the presence of adenosine to assess the protective effectiveness of this agent.
Results:
Hyperkalemic solutions induced intracellular Ca2+ loading (estimated intracellular Ca2+ concentration, 88 +/- 5 nmol/L before and 1,825 +/- 112 nmol/L after addition of 16 mmol/L KCl). Adenosine (1 mmol/L) prevented K(+)-induced Ca2+ loading (intracellular Ca2+ concentration, 86 +/- 6 nmol/L before and 85 +/- 8 nmol/L after exposure to K+). Whereas glyburide (3 mumol/L), an antagonist of adenosine triphosphate-sensitive K+ channels, had no effect, staurosporine (200 nmol/L) and chelerythrine (5 mumol/L), two inhibitors of protein kinase C, did abolish the action of adenosine.
Conclusions:
Adenosine prevents hyperkalemia-induced Ca2+ loading in cardiomyocytes. This effect is due to a direct action on ventricular cells, as the preparation employed was free from atrial, neuronal, and vascular elements, and appears to be mediated through a protein kinase C-dependent mechanism. The property of adenosine to prevent hyperkalemia-induced Ca2+ loading may contribute to the cytoprotective efficacy of this agent as an adjunct to conventional hyperkalemic cardioplegic solutions.