Involvement of intracellular Ca2+ release mechanism in adenosine-induced cardiac Ca2+ current inhibition.
BACKGROUND
Myocardial contractility is regulated by changes in the free intracellular Ca2+ concentration [Ca2+]i, which is determined by concerted interactions of Ca2+ influx through voltage-dependent Ca2+ channels, release of Ca2+ from intracellular pools, and Ca2+ extrusion systems. Although adenosine has been reported to attenuate postischemic stunning, the mechanism is unknown.


METHODS
The patch clamp technique and the Ca(2+)-sensitive fluorescence dye FURA II were used in isolated ventricular cardiomyocytes to study the effects of adenosine on the L-type Ca2+ channel current (ICa) and on [Ca2+]i.


RESULTS
Adenosine decreased the basal ICa by 76% +/- 4% (100 nmol/L, n = 48) and simultaneously elevated [Ca2+]i up to 1.8 mumol/L (n = 37) by adenosine-A1-receptor activation. The adenosine-evoked responses were not sensitive to pertussis toxin (n = 12), but intracellular application of guanosine diphosphate-beta sulfate (10 mumol/L) reduced the effects of adenosine by 86.7% +/- 7% (n = 9). Block of intracellular Ca2+ release by ryanodine and thapsigargin attenuated, whereas intracellularly applied inositol 1,4,5-trisphosphate (n = 18) mimicked the adenosine-evoked responses.


CONCLUSIONS
These findings suggest that coupling of adenosine to A1-receptors induced G protein-mediated activation of phospholipase C followed by generation of inositol 1,4,5-trisphosphate, which releases Ca2+ from intracellular Ca2+ stores. The inhibition of ICa by depletion of intracellular Ca2+ stores could play a major role in preventing ischemia-induced Ca2+ overload.
Eckert
R
R
Department of Surgery and Physiology, University of Wisconsin Medical School, Madison.
Utz
J
J
Trautwein
W
W
Mentzer
R M
RM
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000502:physiology; D006168:Guinea Pigs; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011983:Receptors, Purinergic / Q000032:analysis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D015220:Calcium Channels; D011983:Receptors, Purinergic; D015544:Inositol 1,4,5-Trisphosphate; D019204:GTP-Binding Proteins; D000241:Adenosine; D002118:Calcium