Adenosine and carbachol are not equivalent in their effects on L-type calcium current in rabbit ventricular cells.
Adenosine is one of the most important inhibitory modulators of heart function, producing negative inotropic, chronotropic and dromotropic effects and is also a major regulator of coronary circulation. The decrease in contractility by adenosine is mediated through inhibition of adenylyl cyclase by Gi-proteins coupled to adenosine receptors. However, little is known about the developmental differences in the effect of adenosine on cardiac cells. We have now shown that there is a striking developmental difference in the inhibitory effect of adenosine on isoproterenol-stimulated ICa between adult and newborn rabbit ventricular cells. Adenosine had no significant inhibitory effect on 0.1 muM isoproterenol-stimulated ICa in adult cells, while it completely blocked the 10 muM isoproterenol-stimulated ICa in newborn cells with an inhibitory potency similar to carbachol in newborn cells. Similarly, adenosine did not decrease the isoproterenol-stimulated cAMP levels in adult cells while it inhibited isoproterenol-stimulated cAMP levels significantly and equipotently to carbachol in newborn. However, for forskolin-stimulated ICa and cAMP levels in newborn cells, adenosine had a much lower inhibitory potency than carbachol. In adult cells, forskolin-stimulated ICa and cAMP levels were not affected by adenosine. We showed previously that the Gia3 isoform of inhibitory G protein was present in newborn cell membranes, but not detectable in adult cell membranes. We have now used a synthetic decapeptide corresponding to the C-terminal sequence of Gia3 in the patch pipette and have shown a selective partial block of the inhibitory action of adenosine for isoproterenol-stimulated ICa, suggesting that the inhibitory action of adenosine on ICa is mediated primarily through the Gia3 pathway.
Kumar
R
R
Department of Pediatrics, Emory University School of Medicine, Atlanta GA 30322, USA.
Akita
T
T
Joyner
R W
RW
D000241:Adenosine / Q000493:pharmacokinetics*; D000375:Aging / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015220:Calcium Channels / Q000187:drug effects*; D002217:Carbachol / Q000493:pharmacokinetics*; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D011817:Rabbits; D013268:Stimulation, Chemical; D013810:Therapeutic Equivalency
D015220:Calcium Channels; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D000241:Adenosine; D007545:Isoproterenol