A1 adenosine receptors potently regulate heart rate in mammalian embryos.
A1 adenosine receptors (A1ARs) have been recently shown to be expressed in rodent embryonic hearts at very early stages of development. To determine the functional significance of fetal cardiac A1AR expression during embryogenesis, murine fetal heart preparations were studied between postconceptual days 9 and 12. Dose-response curves generated using a variety of adenosine agonists revealed that A1AR activation potently regulated fetal heart rates. The A1AR agonist, N6-cyclopentyladenosine, inhibited heart rates in a dose-dependent manner (half-maximal effective concentration = 3.6 x 10(-8) M) and stopped fetal cardiac contractions in 63% of preparations. In contrast, A2a and A2b receptor activation did not alter heart rates, and activation of A3 receptors produced modest declines in heart rates. Endogenous adenosine also acted tonically to suppress fetal heart rates, as demonstrated by the A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine, increasing heart rates, whereas the adenosine reuptake blocker dipyridamole lowered fetal heart rates. Pertussis toxin treatment blocked A1AR action, showing that A1AR action was G protein mediated. Using drugs that alter cAMP levels and ion channel action, we were able to show that A1AR action involves events mediated by cAMP, ATP-dependent K, L-type calcium, sodium, and chloride channels, and the pacemaker current. These data show that adenosine and A1ARs potently regulate mammalian heart rates via multiple effector systems at very early stages of prenatal development.
Hofman
P L
PL
Section of Pediatric Endocrinology, Herman B. Wells Center for Pediatric Research, James Whitcomb Riley Hospital, Indianapolis, Indiana 46202, USA.
Hiatt
K
K
Yoder
M C
MC
Rivkees
S A
SA
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008024:Ligands; D051379:Mice / Q000196:embryology; D008810:Mice, Inbred C57BL; D058906:Purinergic P1 Receptor Agonists; D011983:Receptors, Purinergic / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000502:physiology*
D007473:Ion Channels; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D011983:Receptors, Purinergic; D018047:Receptors, Purinergic P1; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000241:Adenosine