Ionic basis of ryanodine's negative chronotropic effect on pacemaker cells isolated from the sinoatrial node.
Spontaneous electrical activity and indo 1 fluorescence ratios were recorded simultaneously in cultured pacemaker cells isolated from the rabbit sinoatrial node. Ryanodine (10 microM) reduced the amplitude of action potential-induced intracellular Ca2+ (Ca2+i) transients by 19 +/- 3%, increased the time constant for their decay by 51 +/- 5%, and slowed spontaneous firing by 32 +/- 3%. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester (AM; 25 microM) inhibited the Ca2+i transients and slowed spontaneous firing by 28 +/- 4%. Ryanodine did not alter hyperpolarization-activated or time-independent inward current, but it reduced the sum of L- and T-type Ca2+ currents (ICa,L and ICa,T) in both the presence and absence of BAPTA-AM. In contrast, ICa,L was unchanged by ryanodine. Slow inward current tails, presumed to be Na/Ca exchange current (INa/Ca), were abolished by BAPTA or ryanodine. The results suggest that a decrement of ICa,T, due to reduction of the intracellular Ca2+ concentration or a direct effect of ryanodine on T-type Ca2+ channels, contributes to the negative chronotropic effect. Another possibility, based primarily on theory and results in other preparations, is that a reduction of INa/Ca, as a consequence of the smaller action potential-induced Ca2+i transients, contributes to the effect of ryanodine.
Li
J
J
Department of Physiology, Texas Tech University Health Sciences Center, Lubbock 79430, USA.
Qu
J
J
Nathan
R D
RD
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009532:Nickel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D002614:Chelating Agents; D019837:Ryanodine Receptor Calcium Release Channel; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D012433:Ryanodine; D002110:Caffeine; D004533:Egtazic Acid; D009532:Nickel; D002118:Calcium