title: Beat-to-beat cycle length variability of spontaneously beating guinea pig sinoatrial cells: relative contributions of the membrane and calcium clocks.
abstract: The heartbeat arises rhythmically in the sino-atrial node (SAN) and then spreads regularly throughout the heart. The molecular mechanism underlying SAN rhythm has been attributed by recent studies to the interplay between two clocks, one involving the hyperpolarization activated cation current If (the membrane clock), and the second attributable to activation of the electrogenic NaCa exchanger by spontaneous sarcoplasmic releases of calcium (the calcium clock). Both mechanisms contain, in principle, sources of beat-to-beat cycle length variability, which can determine the intrinsic variability of SAN firing and, in turn, contribute to the heart rate variability. In this work we have recorded long sequences of action potentials from patch clamped guinea pig SAN cells (SANCs) perfused, in turn, with normal Tyrode solution, with the If inhibitor ivabradine (3 µM), then back to normal Tyrode, and again with the ryanodine channels inhibitor ryanodine (3 µM). We have found that, together with the expected increase in beating cycle length (+25%), the application of ivabradine brought about a significant and dramatic increase in beat-to-beat cycle length variability (+50%). Despite the similar effect on firing rate, ryanodine did not modify significantly beat-to-beat cycle length variability. Acetylcholine was also applied and led to a 131% increase of beating cycle length, with only a 70% increase in beat-to-beat cycle length variability. We conclude that the main source of inter-beat variability of SANCs firing rate is related to the mechanism of the calcium clock, whereas the membrane clock seems to act in stabilizing rate. Accordingly, when the membrane clock is silenced by application of ivabradine, stochastic variations of the calcium clock are free to make SANCs beating rhythm more variable.
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy; Center of Excellence for Toxicological Research, University of Parma, Parma, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Zaniboni
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cacciani
authors.affiliation: Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Lux
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D017136:Ion Transport; D000077550:Ivabradine; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010507:Periodicity; D061251:Primary Cell Culture; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D001552:Benzazepines; D002317:Cardiovascular Agents; D018679:Cholinergic Agonists; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D012433:Ryanodine; D000077550:Ivabradine; D012964:Sodium; D000109:Acetylcholine; D002118:Calcium