Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts.
Cardiac pathologies are associated with increased late INa that contributes to the dysregulation of ion homeostasis and causes electrical and contractile dysfunction. This study was designed to test the hypothesis that an increased late sodium channel current (INa) leads to Ca2+ overload and left ventricular (LV) dysfunction, and thereby inhibition of late INa (e.g., by ranolazine) improves Ca2+ homeostasis and reduces LV dysfunction. Intracellular Ca2+ ([Ca2+]i) and LV function were measured simultaneously in rat isolated perfused hearts. Augmentation of late INa with sea anemone toxin-II (ATX-II, 12 nM) increased diastolic [Ca2+]i (d[Ca2+]i), and impaired LV mechanical function, but had no effect on [Ca2+]i transient amplitude. Although ranolazine (4 and 9 microM), an inhibitor of late INa, had no direct effects on d[Ca2+]i or LV function, it significantly reduced the deleterious effects of ATX-II. Global ischemia increased d[Ca2+]i and inhibited Ca2+ transient amplitude. During reperfusion, Ca2+ transient amplitude recovered fully, but d[Ca2+]i remained elevated and LV function was depressed, indicative of Ca2+ overload. Ranolazine (9 microM) reduced d[Ca2+]i accumulation during ischemia as well as reperfusion and improved recovery of LV function. These results show that augmentation of late INa with ATX-II or by ischemia is associated with diastolic Ca2+ overload and LV dysfunction. The beneficial effects of ranolazine in reducing Ca2+ overload and LV mechanical dysfunction during ischemia/reperfusion is consistent with the inhibition of late INa mechanism of action.
Fraser
Heather
H
CV Therapeutics Inc., Palo Alto, CA 94304, USA. heather.fraser@cvt.com
Belardinelli
Luiz
L
Wang
Lianguo
L
Light
Peter E
PE
McVeigh
Jeffrey J
JJ
Clanachan
Alexander S
AS
D000083:Acetanilides; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003064:Cnidarian Venoms / Q000633:toxicity; D003971:Diastole; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D000083:Acetanilides; D003064:Cnidarian Venoms; D010879:Piperazines; D015222:Sodium Channels; C028800:toxin II (Anemonia sulcata); D000069458:Ranolazine; D002118:Calcium