Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

Abstract

SummaryQT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca 2+ cycling is the proximate cause of EADs, and Ca 2+ cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP.In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 ± 1.3 minutes and 10.3 ± 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01 Key words: Calcium, QT, Heart failure, Protein kinase A, Rabbit, Torsades de Pointes P rolongation of the action potential duration (APD), the result of a reduction in net repolarizing current or an increase in depolarizing current, translates to lengthening of the QTc interval on the electrocardiogram, the culprit marker for torsades de pointes (TdP). It has been shown previously that early afterdepolarizations (EADs) and transmural dispersion of repolarization (TDR) are the candidates for causes of TdP.1,2) While TDR serves as a substrate for the initial EADs and subsequent re-entrant tachycardia, 2) EADs can trigger a new action potential (AP) and augment electrical heterogeneity in neighboring regions of myocardium. Thus, EADs can provide not only the trigger but also the substrate for the initiation and perpetuation of TdP.3)It was suggested that EADs are associated with reactivation of long lasting Ca 2+ channels (I CaL ) in the setting of APD prolongation.4) A Ca 2+ entry blocker has been shown to attenuate clofilium-induced TdP in anesthetized rabbits. 5) Recently, the Na + /Ca 2+ exchange (NCX) was suggested to produce triggered arrhythmias in heart failure (HF) by prolonging the plateau phase of the AP, thereby providing time for the reactivation of I CaL which then causes the EADs.6) The effects of NCX blocker on ventricular arrhythmias are still controversial; however, KB-R7943, a specific blocker of the reverse mode of NCX, has been shown to suppress arrhythmia in guinea pigs. 7)In the setting of HF, abnormalities in Ca 2+ handling, reduction in cardiac contractility, and diminution in β-adrenergic receptor responsiveness due to an increase in circulating catecholamine were reported in both humans and animals. [8][9][10] The underlying mechanisms of HF are still unclear; however, protein kinases (eg, cAMP dependent protein kinase, PKA; Ca 2+ /calmodulin dependent protein kinase II, CaMKII) are known to regulate cardiac function and it is possible that altered activity of pro...

Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits

“…[4] In two (out of 10) cases, these deaths were attributed to spontaneous VT and genetic ablation of the CaMKII phosphorylation site significantly reduced the incidence of pacing-induced VT.[4] In contrast to the studies in mice, CaMKII inhibition by KN-93 in ischemic HF rabbits with drug-induced torsades de pointes (TdP) failed to significantly reduce TdP incidence or time of onset. [5] This difference may be due to the HF etiology or the mechanism of TdP induction (I Kr inhibition resulting in AP duration (APD) prolongation and EADs), although KN-93 has been shown to suppress EADs induced by oxidative stress in rabbit ventricular myocytes[20] and EAD-mediated arrhythmias in transgenic mice overexpressing a constitutively active form of CaMKIV. [2] In the current study, in vivo pretreatment with KN-93 increased the arrhythmia threshold without altering heart rate (i.e.…”

“…CaMKII, which is activated in the failing heart,[1] is a critical regulator of multiple ion channels and calcium-handling proteins implicated in arrhythmogenesis. Despite abundant in vitro data linking CaMKII to arrhythmias in hypertrophied or failing hearts (see Swaninathan et al for review[1]), few studies have directly tested the antiarrhythmic effect of CaMKII inhibition in HF in vivo ,[2–5] with those that have largely limited to studies using transgenic mouse models. It is well established that mice exhibit profound differences in action potential (AP) shape, ionic currents, calcium handling and contractile protein isoforms compared to either rabbit or human hearts.…”