BackgroundPatients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation ΔK210 in cardiac troponinT.Methodology/Principal FindingsBy 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K+ (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K+ channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed.Conclusions/SignificanceOur results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart.

No abstract

ABSTRACT. Effects of ketamine on the sodium (I Na ) and L-type calcium currents (I Ca ) were examined by using whole-cell patch clamp techniques in guinea pig single ventricular myocytes. The mode of action of ketamine was compared with those of quinidine, a sodium channel blocker, and verapamil, a calcium channel blocker. Ketamine (30-300 µM) inhibited both I Na and I Ca in a concentrationdependent manner. Quinidine (30 µM) and verapamil (0.1 µM) produced use-dependent depression of I Na and I Ca , respectively. The amplitude of I Na elicited by the first depolarizing pulse after a long quiescent period was slightly decreased by quinidine. During a train of depolarizing pulse the current amplitude decreased gradually, and reached a steady state level in the quinidine-treated cells (use-dependent block, UDB). Verapamil produced a similar mode of inhibition of I Ca , i.e., UDB. In contrast, ketamine produced significant decrease in I Na and I Ca elicited by the first depolarizing pulses and the decreases of both currents were not augmented during a train of depolarizing pulses. From these results, it can be concluded that ketamine produces tonic block of the cardiac sodium and calcium channels and the mode of inhibition is clearly different from UDB by quinidine and verapamil. -KEY WORDS: calcium current, cardiac myocyte, ketamine, sodium current, tonic block.J. Vet. Med. Sci. 60(4): 479-483, 1998 MATERIALS AND METHODSCell preparations: Guinea pigs, weighing 200-350 g, were used in this study. Single ventricular cells were isolated by an enzymatic dispersion, as previously described [11]. Briefly, the heart was removed from the open-chest guinea pig anesthetized with pentobarbital Na, and mounted on a modified Langendorff perfusion system for retrograde perfusion of the coronary circulation with a normal HEPESTyrode solution. The perfusion medium was then changed to a nominally Ca-free HEPES-Tyrode solution and then to a solution containing 0.02% w/v collagenase (Wako, Osaka, Japan). After digestion, the heart was perfused with a high K + and low Cl -solution (modified Kraftbrühe (KB) solution) [17,22]. Ventricular tissue was cut into small pieces in the modified KB solution and gently shaken to isolate cells. Dispersed cells were stored in the KB solution at 4°C and used over the next 7-10 hr.Recording techniques: Whole-cell membrane currents were recorded by patch clamp method [9]. Single ventricular cells were placed in a recording chamber (1-ml volume) attached to an inverted microscope (Olympus IMT-2, Tokyo, Japan) and superfused with the HEPES-Tyrode solution at a rate of 3 ml/min. The temperature of the external solution was kept constant at 36 ± 1°C. Glass patch pipettes with a diameter of 1.5 mm were filled with a pipette solution. The resistance of the patch pipette filled with the pipette solution was 2-3 MΩ. The tight-seal, whole cell voltage clamp technique was used. After the gigaohmseal between the tip of the electrode and the cell membrane was established, the membrane patch was disrupted by K...

No abstract

No abstract