action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283: H1031-H1041, 2002. First published May 30, 2002 10.1152/ ajpheart.00105.2002.-Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K ϩ current (IK1) was homogeneously reduced by ϳ41% (at Ϫ60 mV) in the three cell types. Transient outward K ϩ current (Ito1) was decreased by 43-45% at ϩ30 mV, and the slow component of the delayed rectifier K ϩ current (IKs) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K ϩ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of IK1, Ito1, and IKs increases APD and favors occurrence of EADs. heterogeneity; early afterdepolarizations; congestive heart failure; arrhythmias

.-We studied the effects of osmotic swelling on the components of excitation-contraction coupling in ventricular myocytes. Myocyte volume rapidly increased 30% in hyposmotic (0.6T) solution and was constant thereafter. Cell shortening transiently increased 31% after 4 min in 0.6T but then decreased to 68% of control after 20 min. In parallel, the L-type Ca 2ϩ current (ICa-L) transiently increased 10% and then declined to 70% of control. Similar biphasic effects on shortening were observed under current clamp. In contrast, action potential duration was unchanged at 4 min but decreased to 72% of control after 20 min. Ca 2ϩ transients were measured with fura 2-AM. The emission ratio with excitation at 340 and 380 nm (f 340/f380) decreased by 12% after 3 min in 0.6T, whereas shortening and I Ca-L increased at the same time. After 8 min, shortening, I Ca-L, and the f340/f380 ratio decreased 28, 25, and 59%, respectively. The results suggest that osmotic swelling causes biphasic changes in I Ca-L that contribute to its biphasic effects on contraction. In addition, swelling initially appears to reduce the Ca 2ϩ transient initiated by a given ICa-L, and later, both I Ca-L and the Ca 2ϩ transient are inhibited.osmolarity; action potential duration; calcium current; calcium transient; cell shortening SWELLING OF CARDIAC MYOCYTES is a prominent aspect of the response to ischemia-reperfusion and elective cardioplegia and also may arise in renal insufficiency and syndromes with inappropriate secretion of antidiuretic hormone. Altered myocyte hydration has important functional consequences. Osmotic perturbations modulate both electrical activity (for reviews, see 34,38,42) and the ability of cardiac muscle to contract (5,16,17). Although facets of the contractile response to osmotic swelling are known from studies on multicellular preparations, little mechanistic information is available at the single cell level to explain the implications of myocyte swelling for excitation-contraction (E-C) coupling. Moreover, the effect of swelling on L-type Ca 2ϩ current (I Ca-L ), a critical aspect of E-C coupling, remains controversial. Under ruptured patch voltage-clamp conditions, for example, swelling is reported to enhance I Ca-L in rabbit atrial and sinoatrial node cells (22), depress I Ca-L in rat ventricular cells (4), and to have no significant effect in guinea pig (13, 31) and canine (44) ventricular cells. A swelling-induced enhancement of I Ca-L also has been claimed based on fura 2 measurements of diltiazem-sensitive Ca 2ϩ influx (36). It is unclear whether these differences in the response of I Ca-L to myocyte swelling arise from species differences or from methodological issues, such as the composition of the patch pipette solution, the effectiveness of cell dialysis, or the variable extent of myocyte swelling under ruptured-patch conditions (6, 33). Several other species differences in E-C coupling, including the sensitivity of contraction to inhibition of the sarcoplasmic reticulum (SR), are well known (2).The present stu...

Human ether á-go-go gene potassium channels (hEAG1 or Kv10.1) are expressed in brain and various human cancers and play a role in neuronal excitement and tumor progression. However, the functional regulation of hEAG channels by signal transduction is not fully understood. The present study was therefore designed to investigate whether hEAG1 channels are regulated by protein tyrosine kinases (PTKs) in HEK 293 cells stably expressing hEAG1 gene using whole-cell patch voltage-clamp, immunoprecipitation, Western blot, and mutagenesis approaches. We found that the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556 (10 μM), but not the platelet growth factor receptor (PDGFR) kinase inhibitor AG1295 (10 μM) or the Src-family inhibitor PP2 (10 μM), can inhibit hEAG1 current, and the inhibitory effect can be reversed by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Immunoprecipitation and Western blot analysis revealed that tyrosine phosphorylation level of hEAG1 channels was reduced by AG556, and the reduction was significantly countered by orthovanadate. The hEAG1 mutants Y90A, Y344A and Y485A, but not Y376A and Y479A, exhibited reduced response to AG556. Interestingly, the inhibition effect of AG556 was lost in triple mutant hEAG1 channels at Y90, Y344, and Y485 with alanine. These results demonstrate for the first time that hEAG1 channel activity is regulated by EGFR kinase at the tyrosine residues Tyr90, Try344, and Try485. This effect is likely involved in regulating neuronal activity and/or tumor growth.

The TC4 titanium alloy was subjected to high static magnetic field (HSMF) treatment with different magnetic induced intensities (B=0、1T、2T、3T、4T、5T、6T and 7T). The effects of B on the texture, dislocation density, grain size, tensile properties and micro-hardness of TC4 titanium alloy were investigated, and the influence mechanism of magneto-plastic effect on the plastic deformation ability of titanium alloy was also been studied. The results showed that the dislocation density had been increased after the HSME treatment. It reached a maximum when B=2 T, which was enhanced by 1.6 times compared to that of the untreated samples. In the view of quantum scale,the magnetic field promoted the transition of radical pairs from singlet to triplet state, which caused the movement of dislocation, led to the dislocation depinning from the depinning center, and increased the flexibility of dislocation. Subsequently, the inevitability of optimized 2T parameter was further discussed in the dislocation pile-up. Furthermore, the magnetic field not only promoted the orientation preference of crystal plane along the slipping direction, but also had the effect on the grain refinement. Meanwhile the elongation had been increased due to HSMF treatment. The average elongation of TC4 alloy was 13.12% which was enhanced by 31.07% compared to that of the untreated sample which was 10.01%. And, the elongation increased with the increment of magnetic induction intensity B. The HSME treatment could also play a role in hardening alloys. When B=2 T the micro-hardness was 344.88 HV, which was increased by 8.09% compared to that without treatment. The micro-hardness was consistent with the change of the "point" of the dislocation density, which was characterized by dislocation strengthening.

In Mg-Al alloy β (Mg17Al12) phase is the main precipitate and reinforced phase. The microstructure and performance of alloy are strongly dependent on the morphology and behavior of β phases. In this paper, a kind of Mg-Al alloy is chosen as the research object with 8.92 weight percent aluminum element. The alloy is subjected to cycling cryogenic treatment. The microstructure evolution and thermodynamic balance are analyzed by scanning electronic microscope and Thermo-CALC software. The results show that after two cryogenic treatments the quantity of the precipitate hardening β phase increases and the sizes of the precipitates are refined from 8~10 μm to 2~4μm. This is expected to be due to the decreased solubility of aluminum in the matrix at low temperatures and the significant plastic deformation due to internal differences in thermal contraction between phases and grains.