title: Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart. A possible ionic mechanism for reduced excitability and postrepolarization refractoriness.
abstract: Previously, we have shown abnormalities in Vmax and in the recovery of Vmax in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart (myocytes from the EBZ [IZs]). Thus, we sought to determine the characteristics of the whole-cell Na+ current (INa) in IsZs and compare them with the INa of cells from noninfarcted hearts (myocytes from noninfarcted epicardium [NZs]). INa was recorded using patch-clamp techniques under conditions that eliminated contaminating currents and controlled INa for measurement (19 degrees C, 5 mmol/L [Na+]zero). Peak INa density (at -25 mV) was significantly reduced in IZs (4.9 +/- 0.44 pA/pF, n = 36) versus NZs (12.8 +/- 0.55 pA/pF, n = 54; P < .001), yet the half-maximal activation voltage (V0.5), time course of decay, and time to peak INa were no different. However, in IZs, V0.5 of the availability curve (I/Imax curve) was shifted significantly in the hyperpolarizing direction (-80.2 +/- 0.48 mV in NZs [n = 45] versus -83.9 +/- 0.59 mV in IZs [n = 27], P < .01). Inactivation of INa directly from a depolarized prepotential (-60 mV) was significantly accelerated in IZs versus NZs (fast and slow time constants [T1 and T2, respectively] were as follows: NZs [n = 28], T1 = 71.5 +/- 5.6 ms and T2 = 243.7 +/- 17.1 ms; IZs [n = 21], T1 = 36.3 +/- 2.4 ms and T2 = 153 +/- 11.3 ms; P < .001). Recovery of INa from inactivation was dependent on the holding potential (VH) in both cell types but was significantly slower in IZs. At (VH) = -90 mV, INa recovery had a lag in 18 (82%) of 22 IZs (with a 17.6 +/- 1.5-ms lag) versus 2 (9%) of 22 NZs (with 5.9- and 8.7-ms lags); at VH = -100 mV, T1 = 60.9 +/- 2.6 ms and T2 = 352.8 +/- 28.1 ms in NZs (n = 41) versus T1 = 76.3 +/- 4.8 ms and T2 = 464.4 +/- 47.2 ms in IZs (n = 26) (P < .002 and P < .03, respectively); at VH = -110 mV, T1 = 33.4 +/- 1.8 ms and T2 = 293.5 +/- 33.6 ms in NZs (n = 21) versus T1 = 44.3 +/- 2.9 ms and T2 = 388.4 +/- 38 ms in IZs (n = 18) (P < .002 and P < .07, respectively). In sum, INa is reduced, and its kinetics are altered in IZs. These changes may underlie the altered excitability and postrepolarization refractoriness of the ventricular fibers of the EBZ, thus contributing to reentrant arrhythmias in the infarcted heart.
authors.affiliation: Department of Pharmacology, Columbia University, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pu
authors.forename: P A
authors.initials: PA
authors.lastname: Boyden
mesh_terms: D000818:Animals; D004285:Dogs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007473:Ion Channels; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000378:metabolism / Q000503:physiopathology*; D012964:Sodium / Q000378:metabolism / Q000502:physiology*
chemical_list: D007473:Ion Channels; D012964:Sodium