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This study tested the hypothesis that combination ion channel blockers of the transient outward current (I(to)) and the rapid component of the delayed rectifying current (I(Kr)) would produce greater prolongation of the ventricular action potential duration (APD) and increased dispersion of the APD in hypertrophied hearts compared with control hearts. Isolated rabbit hearts were studied 48 +/- 5 days postabdominal aortic banding. Left ventricular endocardial and epicardial APDs were significantly greater at baseline in the hypertrophied group than in controls (P <.05). The magnitude of APD prolongation induced by the I(to) blocker 4-aminopyridine (4-AP) and combination 4-AP and the I(Kr) blocker dofetilide was greater in the hypertrophied hearts than in the normal hearts (P <.01). Mean APD dispersion was significantly greater in the hypertrophied group than in the control hearts at baseline (P <.05). 4-AP increased APD dispersion by a similar magnitude in the hypertrophied hearts (10 +/- 10 ms) and the control hearts (8 +/- 8 ms, P = NS), whereas the combination 4-AP and dofetilide increased APD dispersion by a greater magnitude in the hypertrophied hearts (41 +/- 28 ms) than the control hearts (21 +/- 11 ms, P <.05). Ventricular fibrillation occurred spontaneously in four hypertrophied hearts (40%) during combination drug perfusion and in none of the control hearts (P <.05). Thus, combination I(to) and I(Kr) blockers cause greater prolongation APD and increased APD dispersion in left ventricular hypertrophy, and this is associated with the development of ventricular fibrillation.

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INTRODUCTION: Increased dispersion of ventricular repolarization is observed in cardiac hypertrophy and is associated with sudden cardiac death. At present, there is little information about the effects of cardiac hemodynamics and antiarrhythmic drugs on dispersion of repolarization in disease states. We compared the effects of increasing afterload and the Class III antiarrhythmic drug, dofetilide, on dispersion of ventricular repolarization in hypertrophied rabbit hearts to normal rabbit hearts. METHODS AND RESULTS: Cardiac hypertrophy was induced in rabbits by abdominal aortic banding. Isolated hearts were studied 49+/-4 days postsurgery in the working heart mode using a blood-buffer perfusate. The action potential duration (APD) was measured from eight sites on the epicardium of the heart at low (50+/-7 mmHg) afterload and high afterload (97+/-12 mmHg) at baseline and during dofetilide perfusion. APD dispersion, determined as the difference between the maximal and minimal APD, was greater in hypertrophied hearts (42+/-8 msec) compared with control hearts (26+/-8 msec, P < 0.05) at baseline and low afterload. Increasing afterload caused a decrease in APD dispersion in hypertrophied hearts (P < 0.05) but not in control hearts, and APD dispersion was similar in hypertrophied hearts (31+/-9 msec) compared with control hearts (30+/-9 msec, P = NS). During dofetilide perfusion, APD dispersion remained greater in hypertrophied hearts (60+/-39 msec) compared with control hearts (30+/-13 msec, P < 0.05) at low afterload but not high afterload. Increasing afterload caused shortening of the APD in most regions of the control hearts, whereas APD did not shorten significantly in hypertrophied hearts at baseline and tended to increase during dofetilide perfusion. During dofetilide perfusion, the maximal change in APD recorded from the posterior wall of the left ventricle following an increase in afterload was -18+/-21 msec in control hearts and 7+/-21 ms in hypertrophied hearts (P < 0.05). CONCLUSION: Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy.

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Recent reports of subclinical phonetic deficits in posterior and most particularly in Wernicke's aphasics have challenged the traditional dichotomy which characterized speech deficits in aphasia as anterior/phonetic and posterior/phonological. It is unclear whether the basis of the phonetic deficit in posterior aphasics reflects the fact that the speech production system extends to more posterior regions of the left hemisphere than previously thought or alternatively is the result of generalized brain damage effects. The present study explores the latter possibility by investigating the patterns of speech production in right hemisphere brain-damaged, non-aphasic patients with anterior and posterior lesions. Acoustic analyses conducted on a range of consonant and vowel parameters showed differences between the speech patterns of both anterior and posterior right hemisphere patients and that of Wernicke's aphasics. These findings suggest that the subclinical deficit of Wernicke's aphasics can not simply be ascribed to a generalized brain-damage effect and raise the possibility that the right hemisphere also plays some role, if only a minor one, in the phonetic implementation of speech.

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The density of potassium channels, including the inward rectifying current (IK1), the delayed rectifying current and the transient outward current have been reported to be decreased in cardiac hypertrophy. However, it is not known whether the effects of specific ionic channel blockers are altered in this setting. The effects of barium chloride, which inhibits IK1, of dofetilide, which inhibits the rapidly activating component of the delayed rectifying current, and 4-aminopyridine, which inhibits the transient outward current, were studied in isolated perfused working rabbit hearts. Cardiac hypertrophy was induced in rabbits by aortic banding. Hearts were removed 43 +/- 8 days after surgery, and electrophysiologic parameters were measured at low (30 cm H2O) and high (100 cm H2O) afterload at base line and during perfusion of barium, dofetilide or 4-aminopyridine. The hearts from banded rabbits weighed more (13.0 +/- 2.3 g) than those from the sham controls (10.0 +/- 1.6 g; P < .001). The action potential duration at 90% repolarization (APD90) was greater in hypertrophied hearts (198 +/- 16 msec) at base line than in control hearts (182 +/- 20 msec; P < .01). Barium (0.025 mM) caused greater prolongation of APD90 in hypertrophied hearts than in control hearts at both low afterload (214 +/- 9 msec vs. 195 +/- 20 msec) and high afterload (200 +/- 10 msec vs. 166 +/- 22 msec, P < .01). This interaction of barium's effects on APD90 and hypertrophy was highly statistically significant (P < .001). In contrast, dofetilide (15 nM) and 4-aminopyridine (1.0 mM) caused similar changes in APD90 in hypertrophied hearts and in control hearts at low afterload and high afterload (P = NS). In isolated ventricular myocytes, IK1 and transient outward densities, but not the rapidly activating component of the delayed rectifying current were decreased in hypertrophied cells compared with control cells (P < .05). Thus the increased effects of barium on prolongation of APD in hypertrophy are probably due to the decreased density of IK1 in hypertrophy and perhaps, in part, to a change in the balance of repolarizing currents that occurs in hypertrophy.

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Effects of crystalloid buffer and blood-buffer perfusates on cardiac electrophysiological parameters were compared in four groups of isolated, working rabbit hearts. Hearts were perfused with Krebs-Henseleit buffer or blood plus Krebs-Henseleit buffer (10% hematocrit) over a range of left ventricular afterload (30-100 cmH2O) and cardiac outputs (30-180 ml/min). Left ventricular monophasic action potential duration (APD) was significantly shorter at low afterload and high cardiac output in buffer-perfused (114 +/- 35 ms) compared with blood-perfused hearts (177 +/- 23 ms, P < 0.001). APD shortened in blood-perfused hearts after an increase in afterload to 100 cmH2O (P < 0.05), and APD was similar in blood-perfused (151 +/- 19 ms) compared with buffer-perfused hearts (142 +/- 24 ms, P = NS). Ventricular effective refractory period (VERP) was significantly shorter at low afterload in buffer-perfused (154 +/- 32 ms) compared with blood-perfused hearts (227 +/- 17 ms, P < 0.001). VERP shortened in blood-perfused hearts after an increase in afterload to 100 cmH2O (P < 0.05) and was similar in blood-perfused (166 +/- 26 ms) compared with buffer-perfused hearts (151 +/- 37 ms, P = NS). Determination of VERP was associated with induction of ventricular fibrillation in 10 of 15 buffer-perfused hearts, whereas ventricular fibrillation was not observed in blood-perfused hearts (P < 0.001). Thus significant differences in ventricular repolarization and cardiac hemodynamics are observed in working rabbit hearts perfused with a blood-buffer perfusate compared with a crystalloid buffer. Blood-perfused working hearts are electrophysiologically more stable.

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Ventricular hypertrophy is associated with several electrophysiologic abnormalities. However, little is known about the pharmacodynamics of antiarrhythmic drugs in the setting of ventricular hypertrophy. We studied the myocardial accumulation and pharmacodynamics of quinidine in 10 control rabbit hearts and 10 with isoproterenol-induced hypertrophy. Hearts were perfused in the working heart configuration. Electrophysiologic measurements were made at low afterload (30 cm H2O) and high afterload (60 cm H2O) at baseline and during quinidine perfusion (972 ng/ml). The myocardial quinidine concentration measured at the end of each experiment was significantly lower in the hypertrophied hearts (25.0 +/- 11.7 micrograms/g) as compared with the control hearts (51.2 +/- 12.7 micrograms/g, p < 0.001). The left ventricular (LV) monophasic action potential (MAP) duration was significantly shorter in the hypertrophied hearts as compared with control hearts at low afterload (166 +/- 27 vs. 192 +/- 24 ms, p < 0.01) and at high afterload (141 +/- 7 vs. 171 +/- 24 ms, p < 0.01). Quinidine prolonged MAP duration to a similar extent in both hypertrophied and control hearts; the MAP prolongation occurred at both low (192 +/- 21 vs. 223 +/- 25 ms, p < 0.02) and high afterloads (179 +/- 15 vs. 216 +/- 20 ms, p < 0.01) in the hypertrophied and control hearts, respectively. However, the ratios of the changes in electrophysiologic parameters to quinidine myocardial concentrations were greater in the hypertrophied hearts than in control hearts (p < 0.05). Therefore, AP duration (APD) is significantly shortened in isoproterenol-induced hypertrophy. The magnitude of quinidine effects on MAP duration and ventricular effective refractory period (VERP) are similar in hypertrophied hearts and control hearts, but the myocardial concentration-effect relations are increased significantly in hypertrophied hearts.

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We have reported previously that propafenone decreased ventricular excitability and prolonged ventricular conduction time in hearts from rabbits treated with a lard diet compared to those from rabbits treated with a safflower oil diet. We hypothesized that these effects might be modulated by the lipid solubility of the drug. Accordingly, we studied the effects of dietary fat on the pharmacodynamics of the hydrophilic drugs, procainamide and tocainide, and the lipophilic drug, quinidine. Weanling rabbits were fed diets of 10% w/w lard or safflower oil for 40 days. Differences in electrophysiological variables were compared at base line and during drug perfusion. The linoleic acid content of isolated sarcolemma was significantly higher in the safflower oil group (31.1 +/- 5.6%) than in the lard group (18.8 +/- 3.9%, P < .001). During quinidine (3 microM) perfusion, the threshold current was significantly greater in the lard group (0.44 +/- 0.18 mA) compared to the safflower oil group (0.24 +/- 0.11 mA, P < .05). During procainamide and tocainide perfusion, the threshold current was similar in the lard and safflower oil groups. During quinidine perfusion, greater prolongation of the endocardial monophasic action potential duration was observed in the safflower oil group (217 +/- 15 msec) compared to the lard group (196 +/- 24 msec, P < .05). Procainamide and tocainide effects on monophasic action potential duration were similar in the lard and safflower oil groups. Thus, dietary fat modulates the effects of the lipophilic drug quinidine on ventricular excitability and repolarization.

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BACKGROUND: The fatty acid composition of the phospholipids in sarcolemma may significantly influence cell membrane functions. We evaluated the effects of dietary fat on the pharmacodynamics of the antiarrhythmic drug propafenone in isolated, perfused rabbit hearts. METHODS AND RESULTS: Three groups of weanling rabbits (n = 9 each group) were fed diets of 10% wt/wt lard, fish oil, or safflower oil for 40 days. Differences in electrophysiological variables were assessed at baseline and during propafenone perfusion. Myocardial concentration-effect relations were determined by plotting electrophysiological effects versus coronary sinus propafenone concentrations. The linoleic acid content of isolated sarcolemma was higher in the safflower group (33.4 +/- 11.4%) than in the lard (13.4 +/- 2.3%, p less than 0.01) and fish oil (8.5 +/- 1.4%, p less than 0.01) groups, whereas the omega-3 fatty acid content was higher in the fish oil group (p less than 0.01). During propafenone perfusion, greater changes in ventricular conduction time were observed in the lard group (22 +/- 11 msec) than in the safflower oil group (10 +/- 7 msec, p less than 0.05), whereas changes in ventricular conduction time in the fish oil group (16 +/- 7 msec) were intermediate between the lard and safflower oil groups. The slopes of the linear myocardial concentration-effect relations describing changes in QRS duration were steeper in the lard group (0.22 +/- 0.07 msec/micrograms/ml) than in the safflower oil group (0.13 +/- 0.04 msec/micrograms/ml, p less than 0.01) but not in the fish oil group (0.17 +/- 0.08 msec/microgram/ml, p = NS). Strength-interval curves were similar at baseline in all three groups. During propafenone perfusion, the threshold current was increased significantly at long coupling intervals (250-380 msec) in the lard group (1.8 +/- 1.0 mA) compared with the safflower oil group (0.8 +/- 0.6 mA, p less than 0.05) but not compared with the fish oil group (1.2 +/- 0.6 mA, p = NS). CONCLUSIONS: Dietary fat significantly alters the fatty acid composition of the phospholipids in sarcolemma. Propafenone effects on ventricular conduction time and ventricular excitability are significantly influenced by the type of dietary fat.

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