The mechanism by which isoproterenol (ISO) prevents the prolongation of action potential duration (APD) and refractory period (RP) by the class III antiarrhythmic agent E-4031 was studied. E-4031 (1 microM) increased RP by 50% with no effect on contractile force in papillary muscles isolated from guinea pig heart. ISO (1 microM) increased force of contraction more than fivefold and decreased RP by 25%. The prolongation of RP by E-4031 was prevented by pretreatment of muscles with ISO. The prolongation of APD in isolated guinea pig ventricular myocytes by 5 microM E-4031 also was antagonized by prior exposure of the cells to 1 microM ISO. Instantaneous currents and delayed rectifier K+ currents, IK, were measured in isolated myocytes using the suction microelectrode voltage-clamp technique. Currents were measured in response to 225-msec depolarizing pulses from a holding potential of -40 mV. Previous studies have demonstrated that IK in these cells results from activation of two distinct outward K+ currents, IKs and IKr (specifically blocked by E-4031). ISO doubled the magnitude of IKs without significant effect on IKr. The instantaneous current, putatively identified as a Cl- current, also was doubled by ISO but was unaffected by E-4031. The augmented conductance of IKs and instantaneous current by ISO results in a decrease in RP. The small effect of E-4031 on APD and RP in the presence of ISO results from the smaller contribution of IKr relative to the augmented repolarizing currents.

Objective

The mechanism by which the antihypertensive agent BRL 34915 (cromakalim) affects action potential duration (APD) and effective refractory period (ERP) in isolated cardiac muscle was investigated. BRL 34915 (13 pM) shortened ERP of ferret (Mustelaputoriusfuro) and guinea pig (Cavia porcellus) papillary muscles in a concentrationdependent fashion. The reduction in ERP resulted from a decrease in APD. ERP and APD of papillary muscles were also reduced during hypoxia produced by bubbling the physiological bathing solution with N2 instead of 02. Reduction of APD during hypoxia has previously been attributed to activation of ATP-sensitive K+ channels in heart. Glyburide, an inhibitor of ATP-sensitive K+ channels, prevented or reversed the shortening of ERP and APD produced by hypoxia and BRL 34915, respectively. These results suggest that BRL 34915 acts by opening ATP-sensitive K+ channels in heart. The actions of BRL 34915 were temperature-dependent, decreasing ERP 64% at 3TC, but having'no effect at 22C. The effect of BRL 34915 on K+ currents was tested directly in voltage-clamped guinea pig ventricular myocytes. As observed with the papillary muscles, BRL 34915 was without effect at 22rC. At 360C, BRL 34915 (after a delay) increased outward currents positive to, and less so at potentials negative to, the K+ current reversal potential. The normal inwardly rectifying current-voltage relationship for peak K+ currents during 200-msec pulses was changed to one that was nearly ohmic. The current activated by BRL 34915 was blocked by glyburide. The data support the hypothesis that BRL 34915, like hypoxia, activates ATPsensitive K+ channels in the heart. Based upon the profound temperature sensitivity of BRL 34915 action, this activation may be indirect, perhaps by means of modulation of an enzymatic activity that regulates gating of these channels. BRL 34915 and glyburide will be valuable tools for studying the role of ATP-sensitive K ' channels in normal and abnormal cardiac function.Potassium (K+) channels of cardiac muscle cells have many functions, including setting ofthe resting membrane potential and determining refractoriness. Some of these channels are regulated by neurohormones, such as acetylcholine (1) physiological concentrations of K+ (5). Thus, total outward K+ conductance is dramatically increased when IK(ATP) channels are activated. Activation of these channels, such as during experimentally induced internal ATP depletion, hypoxia, or treatment with uncouplers of the oxidative phosphorylation pathway (4-8), markedly shortens action potential duration (APD). These channels are probably activated during transient periods of ischemia in intact hearts, perhaps protecting ischemic cells from Ca2+ overload (9) but also increasing extracellular [K and causing a dispersion in refractoriness, events that can precipitate arrhythmias (10).Study of IK(ATP) channels has been facilitated by the discovery that sulfonylurea antidiabetic drugs, such as glyburide, are specific blockers ofthis channel in pancreati...

Introduction Magnetic seizure therapy (MST), in which seizures are elicited with a high-frequency magnetic field, is under development as a new treatment for major depressive disorder. Its use may be justified if it produces the antidepressant effects of ECT, coupled with limited cognitive side effects. This pilot study reports shortened recovery times after MST compared with ECT as a preliminary step to evaluate the usefulness of a new 100Hz MST device. Methods We induced seizures with 100Hz magnetic transcranial stimulation in eleven patients with major depressive disorder during one session of a regular course of ECT. Recovery times after these MST and ECT induced seizures were compared. Results Seizures could be elicited in ten of the eleven patients. Stimulation over the vertex produced tonic-clonic activity on nine out of eleven occasions. Stimulation over the prefrontal midpoint elicited seizures on three out of seven occasions. The mean duration of magnetically induced seizures was 31.3 sec, ranging from 10-86 sec. All patients had an exceptionally quick recovery of orientation: mean of 7 min 12 sec (SD = 2 min 7 sec, range 4 min 20 sec – 9 min 41 sec). The recovery times were on average 15 min 35 sec shorter with MST than with ECT in the same patients (paired-samples t-test: p = 0.00009). Patients reported feeling less confused after MST. Side effects were confined to myoclonic movements, associated with the use of etomidate. Conclusions The new 100 Hz magnetic stimulator elicits seizures in the majority of patients when administered over the vertex. MST was associated with shorter recovery times and less confusion following treatment. Subsequent work will be required to assess the safety and effectiveness of MST in the treatment of depression.