Developmental changes in the delayed rectifier K+ channels in mouse heart.

Expression of cardiac transient outward current and inwardly rectifying K+ current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K+ current (IK, with rapidly and slowly activating components, IKr and IKs, respectively). Accordingly, the purpose of the present study was to assess developmental changes in IK channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of IK, and radioligand assay to examine [3H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD95) by a selective IKr blocker, dofetilide (1 mumol/L), dramatically decreased from fetal (137% +/- 18%) to day-1 (75% +/- 29%) and day-3 (20% +/- 15%) neonatal mouse ventricular tissues (P < .01). Dofetilide did not prolong APD95 in adult myocardium. IKr is the sole component of IK in day-18 fetal mouse ventricular myocytes. However, both IKr and IKs were observed in day-1 neonatal ventricular myocytes. With further development, IKs became the dominant component of IK in day-3 neonates. In adult mouse ventricular myocytes, neither IKr nor IKs was observed. Correspondingly, a high-affinity binding site for [3H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [3H]dofetilide binding studies demonstrate that expression of the IK channel is developmentally regulated in the mouse heart.

Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy.

This article reviews the data which support the use of selected drug combinations to enhance anti-arrhythmic activity. Specifically, we have focused on the mexiletine-quinidine interaction and the relation between anti-arrhythmic efficacy and electrophysiologic effects. In an initial clinical study, we found that combination therapy with mexiletine-quinidine produced enhanced efficacy in suppressing spontaneous ventricular tachycardia with fewer side-effects than high dose monotherapy. This enhanced efficacy has been confirmed in other laboratories. Combination therapy also enhanced suppression of inducible ventricular tachycardia in patients and in animal models. Animal models were used to assess the relation between electrophysiologic effects and anti-arrhythmic efficacy. In the animal studies, combination therapy produced selective prolongation of refractoriness and conduction in the infarct and peri-infarct zones without significant changes in the normal zone. Subsequent studies focused on the relative contribution of sodium channel and potassium channel blocking properties of these drugs to the enhanced activity seen with the combination. Studies using the selective sodium channel blocker tetrodotoxin confirmed that sodium channel blockade was necessary for this interaction. To assess the contribution of prolongation of action potential duration by quinidine to the combined effect we compared the anti-arrhythmic and electrophysiologic effects of the stereoisomers quinidine and quinine given alone and in combination with mexiletine. These experimental data confirm that the property of prolongation of action potential duration by quinidine is essential to the interaction. When comparing quinidine and quinine it is apparent that prolongation of refractoriness in the peri-infarct zone is essential for anti-arrhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association.

We report a patient with chronic, untreated idiopathic hypoparathyroidism who presented with papilledema and progressive deterioration of visual function. The papilledema resolved with treatment of the hypocalcemia. Visual acuity progressively improved as the serum calcium rose during treatment with vitamin D and calcium supplements. Lumbar puncture may also have contributed to the normalization of cerebrospinal fluid pressure and recovery of vision in this patient. The association of hypoparathyroidism and pseudotumor cerebri is rare, and a retrospective review of 41 patients with hypoparathyroidism admitted to two local general hospitals revealed no other cases.