Vasoprotective endothelial effects of a standardized grape product in humans.

The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart disease. In addition to chronic dysfunction of endothelial responses in patients with established heart disease, there is evidence that 'acute insults' can cause measurable dysfunction in vascular response in humans (drug toxicities, hypoxia, high fat meal). Such repeated acute insults may contribute to disease risk in otherwise healthy individuals or promote disease progression in established patients.

Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells.

Stable coexpression of human (h)KCNQ1 and hKCNE1 in human embryonic kidney (HEK)-293 cells reconstitutes a nativelike slowly activating delayed rectifier K+ current (HEK-I(Ks)), allowing beta-adrenergic modulation of the current by stimulation of endogenous receptors in the host cell line. HEK-I(Ks) was enhanced two- to fourfold by isoproterenol (EC50 = 13 nM), forskolin (10 microM), or 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (50 microM), indicating an intact cAMP-dependent ion channel-regulating pathway analogous to the PKA-dependent regulation observed in native cardiac myocytes. Activation kinetics of HEK-I(Ks) were accurately fit with a novel modified second-order Hodgkin-Huxley (H-H) gating model incorporating a fast and a slow gate, each independent of each other in scale and adrenergic response, or a "heterodimer" model.

Improved throughput of PatchXpress hERG assay using intracellular potassium fluoride.

Blockade of the human ether-a-go-go-related gene (hERG) potassium channel, with a consequent possibility of QT prolongation and increased susceptibility to a characteristic polymorphic ventricular arrhythmia, torsade de pointes, is an important cause of withdrawal of drugs from the market. In the aftermath of recent drug withdrawals, regulatory agencies now require in vitro hERG screening of all pharmaceutical compounds that are targeted for human use. To minimize the potential for failure in later-stage drug development, many pharmaceutical and biotechnology companies have begun to use automated patch clamp systems with higher throughput than conventional manual patch-clamp techniques to conduct routine functional hERG screening during drug discovery and early development.

Application of PatchXpress planar patch clamp technology to the screening of new drug candidates for cardiac KCNQ1/KCNE1 (I Ks) activity.

A cardiac safety concern for QT prolongation and potential for pro-arrhythmia exists due to inhibition of the cardiac slowly activating delayed rectifier potassium current, I(Ks). Selective inhibitors of I Ks have been shown to prolong the QT interval in animal models. On the other hand, I Ks has been considered as a target for anti-arrhythmic therapy due to certain biophysical and pharmacological properties and its expression pattern in the heart.

Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats.

Hypertension is a common cause of heart failure, and ventricular arrhythmias are a major cause of death in heart failure. The spontaneous hypertension heart failure (SHHF) rat model was used to study altered ventricular electrophysiology in hypertension and heart failure. We hypothesized that a reduction in the inward rectifier K(+) current (I(K1)) and expression of pacemaker current (I(f)) would favor abnormal automaticity in the SHHF ventricle.

Flunarizine is a highly potent inhibitor of cardiac hERG potassium current.

Flunarizine has been widely used for the management of a variety of disorders such as peripheral vascular diseases, migraine, and epilepsy. The majority of its beneficial effects have been attributed to its ability to inhibit voltage-gated Ca2+ channels in the low micromolar range, albeit non-selectively, as flunarizine has been shown to inhibit a variety of ion channels. We examined the effects of flunarizine on potassium currents through cardiac channels encoded by the human ether-a-go-go related gene (hERG) stably expressed in CHO cells.

Age and anesthetic effects on murine electrocardiography.

Murine models offer potential insights regarding human cardiac disease, but efficient and reliable methods for phenotype evaluation are necessary. We employed non-invasive electrocardiography (ECG) in mice, investigating statistical reliability of these parameters with respect to anesthetic and animal age. Mice (C57BL/6, 8 or 48 weeks) were anesthetized by ketamine/xylazine (K/X, 80/10 mg/kg ip) or by inhalation anesthetic (halothane, HAL; sevoflurane, SEV) and 6 lead ECGs were recorded.

Effects of dihydrotestosterone on cardiac inward rectifier K(+) current.

Unlabelled: There are well-described sexually dimorphic differences both in the electrocardiogram and in the propensity to develop drug-induced arrhythmias. The QT interval and the risk of ventricular proarrhythmia are reduced in males compared with females. Inward rectifier potassium current (IK(1)) is a primary determinant of the ventricular resting membrane potential, and an important contributor to myocardial excitability.