Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation.

Hypokalemia, an abnormally low level of potassium (K + ), is a electrolyte imbalance that commonly occurs in heart failure patients. Hypokalemia is well known to induce lethal ventricular arrhythmia. However, the effects of hypokalemia in failing hearts that have undergone electrophysiological remodeling, i.e., the reactivation of fetal-type ion channels, remain unexplored. We have examined the effect of hypokalemia in the myocytes of transgenic mice overexpressing the hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channel in the heart (HCN2-Tg mice). Perfusion with a mild hypokalemic solution containing 3 mM K + induced ectopic ventricular automaticity in 55.0% of HCN2-Tg mouse myocytes. In the remaining HCN2-Tg mouse myocytes, the resting membrane potential (RMP) was more depolarized than that of wild-type myocytes subjected to the same treatment and could also be hyperpolarized by an HCN channel blocker. We conclude that in hypokalemia in our mice model, the HCN2 channel was constitutively activated at the hyperpolarized RMP, thereby destabilizing the electrophysiological activity of ventricular myocytes.

Background Methamphetamine abuse is a serious public health concern and causes various life-threatening disorders including pulmonary arterial hypertension (PAH). Herein, we present the first case report describing the anesthetic management of a patient with methamphetamine-associated PAH (M-A PAH) undergoing laparoscopic cholecystectomy. Case presentation A 34-year-old female with M-A PAH suffered from deterioration of right ventricular (RV) heart failure due to recurrent cholecystitis and was scheduled for laparoscopic cholecystectomy. Preoperative assessment of PA pressure showed 82/32 (mean, 50) mmHg, and transthoracic echocardiology revealed a slight reduction of RV function. General anesthesia was induced and maintained by thiopental, remifentanil, sevoflurane, and rocuronium. PA pressure gradually increased after peritoneal insufflation; therefore, we administered dobutamine and nitroglycerin to decrease pulmonary vascular resistance (PVR). The patient emerged from anesthesia smoothly. Conclusions Avoiding increased PVR by appropriate anesthesia and medical hemodynamic support is an important consideration for patients with M-A PAH.

The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side.