Cilnidipine is reported to show antihypertensive and neuroprotective actions in a rat brain ischemia model, but is barely distributed to normal brain, suggesting that its uptake into normal brain is inhibited by efflux transporter(s), such as P-glycoprotein (P-gp). Here, we investigated whether P-gp regulates the brain distribution of cilnidipine. Intracellular accumulation of cilnidipine was decreased in P-gp-overexpressing porcine kidney epithelial cells (LLC-GA5-COL150 cells) compared with control LLC-PK1 cells and the decrease was markedly inhibited by verapamil, a P-gp inhibitor. Further, cilnidipine concentration in the brain of P-gp knockout mice was significantly increased after cilnidipine administration, compared with that in wild-type mice. Moreover, when cilnidipine was administered to male spontaneously hypertensive rats (SHR) with tandem occlusion of the distal middle cerebral and ipsilateral common carotid artery, its concentration in the ischemic hemisphere was 1.6-fold higher than that in the contralateral hemisphere. This result was supported by visualization of cilnidipine distribution using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry (MALDI-TOF/MS) imaging. Our results indicated that cilnidipine is normally excluded from the brain by P-gp-mediated efflux transport, but P-gp function is impaired in ischemic brain and consequently cilnidipine is distributed to the ischemic region.

The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic antiarrhythmic drug pilsicainide on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein, and junctional region of the left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Pilsicainide (10 µM) decreased the conduction velocity in the pulmonary vein as well as the left atrium, whose effect on the pulmonary vein was relatively greater than that on the left atrium. The drug prolonged the effective refractory period in the pulmonary vein as well as the left atrium, and the effect of the drug on the pulmonary vein was less than that on the left atrium. The currently observed electrophysiological property of pilsicainide suggests that its effects on reentry within the pulmonary vein are estimated to be weaker than within the left atrium, which may be one of the key considerations for understanding its antiarrhythmic mechanisms in the atrium and pulmonary vein.

Abstract. The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.

We assessed the effects of oseltamivir on the conduction velocity and effective refractory period in the guinea-pig atrium in comparison with those of a class Ic antiarrhythmic drug pilsicainide. The recording and stimulating electrodes were attached on the epicardium close to the sinus nodal region and on the left atrial appendage. Oseltamivir (10-100 µM) as well as pilsicainide (1-10 µM) decreased the atrial conduction velocity in a frequency-dependent manner. Both drugs also increased the effective refractory period in both atria; but the frequency-dependent property of oseltamivir was lacking in the left atrium, and it was less obvious in the right atrium compared with that of pilsicainide. These results suggest that oseltamivir can directly modify the electrophysiological functions in the guinea-pig atrium possibly via combination of Na and K channel-blocking actions.Key words oseltamivir; pilsicainide; atrium; conduction velocity; effective refractory period A neuraminidase inhibitor oseltamivir is one of the most effective drugs against influenza virus infection.1) In a recent study using the halothane-anesthetized dog, we found a supratherapeutic dose of oseltamivir (30 mg/kg, intravenous (i.v.)) can exert the negative chronotropic, inotropic and dromotropic actions on the heart.2) More interestingly, the lower dose (3 mg/kg, i.v.), which is still 10 times higher than therapeutic dose range as an anti-influenza drug, increased the P-wave duration without affecting the other electrocardiographic variables. Since the P-wave duration reflects the intra-atrial conduction time, this observation may evoke a new category of drugs showing atrio-selective actions. However, since oseltamivir is known to be metabolized to the active form inhibiting neuraminidase (Ro64-0802), it is unknown whether oseltamivir itself affects the atrial impulse conduction. Our previous study using the isolated guinea-pig atrium electrically driven at 1 Hz demonstrated that 10-100 µM of oseltamivir can decrease the upstroke velocity of the phase 0 depolarization, but prolong the action potential duration, suggesting that the drug may affect ionic channels in the atrium such as Na + and K + channels.2) Using the isolated atrium of the guinea pig, in this study we assessed the effects of oseltamivir on the conduction velocity and effective refractory period at pacing cycle lengths of 150-250 ms in comparison with those of a class Ic antiarrhythmic drug pilsicainide to better understand electrophysiological profiles of oseltamivir in the atrium. MATERIALS AND METHODSAll experiments were performed according to the Guidelines for Animal Experiments for Toho University. The Hartley guinea pigs of either sex weighing 350-450 g were used in this study.The isolated atrial preparation consists of the entire right and left atrium of a guinea pig, which was incubated with the Krebs-Henseleit solution of the following composition (in mM): NaCl 118.4, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.2, NaHCO 3 24.9, glucose 11.1, gassed with 95% O 2 /5%...

These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug-induced TdP arrhythmias.