Arterial stiffness is often assessed in clinical medicine, because it is not only an important factor in the pathophysiology of blood circulation but also a marker for the diagnosis and the prognosis of cardiovascular diseases. Many parameters have so far been proposed to quantitatively represent arterial stiffness and distensibility, such as pressure-strain elastic modulus (Ep), stiffness parameter (β), pulse wave velocity (PWV), and vascular compliance (Cv). Among these, PWV has been most frequently applied to clinical medicine. However, this is dependent on blood pressure at the time of measurement, and therefore it is not appropriate as a parameter for the clinical evaluation of arterial stiffness, especially for the studies on hypertension. On the contrary, stiffness parameter β is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Although this index is obtained from the PWV between the heart and the ankle, it is essentially similar to the stiffness parameter β, and therefore it does not depend on blood pressure changes during the measurements. CAVI is being extensively used in clinical medicine as a measure for the evaluation of cardiovascular diseases and risk factors related to arteriosclerosis. In the present article, we will explain the theoretical background of stiffness parameter β and the process to obtain CAVI. And then, the clinical utility of CAVI will be overviewed by reference to recent studies.

Cilnidipine is a unique Ca2+ channel blocker with an inhibitory action on the sympathetic N‐type Ca2+ channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca2+ channel blockers with long‐lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N‐type Ca2+ channel‐blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.

The purpose of this study was to assess the cardiovascular effects of an ultra-short-acting beta-blocker, ONO-1101, by using halothane-anesthetized beagle dogs in comparison with esmolol. ONO-1101 (n = 6) or esmolol (n = 6) was administered at four infusion rates of 0.3, 3, 30, and 300 microg/ kg/min. Each infusion was performed over a 30-min period, and the parameters were measured at 20-30 min after the start of each infusion. ONO-1101 significantly decreased the heart rate, rate-pressure product, left ventricular contraction, cardiac output, and relative refractory period of the right ventricle, suppressed the AV nodal conduction, and increased the effective refractory period of the right ventricle, whereas no significant change was observed in the preload and afterload of the left ventricle, intrinsic sinus nodal automaticity, His-Purkinje-ventricular conduction, and the monophasic action-potential duration of the right ventricle. The cardiovascular effects of esmolol were comparable to those of ONO-1101, except that the preload of the left ventricle was significantly increased, and the ventricular repolarization phase was shortened by 300 microg/kg/min of esmolol infusion. Meanwhile, ONO-1101 as well as esmolol significantly reduced the isoproterenol-induced increase in heart rate and ventricular contraction, but the inhibitory action of ONO-1101 was 6-8 times greater than that of esmolol. These results suggest that the suppressive effects of ONO-1101 on cardiovascular performance are significantly less potent than those of esmolol at equipotent beta-blocking doses.

Abstract. We examined the involvement of the Na + /Ca 2+ exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca 2+transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca 2+ transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na + /Ca 2+ exchanger underlies the automaticity of the pulmonary vein myocardium.Keywords: pulmonary vein myocardium, NaPulmonary veins are considered to be involved in the initiation and maintenance of atrial fibrillation, one of the most frequent arrhythmias in clinical practice (1). Pulmonary veins contain a myocardial layer, whose electrical activity is considered to underlie their arrhythmogenic activity (2). The pulmonary vein myocardium has different electrophysiological properties from those of the working myocardium, including lower density of I K1 and a less negative resting membrane potential (3). The precise mechanisms of the pulmonary vein electrical activity as well as its pharmacological properties are now receiving attention as the basis to develop an effective therapeutic strategy against atrial fibrillation.The Na + /Ca 2+ exchanger (NCX) is involved in the physiological and pathophysiological regulation of Ca 2+ concentration in the myocardium. It functions both in the forward (Ca 2+ extrusion) and reverse (Ca 2+ influx) modes, and its functional role may vary with the region and the condition of the myocardium (4, 5). The forward mode NCX activity (inward current) is the major pathway for Ca 2+ extrusion from the cytoplasm and is also considered to be involved in the normal pacemaking of the rabbit sinoatrial node (6). It was postulated that the Ca 2+ released from the sarcoplasmic reticulum (SR) during the diastolic period is pumped out of the cell through the forward mode NCX, which generates an inward current that contributes to the diastolic depolarization of the pacemaker. Although it is possible that such a mechanism is involved in the automaticity of other myocardial regions including the pulmonary vein myocardium, pharmacological evidence is limited because of the lack of an NCX inhibitor with sufficient specificity. SEA0400 {2-[4-[(2,5-difluorophenyl) methoxy] phenoxy]-5-ethoxyaniline} is a potent and selective inhibitor of NCX in cultured neurons, astrocytes, microglia, dog sarcolemmal vesicles, and cultured rat myocytes with negligible affinities towards other transporters, ion channels, and receptors (7). We have previously shown that SEA0400 is a specific inhibitor of NCX in the myocardium (8, 9). SEA0400 (1 μM), which inhibited the NCX current by more than 80%, had no effect on the Na + current, L-type Ca 2+ current, delayed recti...

Background & purpose: The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects. Experimental approach & Key results:In transfected HEK cells, the IC 50 s for I hERG were 4576 and 8567259 mg ml -1 for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg -1 moxifloxacin (total peak-plasma concentrations 4.671.5 and 22.976.8 mg ml -1 ) prolonged the QT c in 6 anaesthetized dogs with chronic AV block by 773 and 21719%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.471.3 and 20.874.9 mg ml -1 ) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 mg kg -1 i.v.) caused QT c prolongation (29715%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.870.7 to 3.871.5 ms; Po0.05). Conclusion & implications:As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.