No abstract

A recent in vitro study demonstrated that supratherapeutic concentrations of sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, blocked I(Kr) and prolonged cardiac repolarization. This study assessed the in vivo cardiohemodynamic and electrophysiologic effects of sildenafil using a halothane-anesthetized, closed-chest canine model (n = 5) to bridge the gap between basic observation and clinical experience. Intravenous administration of sildenafil citrate in doses of 0.03, 0.3, and 3.0 mg/kg for 10 min, which provided sub-to supratherapeutic plasma drug concentrations, did not affect the monophasic action potential duration or effective refractory period of the right ventricle during the sinus rhythm as well as the ventricular pacing at the cycle length of 400 and 300 ms. However, sildenafil decreased the total peripheral resistance, simultaneously inducing positive chronotropic and inotropic effects at the top dose, which gave plasma concentrations at least 10 times higher than the therapeutic range. This cardiohemodynamic profile of sildenafil can be largely explained by reflex sympathetic activation associated with its vasodilator effect. Meanwhile, the lack of prolongation of the ventricular repolarization phase at the therapeutically relevant to moderately supratherapeutic sildenafil concentrations supports the earlier clinical studies that indicate that sildenafil has no effect on electrocardiogram.

miodarone is generally classified as a VaughanWilliams class III agent 1 and previous experimental studies have demonstrated that it effectively blocks the sodium and calcium channels and -adrenoceptors as well as the IKr, IKs, Ito, IK1, IKACh and IKNa potassium channels (IKr: rapidly activating component of delayed rectifier K + current; IKs: slowly activating component of delayed rectifier K + current; Ito: transient outward K + current; IK1: inward rectifier K + current; IKNa: Na + -activated K + current; IKACh: muscarinic acetylcholine receptor-operated K + current). [1][2][3][4][5][6][7][8][9] Amiodarone is now considered one of the most promising drugs for the treatment of life-threatening ventricular tachyarrhythmias in patients with structural heart disease. [10][11][12][13][14] Nevertheless, as with other antiarrhythmic agents, torsade de pointes (TdP) following QT interval prolongation has been a concern during amiodarone therapy in the setting of bradyarrhythmias and hypokalemia, although the incidence of TdP associated with amiodarone therapy is reportedly low. [15][16][17][18][19] However, the extent of the in vivo proarrhythmic potential of amiodarone remains incompletely understood because of the scarcity of adequate experimental model systems.The present study was designed to simultaneously assess the acute electrophysiological and proarrhythmic profiles of amiodarone using a canine chronic atrioventricular (AV) block model. 20,21 The model is a suitable large-animal model for the study of TdP because its hemodynamic status is stable despite an extreme bradycardia of 20-40 beats/min. [20][21][22][23][24][25][26] Previous studies have revealed the functional adaptations that predispose the canine AV block heart to acquired TdP; [21][22][23]26 namely, the repolarization period is prolonged not only by the bradycardia but also by the reduction of the delayed rectifier potassium currents (IKr and Iks). We administered amiodarone orally without anesthesia under continuous ECG monitoring to better mimic the clinical therapy, and compared the results with those of a selective IKr channel blocker, sematilide. 27-29 MethodsAll experiments were carried out according to the Guidelines for Animal Experiments of Yamanashi Medical University. Beagle dogs of either sex weighing approximately 10 kg were obtained through the animal Laboratory for Research of Yamanashi Medical University. Production of Complete AV BlockAV block was induced as previously described. 20 Briefly, the dogs were anesthetized with pentobarbital sodium (30 mg/kg, iv) and artificially ventilated with room air (Shinano, SN-480-3, Tokyo, Japan). Tidal volume and respiratory rate were set at 20 ml/kg and 15 strokes/min, respectively. Heparin calcium (200 IU/kg, iv) was administered to prevent blood clotting. The surface lead II ECG and systemic blood pressure at the right femoral artery were continuously monitored using a polygraph system (Nihon-Kohden, RM-6000, Tokyo, Japan) A quad-polar electrode catheter with a large tip of 4 mm (CordisCir...

The preparation was obtained from a beagle dog of either sex, weighing approximately 10 kg. The dog was anesthetized with pentobarbital sodium (30 mg/kg, iv), given heparin calcium (500 U/kg, iv) and exsanguinated. The heart was excised and plunged into cold Tyrode's solution kept at approximately 4°C.The sinoatrial node preparation consists of the entire right atrium. 5,7 The sinus node artery was cannulated through the right coronary artery. Bipolar recording electrodes were attached on the atrial epicardium close to the sinus nodal region.The papillary muscle preparation consists of the anterior papillary muscle of the right ventricle attached to the interventricular septum. 6,7 The anterior septal artery, which was the sole nutrient artery of the preparation, was directly cannulated. Bipolar stimulating electrodes were attached onto the His-bundle region.Blood-Donor Dog HBD dogs (Kitayama Labes, Yoshiki Farm, Gifu, Japan) of either sex, weighing 17-20 kg, were used as a blood donors. The dog was anesthetized Colforsin daropate is a recently developed water-soluble derivative of forskolin that directly stimulates adenylate cyclase, unlike the catecholamines. The chronotropic, inotropic and coronary vasodilator actions of colforsin daropate were compared with those of isoproterenol, dopamine and dobutamine, using canine isolated, bloodperfused heart preparations. The stimulating effect of each drug on adenylate cyclase activity was also assessed. Colforsin daropate, as well as each of the catecholamines, exerted positive chronotropic, inotropic and coronary vasodilator actions. The order of selectivity for the cardiovascular variables of colforsin daropate was coronary vasodilation >> positive inotropy > positive chronotropy; whereas that of isoproterenol, dopamine and dobutamine was positive inotropy >> coronary vasodilation > positive chronotropy. Thus, a marked characteristic of colforsin daropate is its potent coronary vasodilator action. On the other hand, each drug significantly increased the adenylate cyclase activity in a dose-related manner: colforsin daropate >> isoproterenol > dopamine = dobutamine. These results suggest that colforsin daropate may be preferable in the treatment of severe heart failure where the coronary blood flow is reduced and -adrenoceptor-dependent signal transduction pathway is downregulated. (Circ J 2002; 66: 1150 -1154

This study was designed to determine whether maternal stress levels, state and trait anxiety levels, and stress hormones affect fetal heart rate (FHR) patterns after vibroacoustic stimulation (VAS) at 30 weeks of gestation. A total of 24 healthy pregnant women with a single fetus pregnancy were enrolled. Corticotropin releasing hormone (CRH) and adrenocorticotropic hormone in maternal plasma and cortisol, and chromogranin A in saliva were measured. The FHR patterns after VAS were divided into three types: type I, a long period of acceleration or one acceleration lasting > 1 min or at least two accelerations lasting > 15 s; type II, a biphasic response with acceleration followed by deceleration; and type III, no response or prolonged deceleration. In the high trait anxiety group, CRH levels were significantly higher than in the low trait anxiety group, and FHR patterns after VAS showed mostly a type II response pattern. These findings suggest that stress in pregnant women with high trait anxiety may influence FHR patterns after VAS.