The effectiveness of three new antiarrhythmic drugs, aprindine, mexiletine and tocainide in elevating ventricular fibrillation threshold measured in the Langendorff-perfused rabbit heart and in protecting against ouabain-induced arrhythmias in the Langendorff-perfused guineapig heart has been compared with that of lignocaine. All these drugs have produced a significant rise in the threshold but quantitatively mexiletine was about equal ta, tocainide five times less and aprindine thirty-eight times more potent than lignocaine in this effect. Aprindine differed from the other three drugs in that it had a slow onset of action and its effect was not entirely removed upon reperfusion with the drug-free solution. Only aprindine and mexiletine provided complete protection against ouabain-induced ventricular fibrillation while 3 of 6 and 4 of 6 hearts fibrillated in the presence of lignocaine or tocainide respectively. . The purpose of this study was to investigate the antifibrillatory properties of these three new drugs and to compare their potency with that of lignocaine under the same experimental conditions using two models, a n electrically-induced and a drug-induced ventricu-* Correspondence. lar fibrillation in the Langendorff-perfused heart of rabbits and guinea-pigs. M E T H O D SElectrically-induced fibrillation in the Langendorffperfused rabbit heart New Zealand White rabbits of either sex, 0.9-1.5 kg, were killed by a blow on the head and bled. The heart was rapidly removed and placed in McEwen's solution (1956) containing in mmol litre-l: NaCl 130, KCI 5.6, CaCI, 2.2, NaH,PO, 0.9, NaHCO, 25, glucose 1 I and sucrose 13. This was gassed with 95 % 0, and 5 % CO, and the pH was 7.3 to 7.4. The aorta was immediately cannulated and coronary perfusion was started at a pressure of about 6 KPa (60 cm H,O) a t 37 "C. Perfusion with pure McEwen's solution or this solution with a drug could be selected by turning a tap. A small stainless steel hook was passed through the ventricular apex and connected to a force displacement transducer, by which the amplitude of contraction was recorded on one channel of an oscillograph. Two silver-silver chloride wires were connected to the heart through two wick electrodes which were placed on the anterior surface of the base of the two ventricles to record the electromyogram. This was displayed on an oscilloscope (Airmec type 279) and was recorded on a second channel of the oscillograph. The heart was stimulated through the hook attached t o the apex and another connected to the base of the left ventricle. In order to test whether there was likely to be mechanical

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR)-α activator that lowers triglycerides and influences cytochrome P-450 (CYP-450) epoxygenase-dependent arachidonic acid (AA) metabolism. CYP-450 epoxygenase metabolizes AA to epoxyeicosatrienoic acids (EETs). EETs have coronary dilating and cardiac and renal protective properties. Fibrates possess similar properties due to their CYP-450 epoxygenase-inducing properties that lead to increase in endogenous EET production. In the current investigations, fenofibrate (100 mg/kg, orally) for 2 weeks decreased ischemia-/reperfusion (I/R)-induced premature ventricular contractions (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF) in the isolated rat hearts. Fenofibrate caused marked inhibition of the reperfusion-induced cardiac arrhythmias. The incidence of reperfusion-induced VF decreased from 80% in the control vehicle-treated animals to 33% in the fenofibrate-treated animals (P < 0.001). PVCs were also significantly (P < 0.01) decreased from 223.2 ± 51 in control vehicle-treated animals to 136.8 ± 22 in fenofibrate-treated animals. Total duration of reperfusion-induced VT decreased from 29.2 ± 6.3 s in control, vehicle-treated animals to 4.8 ± 1.3 s in fenofibrate-treated animals, P < 0.001. Heart rate and perfusion pressure were not significantly affected by fenofibrate pretreatment. Diltiazem, a clinically used anti-arrhythmic agent, produced complete protection against I/R-induced cardiac arrhythmias in this model reducing the incidence of VF from 80% in control, vehicle-treated animals to 10% in diltiazem-treated hearts. These findings indicate that fenofibrate suppresses arrhythmias in isolated rat hearts subjected to I/R-induced injury.

We studied the influence of balloon valvuloplasty on alpha- and beta-adrenoceptor densities, plasma catecholamine, and cAMP levels in children and infants with pulmonary stenosis before and 10 min after balloon dilatation, employing as controls children undergoing transcatheter occlusion of patent ductus arteriosus (PDA) with Qp/Qs ratio < 1.5. In the PDA group, the alpha-adrenoceptor density (Bmax) was 3.75 +/- 0.72 fmol/10(7) cells (n = 15) before occlusion and remained unchanged at 3.35 +/- 0.47 fmol 10 min thereafter. In the pulmonary stenosis patients (n = 31), the receptor density was 59% higher (p < 0.05) before, and decreased to PDA levels 10 min after, the procedure. The control beta-adrenoceptor density was 64.8 +/- 11.0 fmol/10(6) cells before, and 71.2 +/- 13.2 fmol 10 min after, occlusion. In the study group, the density was 23% lower (p < 0.07) and increased to the PDA levels 10 min after the dilatation. Compared with the PDA, pre- and postdilatation plasma norepinephrine levels were not significantly changed; epinephrine was slightly elevated before, but increased by 73% after, dilatation; dopamine was 80% (p < 0.05); and cAMP was 37% higher before, and remained elevated at 70 and 23% above the PDA values after, the procedure. Accordingly, alpha-adrenoceptor density is significantly elevated in children with pulmonary stenosis and decreases significantly immediately after balloon valvuloplasty. On the other hand, beta-adrenoceptor density is attenuated and increases toward normal levels after the procedure. The immediate reversal of the receptor levels after balloon valvuloplasty suggests that this procedure exerts acute effects on the sympathetic functional level in this disease.

1 In Langendorff-perfused rabbit hearts, electrical stimulation threshold and ventricular fibrillation threshold (VFT) were measured by applying rectangular impulses of 3 ms duration and increasing current at frequencies of 4 and 20 Hz respectively. 2 Perfusion with lignocaine or one of three new antiarrhythmic drugs, encainide, lorcainide and ORG 6001, produced significant, dose-dependent increases in both thresholds. 3 On a dosage basis, encainide was seven times, lorcainide fourteen times and ORG 6001 twice as potent as lignocaine in raising VFT. 4 In Langendorff-perfused guinea-pig hearts, only lorcainide provided complete protection against ouabain-induced ventricular fibrillation, while 6 of 6,3 of 6 and 2 of 6 hearts fibrillated in the presence of encainide, lignocaine and ORG 6001 respectively, but with infusion durations significantly higher than control.5 These results indicate the potential antifibrillatory activity of these new antiarrhythmic agents.

We studied the a-and P-adrenoceptor activity and catecholamine and cAMP levels in 112 children and infants admitted to the hospital for diagnostic or inte~entional catheterization of tetralogy of Fallot, ventricular septa1 defects with or without hypertension, pulmonary stenosis, coarctation of the aorta, and various complex cyanotic congenital cardiac diseases and compared them with 14 children undergoing transcatheter occlusion of patent ductus arteriosus with insignificant left-to-right-shunts. The mean total platelet a-adrenoceptor density of the study population was elevated by 73%. Both the increases in acyanotic ( p < 0.05) and cyanotic ( p < 0.005) patients as well as the difference between the two groups ( p < 0.01) were significant.Based on the congenital disease classification, the elevation in receptor density was also significant in all groups of patients, except coarctation of the aorta. On the other hand, the mean lymphocyte P-adrenoceptor density was attenuated by 27%, showing significant difference between the acyanotic and the patent ductus arteriosus groups, but none between acyanotic and cyanotic or cyanotic and the patent ductus arteriosus groups. Among the congenital groups, only the left-to-right shunts and the pulmonary stenosis group showed significant ( p < 0.05) decrease in P-adrenoceptor density, whereas the affinity of all the groups toward [125~]iodocyanopindolol was hardly influenced. The plasma levels of all three catecholamines, norepinephrine, epinephrine, and dopamine, were elevated, but cAMP remained unchanged. It seems that the sympathetic nervous system responds to changes triggered by some congenital heart diseases by stimulating a-adrenoceptors, which may be further increased by cyanosis and an attenuation of P-adrenoceptors associated with an increase in plasma catecholamine levels. (Pediatr Res 38: 55-60, 1995) Abbreviations ACY, acyanotic group CYN, cyanotic group TOF, tetralogy of Fallot LRS, left-to-right shunts PST, pulmonary stenosis COA, coarctation of the aorta CPL, complex cyanotic heart diseases PDA, patent ductus arteriosus QpIQs ratio, ratio of pulmonary blood flow to systemic blood flow