Electrophysiological effects of azimilide in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium

There are few investigations on azimilide effects during ischemia/reperfusion. We have therefore investigated low concentrations of azimilide (0.1 and 0.5 mu mol/l) versus Controls on action potential parameters and occurrence of repetitive responses during simulated ischermia and reperfusion. An in vitro model of "border zone" in guinea-pig ventricular myocardium (n = 30) was used. Azimilide 0.5 mu mol/l lengthened action potential duration in normoxic but not in ischemic-like conditions. Therefore an increased dispersion of action potential duration at 90% of repolarization during simulated ischemia in presence of azimilide was seen. Upon reperfusion, both normal and reperfused myocardium. showed azimilide-induced action potential duration increase. There was a neutral effect on the occurrence of arrhythmias during simulated ischemia; however azimilide showed significant (P = 0.033) antiarrhythmic properties following reperfusion. To Mimic I-Kr and I-Ks blocking properties of azimilide we further used dofetilide 10 nmol/l with HMR 1556 1 nmol/l (N = 9), which was accompanied by less severe shortening (P < 0.05) of action potential duration at 90% of repolarization at 30 min of ischemic-like conditions (-43 +/- 9%), as compared with azimilide 0.5 mu mol/l (-64 +/- 5%) but similar to what seen with azimilide 0.1 mu mol/l (-53 +/- 5%) and Controls (-52 +/- 6%). During reperfusion, 2/9 (22%) preparations had sustained activities, which was less than what observed in Controls (5/10, 50%) and with azimilide 0.5 mu mol/l (0/10, 0%), although not statistically different (respectively, P = 0.35 and P = 0.21). Lack versus homogenous class III effects of azimilide in respectively simulated ischemia and reperfusion may explain its different efficacy on arrhythmias, although prevention of reperfusion arrhythmias calls for other than just its I-Kr and I-Ks blocking properties. (c) 2005 Elsevier B.V. All rights reserved

Proarrhythmic effects of DL- and D-sotalol on the "border zone" between normal and ischemic regions of isolated ventricular myocardium and antiarrhythmic effects on reperfusion

Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 mu M) in an in vitro model of "border zone" arrhythmias. Isolated guinea-pig ventricular strips were partly exposed to normoxia ("Normal Zone," NZ) and partly to modified Tyrode's solution ("Ischemic Zone," IZ) for 15 or 30 min ("ischemia"), followed by return to normoxia for 30 min ("reperfusion"). Resting membrane potential, action potential (AP) amplitude, and maximal upstroke velocity of AP were not significantly modified. Dr- And D-sotalol, 5 and 10 mu M, length ened AP duration 90% (APD(90)) in NZ (p < 0.05), whereas these drugs were unable to prevent ischemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to control random variability of analyzed covariates, Dr-and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (chi(2) = 24.79; p = 0.0367): 83 (5 mu M D- and DL-sotalol), 86, and 62% (10 mu M D-and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 mu M DL-sotalol prevented the occurrence of spontaneous arrhythmias (chi(2) = 46.74; p = 0.0001) similar to what seen with the beta-blocking agent propranolol (10 mu M). These data, providing evidence for proarrhythmic effects of DL- and D-sotalol on border-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study results

Effects of bimakalim on human cardiac action potentials: Comparison with guinea pig and nicorandil and use-dependent study

Electrophysiologic effects of K(ATP) channel openers (KCOs) are rarely studied for tissue and species specificity, and use-dependent investigations in human tissues are lacking. We therefore investigated in vitro the concentration-dependent effects of the KCO bimakalim [from 10 nM to 10 μM, at 1,000 ms of cycle length (CL) and 37°C] on human (atrium, n = 4, and ventricle, n = 6) and guinea pig (atrium, n = 7, and ventricle, n = 6) transmembrane action potential (AP). The frequency relation (from CL 1,600 to 300 ms, 31°C) of human atrial AP duration 90% (APD90) shortening (10 μM vs. baseline, n = 7) also was determined. A parallel study was performed with the KCO nicorandil (from 10 nM to 1 mM, n = 3) in human atrial APs, at 31 °C. Resting membrane potential and maximal upstroke velocity of AP were not modified by bimakalim at maximal concentration, whereas AP amplitude was decreased in both guinea pig preparations (p &lt; 0.05); APD90 was shortened in all tissues (p &lt; 0.01). Median effective concentration (EC50) for APD90 shortening at 37°C was 0.54 and 2.74 μM in atrial and ventricular human tissue, respectively, and 8.55 and 0.89 μM in atrial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31°C, EC50 with bimakalim was 0.39 μM; a much higher value was seen with nicorandil (210 μM). Bimakalim (10 μM)-induced APD90 shortening as a function of stimulation rate was greatest at longest CL. Evidence is provided for (a) species (human vs. guinea pig) and tissue (atrium vs. ventricle) differential AP sensitivity to bimakalim; (b) an ≃500-fold higher efficacy of bimakalim versus nicorandil to shorten human atrial APD90; and (c) normal use- dependence of human atrial APD90 shortening with bimakalim at 10 μM

Silent dissemination of HTLV-1 in an endemic area of Argentina. Epidemiological and molecular evidence of intrafamilial transmission

Molecular and epidemiological studies of transmission routes and risk factors for infection by HTLV-1 are extremely important in order to implement control measures, especially because of the high prevalence of HTLV-1 in several regions of the world. San Salvador de Jujuy, Northwest Argentina, is a highly endemic area for HTLV-1 and foci of tropical spastic paraparesis/HTLV-1-associated myelopathy.To gain further insight into the role of intrafamilial transmission of HTLV-1 in a highly endemic region in Argentina.Cross-sectional study in Northwest Argentina. Epidemiological data and blood samples were collected from 28 HTLV-1 infected subjects (index cases) and 92 close relatives/cohabitants. HTLV-1 infection was diagnosed by detection of antibodies and proviral DNA. The LTR region was sequenced and analyzed for genetic distances (VESPA software), in addition to determination and identification of polymorphisms to define HTLV-1 family signatures.Fifty seven of the 120 subjects enrolled had antibodies against HTLV-1 and were typified as HTLV-1 by PCR. The prevalence rate of HTLV-1 infection in family members of infected index cases was 31.52% (29/92). The infection was significantly associated with gender, age and prolonged lactation. Identity of LTR sequences and presence of polymorphisms revealed high prevalence of mother-to-child and interspousal transmission of HTLV-1 among these families.There is an ongoing and silent transmission of HTLV-1 through vertical and sexual routes within family clusters in Northwest Argentina. This evidence highlights that HTLV-1 infection should be considered as a matter of public health in Argentina, in order to introduce preventive measures as prenatal screening and breastfeeding control