Adenosine, a potent natural suppressor of arachidonic acid release and leukotriene biosynthesis in human neutrophils.
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Adenosine↗
Biomedical subjects
S Picard
Publications and source records attributed to S Picard.
Synthetic optically pure statins.
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Journal Article↗
Cicletanine prevents the excitation-conduction blocks induced by terfenadine in ischemic myocardium.
Terfenadine, a histamine H(1) receptor antagonist, has been associated with clinical ventricular arrhythmias and in vitro excitation-conduction blocks, whereas anti-ischemic and antiarrhythmic effects have been shown with cicletanine, a prostacyclin generation stimulator. We aimed at determining in vitro if cicletanine can protect the ischemic myocardium from excitation-conduction blocks and specifically those induced by terfenadine. In a double-chamber bath, isolated guinea pig ventricular strips were partly exposed to normoxia and partly to ischemic, then reperfused, conditions, in the presence of 10 microM terfenadine, 10 microM indomethacin (prostacyclin generation blocker) or the solvent (dimethylsulfoxide 1:100, control) randomly allocated, and thus either in the absence (n=20) or presence (n=21) of 10 microM cicletanine during the total protocol duration. The multivariate Cox's model was used to predict the excitation-conduction block events and to assess the estimated survival of preparations (excitation-conduction block-free rate). Cicletanine protected the preparations (relative risk=0.08, t=-3.28) from the ischemia-induced excitation-conduction blocks (estimated survival=0.83 versus 0.30 in control), and this effect was abolished by indomethacin (estimated survival=0.35). Terfenadine enhanced 3. 58-fold the risk of occurrence of excitation-conduction blocks during ischemia (t=2.10) and this effect was inhibited by cicletanine pretreatment (estimated survival=0.40 versus 0.10 in untreated preparations). In conclusion, these in vitro findings have provided evidence for (1) protective effects of cicletanine against ischemia-induced excitation-conduction blocks, possibly related to its stimulating activity on local prostacyclin generation, and (2) efficacy of cicletanine to prevent excitation-conduction blocks induced by terfenadine in ischemic cardiac tissue.
Animals↗
Cosegregation analysis in genetic crosses suggests a protective role for atrial natriuretic factor against ventricular hypertrophy.
In most rat models studied to date, increased ventricular mass is associated with high ventricular expression of the atrial natriuretic factor (ANF) gene. However, it is unknown whether ANF plays a beneficial or detrimental role in the course of left ventricular hypertrophy or whether ANF gene expression could be genetically linked to cardiac mass. To address such questions, we performed a cosegregation analysis in genetic crosses of inbred strains of rats. To select strains with the appropriate phenotypic characteristics, we first compared the ventricular abundance of ANF mRNA to ventricular mass (corrected for body weight) in 2 recombinant inbred strains derived from Wistar-Kyoto (WKY)/spontaneously hypertensive rat (SHR) hybrid crosses, ie, WKY-derived hyperactive (WKHA) and WKY-derived hypertensive (WKHT) rats, as well as in their parental inbred strains. In the 2 such strains that were normotensive, we observed that ventricular mass was higher in WKHA than in WKY rats, yet ventricular ANF mRNA was less abundant in WKHA than in WKY rats. Within a segregating population of F2 animals generated from a cross between WKY and WKHA genitors, the abundance of ventricular ANF mRNA and peptide correlated inversely with left ventricular mass, in contrast to the positive correlation observed with beta-myosin heavy chain mRNA. Finally, in the equally hypertensive SHR and WKHT strains, we found that ventricular mass was higher in SHR than in WKHT, yet ventricular ANF mRNA was less abundant in SHR than in WKHT. These results demonstrate for the first time that low ventricular ANF gene expression can be linked genetically to high cardiac mass independently of blood pressure and are consistent with a protective role for ANF against left ventricular hypertrophy.
Actins↗
Induction of intrauterine growth restriction with a low-sodium diet fed to pregnant rats.
OBJECTIVE: A low-sodium diet fed to female rats before mating through parturition leads to pups of lower weight. We characterized the effect of low dietary sodium during the last week of gestation (after fetal organogenesis) on fetal and maternal homeostasis. STUDY DESIGN: Pregnant Sprague-Dawley rats were randomly assigned to a control group or to a group fed a low-sodium diet from gestational days 15 through 22. Systolic blood pressures were measured throughout pregnancy. On day 22 plasma volume was measured and blood samples were taken for electrolyte and hormonal measurements. Fetal and placental weights were also determined. RESULTS: Plasma renin activity and aldosterone level were significantly higher in the experimental group than in the control group. Plasma volume was significantly lower in pregnant rats receiving a low-sodium than in those receiving a control diet. Rats receiving a low-sodium diet had pups of lower weight and length (4.45 +/- 0.22 g, 3.90 +/- 0.06 cm) than pups of the control group (5.21 +/- 0.12 g, 4.10 +/- 0.02 cm). Pups born to mothers with low-sodium diets recuperated from intrauterine growth restriction by 14 days after birth. CONCLUSION: These data indicate that a low-sodium diet given to pregnant rats for the last 7 days of gestation leads to reduced plasma volume expansion and fetal growth restriction. This could prove to be a simple animal model for studying the relationship between maternal plasma volume and fetal growth.
Aldosterone↗
KATP channels and 'border zone' arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions.
1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias.
ATP-Binding Cassette Transporters↗
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 microM, at 1,000 ms of cycle length (CL) and 37 degrees 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 degrees C) of human atrial AP duration 90% (APD90) shortening (10 microM 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 degrees 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 < 0.05); APD90 was shortened in all tissues (p < 0.01). Median effective concentration (EC50) for APD90 shortening at 37 degrees C was 0.54 and 2.74 microM in atrial and ventricular human tissue, respectively, and 8.55 and 0.89 microM in atrial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31 degrees C, EC50 with bimakalim was 0.39 microM; a much higher value was seen with nicorandil (210 microM). Bimakalim (10 microM)-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 approximately 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 microM.
Action Potentials↗
Protection of human myocardium in vitro by K(ATP) activation with low concentrations of bimakalim.
We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel activation by bimakalim, at concentrations devoid of both negative inotropic and action-potential duration (APD) shortening effects, might exhibit myocardial protection after hypoxia and reoxygenation in human atrial myocardium by using 112 preparations. The recovery of contractility of human atrial trabeculae, subjected either to short-duration (5 min) or to long-duration (60 min) and severe (high pacing rate) hypoxia followed by reoxygenation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nM bimakalim, 1 microM glibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD90 were studied. At concentrations <100 nM, bimakalim showed no negative inotropic effects and did not modify significantly APD90 either in normoxia or in hypoxic conditions. In the short-duration hypoxia protocol, preparations treated with bimakalim showed a dobutamine-induced %DT increase significantly higher (p < 0.001) than in controls and similar to that observed in the absence of hypoxia. This bimakalim effect was blocked by glibenclamide. In the long-duration hypoxia protocol, %DT after dobutamine was 50% of that observed in normoxic preparations. Preparations treated with bimakalim showed after dobutamine %DT more than twofold above controls (p < 0.001), whereas in the glibenclamide group, recovery of DT with dobutamine remained 50% of what observed in normoxia (p < 0.001). In conclusion, exposure to hypoxia (either short- or long-lasting) and reoxygenation affects contractility of human atrial myocardium with pronounced reduction of the positive inotropic action of dobutamine. Pretreatment with bimakalim restores the response expected in the absence of hypoxia, and glibenclamide blocks the effect of bimakalim or further impairs the response to dobutamine when used alone before long-duration hypoxia. Evidence is provided for protective effects of the K(ATP) opener bimakalim on the human myocardial contractile function in conditions of hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90 shortening are not contributory.
Adenosine Triphosphate↗
Activation of leukotriene synthesis in human neutrophils by exogenous arachidonic acid: inhibition by adenosine A(2a) receptor agonists and crucial role of autocrine activation by leukotriene B(4).
We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is the consequence of A(2a) receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when adenosine is eliminated from PMN suspensions by the addition of adenosine deaminase, or when cells are incubated with adenosine A(2a) receptor antagonists, important quantities (40-80 pmol/10(6) cells) of 5-lipoxygenase products are synthesized by PMN incubated with 1 to 5 microM exogenous AA. The selective A(2a) receptor agonist CGS21680 was a very potent inhibitor of the AA-induced leukotriene (LT) synthesis, showing an IC(50) of approximately 1 nM. The mechanism of AA-induced stimulation of LT synthesis observed in the absence of extracellular adenosine was investigated. In adenosine deaminase-treated PMN, exogenous AA induced Ca(2+) mobilization and the translocation of 5-lipoxygenase to nuclear structures. A time lag of 20 to 60 s (variable between PMN preparations) was observed consistently between the addition of AA and the elevation of intracellular Ca(2+) concentration (and LT synthesis), indicating that AA itself did not trigger the Ca(2+) mobilization in PMN. This AA-induced Ca(2+) mobilization, as well as the corresponding 5-lipoxygenase translocation and stimulation of LT synthesis, was blocked efficiently by the LT synthesis inhibitor MK0591, the LTB(4) receptor antagonists CP105696 and LY223982, and the LTA(4) hydrolase inhibitor SC57461A. These data demonstrate that AA is a highly potent and effective activator of LT synthesis and acts through a mechanism that requires an autocrine stimulatory loop by LTB(4).
Adenosine↗
Implication of D2-like dopaminergic receptors in the median eminence during the establishment of long-day inhibition of LH secretion in the ewe.
In ewes, photoperiod modulates LH release and dopaminergic terminals in the median eminence (ME) have a critical role in the establishment of long-day inhibition of LH secretion. This study was undertaken to determine the type of dopaminergic receptors, D1-like or D2-like, that mediate the action of dopamine on LH secretion at the ME level in this situation. This was assessed, in ovariectomized and estradiol-treated ewes, with the use of reverse microdialysis in the ME in three experiments: first, when LH secretion was stimulated by short days, by determining the response to three doses (0.01, 0.1 or 1 mg/ml) of a D1-like (SKF38393) and a D2-like (quinpirole) agonist; secondly, during early long-day inhibition of LH secretion, by determining the ability of SKF38393 and quinpirole (1 mg/ml) to mimic the inhibitory effects of dopamine, after a blockade of its synthesis with alpha-methyl-para-tyrosine (alphaMPT; 2 mg/ml); and thirdly, during early long-day inhibition of LH secretion, by determining the response to three doses (0.009, 0.09 or 0.9 mg/ml) of a D1-like (SCH23390) and a D2-like (sulpiride) antagonist. In none of the conditions was effect of the D1-like analogs on LH secretion found, compared with the control treatments. In contrast, the D2-like analogs caused changes in LH secretion. First, with short days, quinpirole in the highest dose significantly reduced mean LH concentration (P<0.05) and LH pulse frequency (P<0.01). Secondly, with long days, addition of quinpirole to alphaMPT caused a significant decrease in LH secretion relative to alphaMPT alone (P<0.05). Thirdly, with long days, sulpiride at the highest dose significantly increased mean LH concentration (during the first 3 h of treatment, P<0.05) and LH pulse frequency (P<0.05). Prolactin secretion was also determined in these experiments, and D2-like agonist and antagonist caused an inhibition and a stimulation of prolactin secretion, respectively. These results demonstrate that, in the ME, inhibitory action of dopamine on LH secretion, critical for the initiation of long-day-induced inhibition, is mediated by D2-like, not D1-like, dopaminergic receptors.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
[Lipotoxicity and glycemic regulation].
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Blood Glucose↗
The GnRH increase following progesterone withdrawal is associated with an increased glutamatergic tone in the preoptic area of the ovariectomized ewe.
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Animals↗
KATP channel modulators and myocardial damages induced by ischemia-reperfusion: membrane lipids injury and arrhythmias.
Although KATP channels have been proposed as playing a role in most types of myocardial damage associated with ischemia/reperfusion, the potential benefits of KATP channel modulators against the biochemical and electrical disturbances observed during ischemia remain unclear. We have thus studied the effects of glibenclamide and cromakalim, KATP channel blocker and opener respectively, on membrane lipid injury and arrhythmias, in a model of ischemic-reperfused guinea-pig myocardium. Ventricular strips were prelabeled with [3H] arachidonic acid, then subjected to normal conditions (Time-related Control) or to simulated ischemic-reperfused conditions in absence of drug (Control) or in presence of glibenclamide 10 microM or cromakalim 10 microM. The release of radioactive compounds was counted by liquid scintillation spectrometry, while action potentials (AP) were recorded with intracellular microelectrodes. Reperfusion induced a significant increase of arachidonic acid release (P < 0.05 versus Time-related Control). Glibenclamide inhibited the reperfusion-induced arachidonic acid release while cromakalim only delayed it (respectively 483 +/- 87 dpm/g, P < 0.05 and 790 +/- 143 dpm/g. NS versus 838 +/- 80 dpm/g for Control, after 30 min of reperfusion). Unlike glibenclamide, cromakalim was proarrhythmic during reperfusion (in 100% of preparations versus 33% in Control or in presence of glibenclamide, P < 0.05). This in vitro study shows that glibenclamide prevented the reperfusion-induced membrane arachidonic acid release, without proarrhythmic effect, whereas cromakalim, associated with proarrhythmicity, was unable to protect myocardium from cell lipid damage.
Action Potentials↗
Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus.
Paraoxonase (PON) is an HDL-bound enzyme capable of hydrolyzing lipid peroxides and believed to be in part responsible for the protective effect of HDL against LDL oxidation. Its activity is mainly determined by a gene polymorphism of the PON 1 gene (Glu-Arg 192). Low activity has been related to an elevated incidence of myocardial infarction. In several case-control studies, however, the high activity B allele is paradoxically more prevalent in patients. We have re-investigated this relationship, using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. Genotypes were determined in 197 non insulin-dependent diabetic patients (HbAlc 8.8+/-0.15%, BMI 28.3+/-0.36). IMT, measured by high resolution mode B ultrasound, was the same for all genotypes (AA: 0.83+/-.013, AB 0.82+/-.017 and BB: 0.81+/-.034 mm). Bearers of the B allele displayed higher Lp(a) concentration (AA: 197+/-28, AB: 221+/-26, BB: 225+/-45 mg/l, P=0.024) with a significant linear trend (P < 0.005). Multiple regression showed age and systolic blood pressure, but not Lp(a), to be the main determinants of IMT variability without the contribution of the PON genotype. No consistent differences could be found between genotypes in the peroxidizability of LDL (lag-time, rate of diene production and maximal concentration). Our data support the view that there is no association between the early changes of atherosclerosis as defined by carotid IMT and variation in codon 192 of PON 1.
Age Factors↗
Blockade of tyrosine hydroxylase activity in the median eminence partially reverses the long day-induced inhibition of pulsatile LH secretion in the ewe.
The photoperiod-induced stimulation of LH secretion is associated with a decrease in dopamine content, as well as in the activity of its rate limiting enzyme, tyrosine hydroxylase (TH), in the median eminence (ME) of the ewe. We therefore hypothesize that ME-TH activity can constitute a limiting factor of photoperiod-induced inhibition of LH pulsatile secretion. To test this hypothesis, we studied whether the inhibition of ME-TH activity can reverse the long day-induced inhibition of LH. Using microdialysis, a 3 mM solution of alpha methyl-p-tyrosine (alpha MPT; a competitive inhibitor of TH), was administered in the ME of ovariectomized ewes bearing a 0.5 cm oestradiol implant at the beginning of a LD-induced inhibition of LH secretion. The vehicle solution was infused for 4 h followed by a 3 mM alpha MPT solution infused for an additional 4 h. LH pulsatile secretory patterns within the same animal were compared between the control period and the alpha MPT period. alpha MPT infusion in the ME was associated with an increase in LH pulse frequency whereas it did not affect prolactin secretion. In conclusion, our results suggest that the inhibition of TH activity in the ME causes a stimulation of LH secretion in long-day inhibited ewes.
Animals↗
Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B4 in chemotactic peptide-stimulated human neutrophils.
The goal of this study was to explain the priming effect of lipopolysaccharides (LPS) in human polymorphonuclear leukocytes on leukotriene B4 (LTB4) biosynthesis after stimulation with the receptor-mediated agonist formyl-methionyl-leucyl-phenylalanine (fMLP). This priming effect for LTB4 biosynthesis was maximal after a 30 min preincubation with LPS but was lost when incubations were extended to 90 min or longer. Priming with LPS resulted in an enhanced maximal activation of 5-lipoxygenase (5- to15-fold above unprimed cells) as well as a prolonged activation of the enzyme after stimulation with fMLP compared to that measured in unprimed cells. The activation of 5-lipoxygenase was associated with its translocation to the nuclear fraction of the cell after stimulation of LPS-primed cells but not of unprimed cells. Priming of cells with LPS also resulted in an enhanced capacity (fivefold increase) for arachidonic acid (AA) release after stimulation with fMLP compared to unprimed cells as measured by mass spectrometry. This release of AA was very efficiently blocked in a dose-dependent manner by the 85 kDa cytosolic phospholipase A2 (PLA2) inhibitor MAFP (IC50=10nM) but not by the 14 kDa secretory PLA2 inhibitor SB 203347 (up to 5 microM), indicating that the 85 kDa cPLA2 is the PLA2 responsible for AA release in response to receptor-mediated agonists. In accord with inhibitor studies, the LPS-mediated phosphorylation of cPLA2 followed the same kinetics as the priming for AA release, and a measurable fMLP-induced translocation of cPLA2 was observed only in primed cells. As with AA release and LTB4 biosynthesis, both the phosphorylation and capacity to translocate cPLA2 were reversed when the preincubation period with LPS was extended to 120 min. These results explain some of the cellular events responsible for the potentiation and subsequent decline of functional responses of human polymorphonuclear leukocytes recruited to inflammatory foci.
Arachidonate 5-Lipoxygenase↗
Proarrhythmic and antiarrhythmic effects of bupivacaine in an in vitro model of myocardial ischemia and reperfusion.
BACKGROUND: Bupivacaine may have toxic cardiovascular effects when accidentally administered by intravascular injection. However, its electrophysiologic effects in the presence of myocardial ischemia remain unknown. The authors evaluated the electrophysiologic and anti- and proarrhythmic effects of bupivacaine in an in vitro model of the ischemic and reperfused myocardium. METHODS: In a double-chamber bath, a guinea pig right ventricular muscle strip was subjected partly to normal conditions and partly to simulated ischemia followed by reperfusion. The electrophysiologic effects of bupivacaine were studied at 1, 5, and 10 microM concentrations. RESULTS: Bupivacaine (5 and 10 microM) decreased the maximal upstroke velocity of the action potential (Vmax) in normoxic conditions and further decreased (10 microM) the Vmax decrease induced by ischemic conditions. Bupivacaine reduced the mean occurrence time to the onset of myocardial conduction blocks (9 +/- 3 min; mean +/- SD; P < 0.005 with 5 and 10 microM, compared with 17 +/- 6 min during simulated ischemia with no drug or control), and it increased the number of preparations that became inexcitable to pacing (55% of preparations, with 1 microM and 100% with 5 and 10 microM, compared with 17% for the control group). The incidence of spontaneous arrhythmias was reduced by 5 and 10 microM bupivacaine during ischemia and reperfusion and was enhanced by 1 microM bupivacaine during the ischemic phase. CONCLUSIONS: In guinea pig myocardium under ischemic conditions, bupivacaine induced a loss of excitability at concentrations of 5 and 10 microM. Proarrhythmic effects observed at 1 microM were considered as lower than the cardiotoxic range in normoxic conditions. The incidence of reperfusion arrhythmias was decreased at all concentrations.
Action Potentials↗
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 microM) 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. DL- And D-sotalol, 5 and 10 microM, lengthened AP duration 90% (APD90) 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, DL- and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (chi2 = 24.79; p = 0.0367): 83 (5 microM D- and DL-sotalol), 86, and 62% (10 microM D- and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 microM DL-sotalol prevented the occurrence of spontaneous arrhythmias (chi2 = 46.74; p = 0.0001) similar to what seen with the beta-blocking agent propranolol (10 microM). 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.
Action Potentials↗