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.

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.

Felodipine protects human atrial muscle from hypoxia-reoxygenation dysfunction: a force-frequency relationship study in an in vitro model of stunning.

AIMS: We aimed at investigating contractile changes after hypoxia-reoxygenation and dobutamine challenge in superfused human atrial pectinate muscle to see whether high versus low stimulation rate during hypoxia might account for outcome differences compatible with the definition of an in vitro model of myocardial stunning and whether pretreatment with the dihydropyridine Ca2+ entry blocker felodipine might afford protection. METHODS: Human right atrial trabeculae obtained from adult patients were superfused in an organ bath with oxygenated (O2 content 16 ml/l) and modified (NaHCO3 25.7 mmol/l) Tyrode's solution at 37 degrees C. Dobutamine (1 nmol/l to 10 micromol/l) was superfused in 10 oxygenated preparations to select the optimal drug concentration to be used in another 22 which were randomized. Group (A) consisted of time-related controls (Tyrodes's solution for 225 min at cycle length (CL) 1600 ms and no dobutamine). There were two test groups, respectively: (B) low (1600 ms CL) and (C) high (400 ms CL) stimulation rate. After 60 min of stabilization, in groups B and C, hypoxic superfusion (O2 content 5 ml/l) lasted 60 min, then reoxygenation (60 min) and dobutamine challenge (1 micromol/l, 15 min) were performed. Analysis of variance for repeated measures with the Greenhouse-Geisser correction, and a repeated measures model with structured covariance (preparation mass, length, width and time-varying time to peak tension) matrices were used whereby grouping (G), time (T) and G x T interaction were weighted. Force-frequency relationship and post-pausal potentiation were studied after each phase. Electrophysiology, histomorphometry and electron microscopy were carried out (n=6). Felodipine (0.1 micromol/l, n=5) pretreatment (15 min before hypoxia) was given in parallel experiments. RESULTS: Time-related controls showed approximately 10% per hour decrease of developed tension and the Paradise test provided approximately 80% of control values. In test groups (as compared to baseline values) contractility was decreased approximately 65% after hypoxia-reoxygenation and it increased approximately 25% after dobutamine (G, 0.0065

The shape of human atrial action potential accounts for different frequency-related changes in vitro.

We aimed at investigating frequency-related changes of human atrial action potential (AP) in vitro to see whether baseline AP shape might account for different responses to increasing stimulation rates. Human right atrial trabeculae (n = 48) obtained from adult (n = 38, mean age 59 +/- 8, range 45-72 years) consecutive patients (approximately equal to 30% of those operated upon by a single surgeon; 1.26 preparations per patient, range 1-2) were superfused in an organ bath with oxygenated (O2 content 16 ml/l) and modified (NaHCO3 25.7 mmol/l) Tyrode's solution at 31 degrees C. Baseline electrophysiology (pacing: 1 ms duration, 2-4 mA current intensity) at cycle length (CL) of 1000 ms was recorded in 90% (43 out of 48) of the preparations. The frequency-related protocol (CL from 1600 to 300 ms) was, however, undertaken in 23 (48%) preparations because 20 (42%) became pacing unresponsive immediately after baseline recordings. No statistical differences were seen when baseline electrophysiological parameters (mean +/- SD) were grouped according to late pacing responsiveness (n = 43 vs. n = 23): respectively, resting membrane potential (RMP) was -74 +/- 6 vs. -75 +/- 4 mV, maximal upstroke velocity (Vmax) 172 +/- 60 vs. 173 +/- 39 V/s, AP amplitude (APA) 89 +/- 11 vs. 91 +/- 8 mV and AP durations were at 30% (APD30%) 10 +/- 13 vs. 13 +/- 18 ms, 50% (APD50%) 45 +/- 79 vs. 62 +/- 91 ms and 90% (APD90%) 383 +/- 103 vs. 407 +/- 108 ms. To classify baseline AP shape, two criteria were adopted: criterion 1 ("objective"), based on APA (cut-off 90 mV) and APD90% (cut-off 500 ms) computed values and criterion 2 ("visual") derived from the literature. These criteria enabled us to differentiate three AP shape types: type 1 (spike and dome), type 3 (no dome) and type 4 (extremely prolonged). At baseline, the two criteria diagnosed different proportions of AP shape types. There were, however, no intra-type statistical differences among electrophysiological parameters. By criterion 1, analysis of variance (ANOVA) showed significant inter-type differences of RMP,Vmax, APA, APD50 and 90% and by criterion 2 of APA, APD30, 50 and 90%, respectively. To facilitate comparisons with previous published data, criterion 2 was selected to analyse frequency-related changes of AP shape types. At low stimulation rate, ANOVA for repeated measures (with Greenhouse-Geisser epsilon correction) showed inter-type differences for APD30, 50 and 90% (P = 0.00005). RMP, Vmax, APA and APD90% were overall frequency-related (P = 0.00005). Inter-type frequency-related differences were however seen only for APD90%. Human atrial AP durations (30, 50 and 90%) enable differentiation among AP shape types (1, 3 and 4). By a standardized use-dependent protocol overall RMP, Vmax, APA and APD90% are frequency-related. AP shape accounts for frequency-related changes of APD90% only. A type 4 AP shape with much prolonged AP duration had a flat frequency dependence. At high stimulation rates, adult type 1 and 3 AP shapes are indistinguishable. Use-dependent and pharmacological investigations in human atrial myocytes need to take AP shape into account.

Activation or block of adenosine triphosphate-sensitive potassium channel have opposite effects on postcardioplegic myocardial dysfunction, "stunning". A multivariate prediction based on relative operating characteristic curve.

The relative effects of nicotinic acid (NA) and nitroglycerin (NT) added to cold high K+ cardioplegia were studied, to represent the two moieties of the adenosine triphosphate-sensitive potassium channel (KATP) activator nicorandil (N). In addition, we made a pooled analysis of a large series of experiments performed in our Laboratory to investigate the effects of KATP activation by N, or block (by glibenclamide, G), on postcardioplegic myocardial dysfunction. In both studies, reversibility from myocardial dysfunction (stunning) was assessed by the positive inotropic agent dobutamine. Guinea pig papillary muscle preparations were immersed in Tyrode's solution (O2 content 16 ml/l, 37 degrees C), then hypoxic (O2 content 5 ml/l) superfusion with hypothermic (20 degrees C) cardioplegic Saint Thomas' Hospital solution (STHS) was performed for 120 min. We investigated: A) 5 groups based on treatments added to STHS: 1) saline (Control (C)); 2) N = 1 mmol/L; 3) G = 1 mumol/L (also given for 15 min in Tyrode's solution); 4) NA = 1 mmol/L; 5) NT = 100 mumol/L; B) 76 consecutive experiments and we defined, independent of whether just before or during STHS: 1) KATP activation (by N, in the concentration range 1 mumol/L to 1 mmol/L, n = 36); 2) KATP block (by G 1 mumol/L, either alone or just before N, n = 20); 3) controls (n = 20) (either saline, n = 12, or saline plus dimethyl sulfoxide, as vehicle, at the ratio 100 to 1, n = 8). Absolute isometric contractility variables were evaluated along with percent changes of baseline values: 1) at 30 s of STHS, 2) after 60 min of reoxygenation with Tyrode's solution and 3) following further 15 min of dobutamine 10 mumol/L. In all preparations, developed tension (DT), time to peak tension (TPT), DT/TPT and time to arrest (TTA) were measured. In study A): TTA was significantly abbreviated (intergroup F = 5.79, p < 0.001) in N (49 +/- 11 s, mean +/- SD) p < 0.01 vs C and NA). At 30 s of STHS %DT/TPT was unchanged among groups. By contrast, after 60 min of reoxygenation %DT/TPT in N (118 +/- 35%, p < 0.05 vs C, p < 0.01 vs G) was improved (intergroup F = 5.48, p < 0.002). G, NA and NT showed recovery of contractility similar to C. However, after dobutamine the poorest %DT/TPT were seen in G (p < 0.01 vs C, p < 0.05 vs N). In study B): using the multivariate logistic model, with KATP activation, the odds of normal contractile response, respectively at 60 min of reoxygenation (t = 2.81) and after dobutamine (t = 3.22), were 29.8 and 8.86 of controls, whereas TTA (t = -1.59) was inversely related. Moreover, with KATP block the odds after dobutamine was 0.204 of controls. The relative operating characteristic plots showed areas under the curve greater than 0.7, which is evidence for accurate assessment of the predictive rules adopted. This is the first report where a probabilistic approach to cardioplegia-related experiments showed high accuracy in predicting the recovery of post-hypoxic contractile function (stunning). The results indicate that on postcardioplegic stunning: 1) KATP activation by N and KATP block by G (both given prior to or contemporary with hypoxia) have opposite effects; 2) the favorable effects of nicorandil seem unrelated to its nicotinamide or nitrose moieties.

Activation of ATP-dependent K+ channels enhances myocardial protection due to cold high potassium cardioplegia: a force-frequency relationship study.

The hypothesis that nicorandil might enhance myocardial protection due to cold St Thomas' Hospital (STH) solution ([K+]o 16 mmol/l) through opening of cardiac KATP channels was assessed in isometrically contracting guinea-pig papillary muscles submitted to 120 min of cardioplegic hypoxia followed by 60 min of normothermic reoxygenation. Right ventricular papillary muscles were paced (2 ms, 4 mA) in an organ bath and superfused with oxygenated (O2 content 16 ml/l) Tyrode's solution (37 degrees C). The force-frequency relationship in the range 1600-300 ms cycle length (CL) was studied. Preparations were randomized to receive 120 min cold (20 degrees C), non-oxygenated (O2 content 5 ml/l) STH solution while continuously stimulated at 1600 ms CL, with: (1) saline (No-additive, n = 12); (2) DMSO 1% (Vehicle, n = 8); (3) nicorandil 1 mmol/l (n = 8); (4) nicorandil 1 mmol/l plus glibenclamide 1 mumol/l, the latter also given, before STH solution, in Tyrode's solution for 15 min (n = 8); (5) glibenclamide 1 mumol/l, also circulated, before STH solution, in Tyrode's solution for 15 min (n = 8); (6) nitroglycerin 100 mumol/l (n = 4); in addition, we studied: (7) STH solution with no-additive and no-pacing (n = 4); (8) cold Tyrode's in place of cold STH solution (n = 4). Inotropic state was investigated by measuring: (i) velocity of developed tension (DT), obtained by dividing DT by time to peak tension; (ii) percentage (from precardioplegia values) velocity changes of DT; (iii) log velocity of DT. Post-cardioplegic recovery of contractility (including force-frequency relationship) was assessed in all preparations: (a) 60 min after reoxygenation with Tyrode's solution; (b) after further 15 min superfusion with the positive inotropic agent dobutamine (10 mumol/l). In parallel experiments, action potential duration (APD) 50% changes induced by nicorandil or glibenclamide plus nicorandil in spontaneously beating atrial (n = 4) or electrically driven (1600 ms CL) ventricular (n = 8) tissues during 10 min of STH solution were investigated. Based on force-frequency relationship, at 60 min reoxygenation, in absence of cardioplegia, the lowest recovery of myocardial contractility was seen (stunning). In STH solution, there was moderate to severe stunning, which was unaffected by removing pacing during cardioplegia, or by vehicle or nitroglycerin. In contrast, nicorandil improved recovery of contractility (F = 3.01, P = 0.0106). After dobutamine, nicorandil preparations showed the highest positive inotropic response, which was completely offset by glibenclamide (F = 3.47, P = 0.0046).(ABSTRACT TRUNCATED AT 400 WORDS)

The risk of myocardial stunning is decreased concentration-dependently by KATP channel activation with nicorandil before high K+ cardioplegia.

BACKGROUND: Drug-induced opening of the adenosine triphosphate-sensitive potassium channel (KATP) during hypoxia and/or ischemia, achieved significant myocardial protection in several in vitro and in vivo models. Pretreatment with KATP openers simulated preconditioning and thus enhanced recovery from ischemia. We have demonstrated that the risk of hypoxia-induced myocardial stunning is reversed by KATP activation with 1 mmol/l nicorandil before cold cardioplegic arrest. Whether lower concentrations were effective is not known. METHODS: In guinea pig papillary muscle preparations contracting isometrically (driven at 1600 ms cycle), nicorandil was superfused (15 min) either 1 mumol/l (n = 4), 30 mumol/l (n = 4), 100 mumol/l (n = 4), or 1 mmol/l (n = 8) in Tyrode's solution (oxygen content 16 ml/l, 37 degrees C, 5 ml/min). Controls were superfused with saline (Tyrode's solution: n = 8). A group containing vehicle (DMSO 1%, n = 8) was also studied. In four preparations the KATP channel blocker glibenclamide 1 mumol/l was given before nicorandil 1 mmol/l. Then, long-lasting (120 min) but moderately hypoxic (oxygen content 5 ml/l: 31% of Tyrode's solution) superfusion with hypothermic (20 degrees C) high K+ (16 mmol/l) cardioplegic solution (5 ml/min) was performed. Recovery of contractility was evaluated after further 60 min of reoxygenation with Tyrode's solution based on DT/TPT (developed tension divided by time to peak tension) as percent of prehypoxia basal values (%DT/TPT60). DT/TPT was also studied following 15 min of inotropic stimulation with dobutamine 10 mumol/l (%DT/TPT75). To assess the risk of stunning, we used a multivariate linear model by all possible subsets analysis (BMDP-9R) aimed at predicting both %DT/TPT60 and %DT/TPT75 (as continuous dependent variables). RESULTS: During cardioplegia induction, time to arrest (TTA) was (mean +/- S.D.) 103 +/- 48s in control preparations which had poor recovery of contractility (stunning) after reoxygenation (%DT/TPT60: 71 +/- 20%; %DT/TPT75: 443 +/- 272%). Nicorandil (1 mumol/l-1 mmol/l) abbreviated TTA concentration-dependently (163 +/- 74, 149 +/- 103, 82 +/- 20, and 56 +/- 27s) and improved both %DT/TPT60 (63 +/- 9, 78 +/- 17, 87 +/- 13, and 98 +/- 11%) and %DT/TPT75 (587 +/- 333, 619 +/- 107, 971 +/- 301, and 666 +/- 400%). Glibenclamide reversed the effects of nicorandil 1 mmol/l (TTA: 165 +/- 30 s, P < 0.01; %DT/TPT60: 43 +/- 12, P < 0.01; %DT/TPT75: 272 +/- 147, P < 0.05). Multivariate prediction of myocardial stunning at both 60 and 75 min reoxygenation showed that nicorandil (30 mumol/l-1 mmol/l) was a significant (P < 0.001) protectant whereas glibenclamide was a significant risk factor (P = 0.009). It is unclear whether negative inotropic effects of nicorandil (%DT/TPT at the end of pretreatment) was mechanistically related to reduced risk of stunning since contribution was seen only to predict %DT/TPT75 (t = 3.24, P = 0.003) whereas a positive association was observed with %DT/TPT60 (t = 1.89, P = 0.068). CONCLUSION: Pretreatment with nicorandil concentration-dependently enhanced the cardioprotective effect of hypothermic high K+ cardioplegia. The risk of myocardial stunning was decreased by KATP opening with nicorandil and increased by KATP block with glibenclamide. Inotropic stimulation with dobutamine might unravel the role of negative inotropic effect of KATP opening as a contributory factor to explain the efficacy of nicorandil in our model.

[The inotropic and bathmotropic effects of beta stimulation: a study comparing dobutamine and dopamine on the guinea-pig papillary muscle in isotonic contraction]. / Effetti inotropi e batmotropi della betastimolazione: studio di confronto tra dobutamina e dopamina nel muscolo papillare di cavia in contrazione isotonica.

The study was aimed at comparing the effects of dobutamine (dob) and dopamine (dop) on isotonic contraction and rhythmicity of isolated guinea-pig papillary muscles (in oxygenated Tyrode at 37 degrees C), by taking into account: 1) the rate of stimulation (50% above the diastolic threshold) at 5 fixed periods: (RR: 1600, 1200, 1000, 800 and 400 ms); 2) 7 log concentrations (logC) of the index amine (from 10(-9) to 10(-3) M). To this end, a dose-relation protocol which explored the effects of all 5 RR and 7 logC was designed and 15 adult female Guinea-pigs (250 to 350 g) were randomized to either the dob (n = 8) or the dop (n = 7) arm. This enabled a total of 525 sets of data to be analyzed: in 38 sets (7.2%) premature contractions (CP) were coded. CP were sustained (freq: > 3) in 25 of these latter 38 sets (4.8%). Compared to the basal state, the amplitude (AMP%) and the log of percent amplitude (logAMP%) and time to peak (TP%) changes of the isotonic (Gould transducer) twitch were calculated along with the log of this latter variable (logTP%). AMP%, log AMP%, TP% and logTP% were linearly correlated with logC at all RR. In the range 1600-400 RR, for both amines, significant linear correlations (magnitude of 0.15 > r < magnitude of 0.70, 0.001 > p < 0.022) were seen for plots of AMP%, logAMP% and TP%:steeper correlations were observed for dop. This was confirmed in multivariate analysis (BMDP-9R) whereby AMP%, logAMP%, TP%, logTP%, CP, and freqCP were dependent variables and coded variables were included to either define the type of treatment (dop versus dob) or logC. In these analyses, logC (t > 11) and dop (t > magnitude of 3) might be used to explain (0.28 > r2 < 0.42, 0.00001 > p < 0.0025) AMP% and logAMP%, meaning that a different inotropic (isotonic) efficacy exists between these 2 amines, at all logC. On the other hand, when CP and freqCP were coded, explanatory variables were AMP% and logAMP% (4.86 > t < 6.95, 0.06 > r2 < 0.09, p < 0.00001), but not the variable used to code the type of treatment (dob versus dop).(ABSTRACT TRUNCATED AT 400 WORDS)

[Increase of potassium conductance and spontaneous electric activity in vitro: comparison of nicorandil and cicletanine]. / Aumento della conduttanza al potassio ed attività elettrica spontanea in vitro: confronto tra nicorandil e cicletanine.

Nicorandil (N) increases potassium conductance in vascular smooth muscle and so induces vasodilation; N also dose-dependently reduces action potential duration (APD). However, it is unclear whether increased potassium conductance, and concomitant APD shortening, might be arrhythmogenic, particularly when myocardial ischemia (where potassium efflux is increased) concurs. Data on the anti-arrhythmic effectiveness of N have also been published: N reduced the spontaneous discharge of sino-atrial node and so reduced heart rate, both in vitro and man. On the other hand, among other vasodilators, cicletanine (C) has been reported to increase potassium conductance, an effect which was advocated to explain its antiarrhythmic potency. In the present investigation the direct myocardial effects of N were compared to those following C in 63 experiments (from 13 Guinea-pigs), using atrial strips (containing sino-atrial node) superfused in 1-compartment bath with normal Tyrode's solution. Using glass microelectrodes, standard electrophysiologic variables were recorded (APA, RMP, APD50%, Vmax) in spontaneously beating atrial tissue, either in Tyrode, dimethyl-sulfoxide (DMSO 1:100, as solvent), C 10(-5) M (in DMSO 1:100), and N 10(-3) M (in DMSO 1:100), whose respective perfusion periods (15 min) were randomized, always following 15 min of washout with Tyrode. Only N was tested in experiments of both 15 and 30 min duration.(ABSTRACT TRUNCATED AT 250 WORDS)

[The prevention of an excitation-conduction block during acute myocardial ischemia: is there a role for prostacyclin or for histamine?]. / Prevenzione del blocco dell'eccitoconduzione durante ischemia miocardia acuta: esiste un ruolo per la prostaciclina o per l'istamina?

We have investigated (multivariate Cox's model) the relative risk of stable excitation-conduction block (ECB) in right ventricular myocardial strips (2 x 5 x 1 mm) from 26 female guinea-pigs, bathed in a 2-compartment chamber (3 ml) on the anterior side of which modified Tyrode's solution (K+ 12 mM, HCO3- 9 mM, pH 7 +/- 0.05, pO2 80 +/- 10 mmHg and absence of glucose) is supraperfused (stimulation rate: 450 ms; wire in the posterior compartment), thus enabling simulation of electrophysiologic changes seen during acute myocardial ischemia. Using glass microelectrodes, action potential amplitude (APA), durations (APD50 and 90%), resting membrane potential (RMP) and upstroke velocity (Vmax) are investigated. The hypothesis was tested of prostacyclin and histamine involvement in the genesis of ischemia-induced ECB in this model. Either a weak prostacyclin stimulator (cicletanine 10(-5) M, IPSEN, Paris, F, in DMSO 1:100; n = 16) or a potent prostacyclin generation blocker (indomethacin 10(-5) M, Sigma, in DMSO 1:100; n = 10) and either DMSO alone (1:100; n = 16) or a specific histaminergic H1 receptor antagonist (terfenadine 10(-5) M, Sigma, in DMSO 1:100; n = 10) were supraperfused using a randomization scheme. Each animal was used twice and either a first or a second occlusion (supraperfusing the modified Tyrode's solution for 30 min) period was performed and the randomized substances were supraperfused, thus enabling obtention of n = 52 experiments for analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Different effects of epoprostenol on ischemia-induced ventricular arrhythmias in dogs.

In 60 randomized dogs the effects of epoprostenol infusion (100 ng/kg/min) on ischemia-induced premature ventricular contractions (PVCs), ventricular tachycardia (VT), ventricular flutters and ventricular fibrillation were studied. The circumflex coronary artery occlusion canine model of sudden death was used. The results demonstrate different effects of epoprostenol on ischemia-induced ventricular arrhythmias: 1) both postischemic (7 of 30 vs 15 of 30, p = 0.0298) and postreperfusion (5 of 23 vs 8 of 15, p = 0.0492) ventricular fibrillations were prevented in epoprostenol dogs with an improvement of the global survival rate (18 of 30 vs 7 of 30, p = 0.0019) as compared to controls; 2) in epoprostenol treated dogs a significantly increased incidence of non lethal arrhythmias-including ventricular flutters that occurred in 12 of 30 dogs vs 4 of 30 in controls (p = 0.0195)--was observed; 3) a positive correlation between the percent diastolic pressure fall 10 min after the start of epoprostenol infusion and the number of non lethal arrhythmias was noted. However, hemodynamic effects of the compound, suggesting an oxygen sparing action, did not preclude the antifibrillatory effectiveness. Thus, the antifibrillatory and antiarrhythmic effects of epoprostenol after circumflex coronary artery occlusion and reperfusion in dogs seem independent from one another.