R56865, an antiarrhythmic drug with class III effects that terminates ouabain induced ventricular tachycardia in an inverse rate dependent manner.

OBJECTIVE: R56865 has been described as a substance that protects cells from intracellular Na+ and Ca2+ overload. The aim of this study was to investigate its mechanism of action, which is at present unknown. METHODS: The haemodynamic and (rate dependent) electrophysiological effects of R56865 (0.48 mg.kg-1) were examined and compared with its antiarrhythmic effect on ouabain-induced ventricular tachycardia (n = 10), and ventricular tachycardia occurring within 24 h of occlusion of the left anterior descending artery (n = 8). The experiments were all performed in dogs. RESULTS: In anaesthetised dogs R56865 increased (p < 0.05) the cycle length of the sinus rhythm, the corrected QT duration (+8%) and the effective refractory period (+16%) of the right ventricle. No rate dependency was found. R56865 had no effect on blood pressure, conduction, or refractoriness of the AV node, nor on conduction in the ventricle. In conscious dogs, R56865 did not change the cycle length of the sinus rhythm, but it did increase the QT duration (+5%, p < 0.05). The cycle length of the slower ouabain induced ventricular tachycardias which were terminated by R56865 increased to a greater extent (+55%) than that of the non-suppressible, faster ventricular tachycardias (+16%): 335(SD 30) ms, n = 5 v 285(10) ms, n = 5. The effect of R56865 on ventricular tachycardias 24 h after infarction was considered to be of minor antiarrhythmic importance. CONCLUSIONS: R56865 has (1) class III effects, (2) a partial effect in terminating ouabain induced ventricular tachycardias which is inverse rate dependent, and (3) a weak effect on ventricular tachycardias 24 h after infarction.

Significance of the number of stimuli to initiate ouabain-induced arrhythmias in the intact heart.

Ouabain-induced arrhythmias are a well-known model used to study triggered activity resulting from delayed afterdepolarizations. In the intact heart, initiation of these arrhythmias is promoted by pacing, especially at fast rates. However, the relevance of the number of stimuli is unknown. In conscious dogs with formalin-induced atrioventricular block, we investigated the effect of variations in pacing mode on 1) the behavior of nonsustained triggered rhythms at progressive levels of ouabain intoxication, and 2) the induction of sustained ventricular tachycardia (VT). Twenty experiments were analyzed. Ouabain was administered as a bolus of 40 micrograms/kg followed by continuous infusion. Every 15 minutes the pacing protocol was repeated, with a maximum of 10, until completion or induction of VT. When VT could not be initiated, the experiment was repeated at least 1 week later, adding 5-10 micrograms/kg ouabain to the bolus and increasing the infusion rate correspondingly. This was repeated until VT could be induced. Four interstimulus intervals (200, 400, 600, and 800 msec) and seven numbers of stimuli (5, 10, 20, 35, 50, 100, and 150) were given in two pacing protocols. The effect of these protocols on 1) the number of induced beats per stimulation train, 2) their first postpacing interval, and 3) induction of VT were studied. Initiation of VT occurred after 75 +/- 42 minutes. The bolus of ouabain needed to induce VT was inversely related to the body weight of the animals. Progression of ouabain intoxication resulted in 1) a significant increase in the number of induced beats per stimulation train and 2) a significant shortening of the first postpacing interval. Stimulation at a faster rate and/or more stimuli resulted in 1) a significantly pronounced increase in the number of induced beats at the higher levels and 2) a significantly shorter first postpacing interval at successive levels of ouabain intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effects of the cholesterol synthesis inhibitor simvastatin in patients with hypercholesterolemia with and without diabetes mellitus]. / De effecten van de cholesterolsyntheseremmer simvastatine bij patiënten met hypercholesterolemie met en zonder diabetes mellitus.

We studied the short-term effects of simvastatin on lipid variables in 33 dyslipidemic patients without and 18 with diabetes mellitus who were on a lipid-lowering diet for at least 3 months. Six diabetic patients had type I, and 12 had type II diabetes mellitus, of whom 5 were using insulin. In the whole group total cholesterol decreased by 28%, from 9.35 (SD 2.10) mmol/l to 6.69 (SD 1.47) mmol/l after 3 months and 6.60 (SD 1.27) mmol/l after 6 months (mean daily dose of simvastatin 21 (SD 12) mg). Calculated LDL-cholesterol showed a decrease of 38%, HDL-cholesterol increased by 10% and plasma triglycerides decreased by 13%. In patients receiving 10, 20, or 40 mg simvastatin daily, the following changes were observed: total cholesterol -26, -31 and -34% and LDL-cholesterol -37, -38 and -39%, respectively. The effect of simvastatin in the diabetic patients was comparable with that in the non-diabetic individuals, although in the diabetics LDL-cholesterol before therapy was lower, as was the daily dose of simvastatin after 6 months (14 versus 24 mg). In the diabetic patients blood glucose control, measured as HbA1c, was not affected. One patient discontinued therapy because of stomach complaints. Our results show that a low daily dose (10 mg) of simvastatin effectively lowers plasma total and LDL-cholesterol and that the drug can be safely used in diabetic patients.

Premature escape beats. A model for triggered activity in the intact heart?

In conscious dogs with complete atrioventricular block, overdrive pacing of the idioventricular rhythm normally results in overdrive suppression (OS). Frequently, however, we observed another response to overdrive, that is, QRS complex or complexes with unexpectedly short coupling intervals followed by normal OS. We have named such a QRS complex a "premature escape beat" (PEB). Based on the response of PEBs to electrical stimulation, we postulate that PEBs are based on triggered activity resulting from delayed afterdepolarizations. This hypothesis was tested in 82 experiments by 1) stimulation under control conditions and in combination with 2) subtoxic and toxic amounts of ouabain 20-50 micrograms/kg, 3) lidocaine 3 mg/kg, and 4) doxorubicin 16-24 mg/m2. The stimulation protocol, which was repeated at random five to 10 times, consisted of 10 and 50 stimuli using interstimulus intervals of 200, 400, 600, and 800 msec. This protocol was not only performed during spontaneous idioventricular rhythm but also during a continuously paced rhythm with interstimulus intervals of 800 msec. It was found that 1) the chance to induce a PEB or PEBs increased and 2) their first postpacing interval significantly decreased using short or fast drives, or both. Ouabain increased significantly and in a dose-dependent manner 1) the ability to induce PEBs and 2) the number of PEBs per stimulation-train, and also shortened their first postpacing interval. Opposite effects were seen after lidocaine, doxorubicin, and continuous pacing as follows: 1) a lower incidence of PEBs and 2) lengthening of their first postpacing interval. These results support our hypothesis that PEBs are based on triggered activity resulting from delayed afterdepolarizations.