Effects of E4031 and quinidine on atrial and ventricular refractoriness in rabbits in vivo.

This study assessed the effects of E4031 and quinidine on refractoriness (ERP) in a new in vivo model in rabbits. Following sinoatrial (SAN) and atrioventricular node (AVN) ablation ERP was determined in atria and ventricles with the shortest S1-S2 interval eliciting a second electrogram defined as the ERP. The effects of E4031 and quinidine (dose ranges 1-8 micromol/kg) were compared. E4031 dose-dependently increased ERP. The maximum change from pre-drug values with E4031 was 27+/-8 msec (a 36+/-12% increase) at 2 Hz in atria and 51+/-9 msec (27+/-5%) at 2 Hz in ventricles. Negative frequency-dependence was observed only in ventricles. Quinidine dose-dependently increased ERP. The maximum increase for quinidine was 23+/-3 msec (28+/-4%) at 2 Hz in atria and 25+/-10 msec (22+/-10%) at 6 Hz in ventricles, but without frequency-dependence in either tissue. In comparison to E4031, quinidine produced smaller changes in ERP and showed minimal frequency dependence. Thus, the added presence of sodium blocking actions with quinidine did not produce greater effects on ERP than I(Kr) blockade alone with E4031. However, quinidine also blocks other potassium currents, such as Ito, and the degree of I(Kr) blockade with E4031 was probably greater than that with the same dose of quinidine. This model may have clinical utility for testing multi-ion channel blocking drugs.

Effects of flecainide on atrial and ventricular refractoriness in rabbits in vitro and in vivo.

This study compared the in vitro versus in vivo effects of flecainide on effective refractory period (ERP) in atrial and ventricular tissue in rabbits. Flecainide (a class 1c agent) was chosen, on the basis of its known pharmacological profile and antiarrhythmic actions, to provide a reference compound for investigating models that suitably predict the clinical effects of antiarrhythmics. The rabbit models used were those previously described by Lowe et al. (2002) and Leung et al. (2003). ERP was measured as the shortest S1-S2 interval that elicited a second contraction (in vitro) or electrogram (in vivo). Flecainide (1-10 microM) in vitro produced a concentration-dependent increase in ERP. The greatest drug-induced change from pre-drug values in vitro occurred with the highest concentration in atria and ventricles at 4 Hz. The change was 30+/-4 msec (33+/-7%) in atria versus 53+/-8 msec (46+/-10%) in ventricles. In vivo, flecainide (1 - 4 micromol/kg) dose-dependently increased atrial ERP at 2 and 6 Hz. The biggest change was 28+/-17 msec (29+/-16%). However, there was no effect at 4 Hz. In the ventricles, a dose-related increase in ERP was only seen at 4 Hz (26+/-6 msec). Flecainide showed no frequency dependence of action on ERP in any preparation. Flecainide produced adverse effects both in vitro and in vivo. A concentration and frequency-dependent negative inotropic effect was seen in vitro, and dose-related hypotension in vivo. The highest dose (8 micromol/kg i.v.) of flecainide was lethal. Flecainide produced the expected electrophysiological and toxicity profile, both in vitro and in vivo. Despite such findings, the drug is used to terminate and prevent atrial arrhythmias clinically. In conclusion our rabbit models for determining ERP may not be useful in predicting the clinical usefulness of a drug like flecainide.

The antihypertensive effects of the Jamaican Cho-Cho (Sechium edule)

The experiments reported in this study constitute a preliminary investigation into the possible hypotensive effect of the Jamaican Cho-Cho (Sechium edule). Experiments were conducted in a random and blind fashion on two sub species of Sechium edule. Both the pulp and the peel were examined for hypotensive activity. Water-soluble extracts were prepared from these components of the fruit and injected into anaesthetised rats. Various cardiovascular parameters were measured including heart rate, mean arterial pressure (MAP) and several ECG intervals. We report that all extracts tested produced a fall in blood pressure with little change in ECG intervals. Extract B produced the least change in heart rate with a fall in MAP of approximately 23 mmHg. Changes in heart rate with all extracts appeared to be minimal as an ED25 value could only be determined for extract A, and ED10 values could not be evaluated for extracts C and D. The mechanism(s) by which these extracts produce their hypotensive effects could not be determined in these preliminary experiments. However, it appears not to involve direct effects on cardiac tissue. This conclusion is based on the finding that it took a minimum of 10 to 15 seconds for the hypotensive action to manifest post bolus. Future experiments will be aimed at delineating the mechanism(s) involved in decreasing MAP.(Au)

The effects of potassium channel agonists, cromakalim and adenosine, in diabetic rat hearts

INTRODUCTION: This study was designed to look at ATP sensitive potassium channels (KATP-sc) in diabetic male Sprague-Dawley rat hearts. Diabetes mellitus was induced using streptozocin (ip). KATP-SC can be found in pancreatic B-cells, cardiac muscle, skeletal muscle, neurones, hypothalamus and smooth muscle. Cromakalim and adenosine were used to construct concentration-response curves. These drugs are KATP-SC openers that cause shortening of action potential duration and hyperpolarisation. This is a novel study as there is a sparsity of information on the effect of KATP-SC openers on the hearts of diabetic animals. We therefore hypothesised that cromakalim and adenosine may have both an effect on the electrical activity as well as the contractility in the diabetic myocardium. METHODS: Male Sprague-Dawley rats (150-250 gm) were treated with streptozotocin (STZ) (60 mg/Kg i.p.). All animals were kept under identical living conditions and allowed free access to food and water for 1 week. Animals were then sacrificed after being anaesthetised with 60 mg/Kg pentobarbital containing 1000 Units/ml heparin. Hearts were being rapidly excised, placed in 4 degrees C. Krebs-Henseleit buffer and mounted in a Langendorff system. Concentration-response curves were constructed for cromakalim (0.01nM-0.1uM), and adenosine (0.1uM-100uM). Parameters measured were heart rate (HR), P-R and QRS intervals, systolic pressure (SP), diastolic pressure (DP) and developed pressure (Dev. Pre.). RESULTS: The results found for cromakalim in diabetic rats and adenosine in normal rats mirrored what has been found in previous studies for these drugs in non-diabetic animals, namely, a decrease in HR, an increase in P-R and QRS and a decrease in SP and Dev. Pre. However, adenosine in diabetic rats showed some unexpected results such as a decrease in P-R, and an increase in SP and Dev. Pre. It is possible that the diabetic state interferes significantly with the actions of adenosine but not as significantly with those of cromakalim. Conclusion: The results indicate that adenosine may not be cardioprotective in diabetic animals. This conclusion may be drawn from the fact that P-R interval decreased with increasing concentrations of adenosine. This may lead to the production of arrhythmias such as life threatening ventricular tachycardia or fibrillation (AU)