Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone.
(25/896)
BACKGROUND: To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts. METHODS AND RESULTS: Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 micromol/L) in tissue bath. Action potential duration at 50% (APD(50)) and 90% (APD(90)) repolarization and upstroke dV/dt (V(max)) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (P<0.0001 for all). Ventricular APD(50) and APD(90) were lengthened by 20% to 49% as a function of dose (P<0.005 to <0.0001) and cycle length (P<0.001). SR100 effects were greater than those of AM100 (P<0.002). V(max) was decreased by both AM100 (P<0.0001) and SR100 (P<0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (P<0.0001 for all). CONCLUSIONS: The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds. (+info)
Inhibition by genistein of the hyperpolarization-activated cation current in porcine sino-atrial node cells.
(26/896)
1 The hyperpolarization-activated cation current (If) was recorded in single pacemaker cells of the porcine sino-atrial node, and the effects of genistein, an isoflavone inhibitor of tyrosine-specific protein kinases was investigated by the whole-cell patch clamp technique. 2 Genistein (20-500 microM) decreased If in a dose-dependent manner with an IC50 value of 62.3 microM and a maximum inhibition of 45.3%. 3 The effect on If appeared without altering the half-activation potential (control, -88.3+/-2.8 mV; genistein, -87.0+/-1.8 mV) and the slope factor (control, 8.0+/-0.3 mV; genistein, 8.6+/-0.7 mV) of the steady-state activation curve. No significant voltage-dependency was detected in the fully-activated current-voltage relation measured by the double-pulse protocols. 4 The inactive form of genistein analogue, daidzein (500 microM) or genistin (200 microM), were without effect. If was not affected by another tyrosine kinase inhibitor, tryphostin-47 (100 microM), but tyrphostin-25 (100-200 microM) suppressed If in an irreversible manner. 5 Neither bath nor intracellular application of the tyrosine phosphatase inhibitor, orthovanadate, affected If, and subsequent application of genistein inhibited If significantly. 6 These data indicate that the inhibition of If by genistein is not mediated through tyrosine kinase inhibition but through nonselective block of the If channels. (+info)
Cardiopulmonary baroreceptor control of muscle sympathetic nerve activity in heat-stressed humans.
(27/896)
Whole body heating decreases central venous pressure (CVP) while increasing muscle sympathetic nerve activity (MSNA). In normothermia, similar decreases in CVP elevate MSNA, presumably via cardiopulmonary baroreceptor unloading. The purpose of this project was to identify whether increases in MSNA during whole body heating could be attributed to cardiopulmonary baroreceptor unloading coincident with the thermal challenge. Seven subjects were exposed to whole body heating while sublingual temperature, skin blood flow, heart rate, arterial blood pressure, and MSNA were monitored. During the heat stress, 15 ml/kg warmed saline was infused intravenously over 7-10 min to increase CVP and load the cardiopulmonary baroreceptors. We reported previously that this amount of saline was sufficient to return CVP to pre-heat stress levels. Whole body heating increased MSNA from 25 +/- 3 to 39 +/- 3 bursts/min (P < 0. 05). Central blood volume expansion via rapid saline infusion did not significantly decrease MSNA (44 +/- 4 bursts/min, P > 0.05 relative to heat stress period) and did not alter mean arterial blood pressure (MAP) or pulse pressure. To identify whether arterial baroreceptor loading decreases MSNA during heat stress, in a separate protocol MAP was elevated via steady-state infusion of phenylephrine during whole body heating. Increasing MAP from 82 +/- 3 to 93 +/- 4 mmHg (P < 0.05) caused MSNA to decrease from 36 +/- 3 to 15 +/- 4 bursts/min (P < 0.05). These data suggest that cardiopulmonary baroreceptor unloading during passive heating is not the primary mechanism resulting in elevations in MSNA. Moreover, arterial baroreceptors remain capable of modulating MSNA during heat stress. (+info)
Epidermal growth factor increases i(f) in rabbit SA node cells by activating a tyrosine kinase.
(28/896)
Our previous results have demonstrated that tyrosine kinase inhibition reduces i(f) in rabbit SA node myocytes, suggesting that tyrosine kinases regulate i(f). One receptor tyrosine kinase the EGF receptor kinase is known to increase heart rate. To determine if this action is mediated through changes in i(f), we examined the effect of epidermal growth factor (EGF) on i(f) with the permeabilized patch-clamp technique. 0.1 microM EGF increased i(f) amplitude in response to single-step hyperpolarizations in the diastolic range of potentials. This increase was 20+/-3%, n=11 at -75 mV. This effect is caused by activating a tyrosine kinase because 50 microM genistein, a tyrosine kinase inhibitor, eliminated this EGF action. A two-step pulse protocol showed that maximal i(f) conductance was increased by EGF. We further examined this conductance change by constructing the activation curve. The maximal i(f) conductance was increased by 23% with no change in midpoint, V(1/2), control=-74+/-2 mV, V(1/2) EGF=-74+/-1 mV. Thus EGF acts via a tyrosine kinase to increase maximal i(f) conductance with no change in the voltage dependence of activation. These results suggest that EGF effects on i(f) contribute to the positive chronotropic effect of EGF on SA node. (+info)
Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit isolated pacemaker cells.
(29/896)
Permeabilized patch whole-cell voltage clamp methods were used to investigate the effects of isoprenaline (ISO) on total delayed rectifier potassium current, iK, in rabbit sino-atrial (SA) node pacemaker cells; total iK is composed of the rapidly activating iKr and the slowly activating iKs, but predominantly iKr in this species. ISO (20 nM) increased the amplitude of total iK and caused a negative shift of approximately 10 mV in the activation curve for iK, both in the absence and in the presence of 300 nM nisoldipine to block the L-type Ca2+ current, iCa,L. The same concentration (20 nM) of ISO increased the spontaneous pacemaker rate of SA node pacemaker cells by 16%. In addition to increasing the amplitude of iK, ISO (20-50 nM) also increased the rate of deactivation of this current. The stimulation of iK by ISO was reversed by 10 microM H-89, a selective protein kinase A inhibitor, but not by 200 nM bisindolymaleimide I, a selective protein kinase C inhibitor. It therefore appears that the mechanisms by which -adrenoceptor agonists increase pacemaking rate in sinoatrial node pacemaker cells include an increase in the rate of deactivation of iK in addition to the well-documented augmentation of iCa,L and the positive shift of the activation curve for the hyperpolarization-activated inward current, if. The observations are also consistent with a role for protein kinase A in the stimulation of iK by ISO in SA node cells. (+info)
Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes.
(30/896)
BACKGROUND: The noble gas xenon (Xe) has been used as an inhalational anesthetic agent in clinical trials with little or no physiologic side effects. Like nitrous oxide, Xe is believed to exert minimal unwanted cardiovascular effects, and like nitrous oxide, the vapor concentration to achieve 1 minimum alveolar concentration (MAC) for Xe in humans is high, i.e., 70-80%. In the current study, concentrations of up to 80% Xe were examined for possible myocardial effects in isolated, erythrocyte-perfused guinea pig hearts and for possible effects on altering major cation currents in isolated guinea pig cardiomyocytes. METHODS: Isolated guinea pigs hearts were perfused at 70 mm Hg via the Langendorff technique initially with a salt solution at 37 degrees C. Hearts were then perfused with fresh filtered (40-microm pore) and washed canine erythrocytes diluted in the salt solution equilibrated with 20% O2 in nitrogen (control), with 20% O2, 40% Xe, and 40% N2, (0.5 MAC), or with 20% O2 and 80% Xe (1 MAC), respectively. Hearts were perfused with 80% Xe for 15 min, and bradykinin was injected into the blood perfusate to test endothelium-dependent vasodilatory responses. Using the whole-cell patch-clamp technique, 80% Xe was tested for effects on the cardiac ion currents, the Na+, the L-type Ca2+, and the inward-rectifier K+ channel, in guinea pig myocytes suffused with a salt solution equilibrated with the same combinations of Xe, oxygen, and nitrogen as above. RESULTS: In isolated hearts, heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction, oxygen consumption, cardiac efficiency, and flow responses to bradykinin were not significantly (repeated measures analysis of variance, P>0.05) altered by 40% or 80% Xe compared with controls. In isolated cardiomyocytes, the amplitudes of the Na+, the L-type Ca2+, and the inward-rectifier K+ channel over a range of voltages also were not altered by 80% Xe compared with controls. CONCLUSIONS: Unlike hydrocarbon-based gaseous anesthetics, Xe does not significantly alter any measured electrical, mechanical, or metabolic factors, or the nitric oxide-dependent flow response in isolated hearts, at least partly because Xe does not alter the major cation currents as shown here for cardiac myocytes. The authors' results indicate that Xe, at approximately 1 MAC for humans, has no physiologically important effects on the guinea pig heart. (+info)
Baroreceptor control of atrioventricular conduction in man.
(31/896)
Although human baroreflexes are known to exert a powerful physiological control on heart rate, little information exists on the physiological control they exert on the atrioventricular conduction system. In 11 normotensive subjects with normal atrioventricular conduction, we altered baroreceptor activity by injection of pressor and depressor drugs (phenylephrine and trinitroglycerin) and recorded mean arterial pressure (MAP, catheter measurements), R-R interval, and pre-His and post-His intervals (A-H and H-V, His bundle recording). With the subjects in sinus rhythm, increasing MAP by 21+/- 1 mm Hg caused a marked lengthening (250 +/- 28 msec), and decreasing MAP by 17 +/- 2 mm Hg a marked shortening (142 +/- 16 msec) of the R-R interval. There was little change in the A-H interval and no change at all in the H-V interval. However, when the R-R interval was kept constant in these subjects by atrial pacing, a similar increase and decrease in MAP caused, respectively, a marked lengthening (49 +/- 6 msec) and shortening (19 +/- 3 msec) of the A-H interval, although the H-V interval remained unaffected. Thus physiological ranges of baroreceptor activation have a marked influence on the atrioventricular node but apparently not on the ventricular portion of the atrioventricular conduction system. This influence is unmasked when pacing prevents the baroreceptor influence on the sinoatrial node. (+info)
The sustained inward current and inward rectifier K+ current in pacemaker cells dissociated from rat sinoatrial node.
(32/896)
1. Myocytes were dissociated from the sinoatrial (SA) node of rat heart using a new enzymatic dissociation technique. Only a small number of isolated SA node myocytes showed regular rhythmic contractions and spontaneous action potentials, and these were used in the present study. 2. The spontaneous action potential was resistant to TTX, and the action potential parameters were similar to those of rabbit and guinea-pig pacemaker cells. Major time- and voltage-dependent currents were the delayed rectifier K+ current IKr, the L-type Ca2+ current ICa,L and the sodium current INa. The hyperpolarization-activated cation current (If) was recorded from approximately 50 % of the cells with hyperpolarization beyond -90 mV. 3. The instantaneous current jump at the onset of a hyperpolarizing pulse showed inward rectification and was largely blocked by Ba2+. This Ba2+-sensitive current corresponded well to the inward rectifier K+ current (IK1), although it was much smaller in amplitude than in the ventricle. 4. A sustained inward current was activated on depolarization from -80 mV to the voltage range of slow diastolic depolarization. The current was blocked by nicardipine, enlarged by isoprenaline and was insensitive to removal of external Ca2+. These characteristics were similar to the sustained inward current, Ist, previously described in the rabbit and guinea-pig SA node cells. 5. The role of Ist was considered by constructing empirical equations, which were applied to the experimental record of the action potential. It is demonstrated that the voltage-dependent activation of Ist constitutes a positive feedback loop with the depolarization of the membrane. (+info)