Electrophysiologic effects of sotalol on the immature mammalian heart.

Sotalol is a beta-blocker with class III antiarrhythmic properties that has recently been used in children for the treatment of supraventricular and ventricular arrhythmias. However, little is known about its electrophysiologic effects on the immature heart. Using intracardiac electrocardiographic recordings and stimulation techniques, 15 canine neonates (8-15 days) and 15 adult mongrel dogs were studied with cumulative doses of sotalol (0.5, 1, 2, and 4 mg/kg plus an additional dose of 8 mg/kg for neonates). Heart rate decreased significantly in the two groups, but more in adult dogs (-43% in adult dogs versus -25% in neonates, p less than 0.05). There was no significant change for QRS duration and His-Purkinje system conduction time interval. QT and atrioventricular nodal conduction time intervals increased in adult dogs and neonates. Sinus node recovery time increased significantly in the two groups, but more in adult dogs. Refractory periods of the atrioventricular (AV) node increased significantly in neonates. Atrial flutter was no longer inducible in 12 of 15 neonates after the 2 mg/kg dose. Atrial effective refractory period increased significantly more in neonates (96%, p less than 0.001) than in adult dogs (58%, p less than 0.001). Ventricular effective refractory periods increased significantly both in neonates (46%) and adult dogs (50%), in a similar way. In conclusion, sotalol has greater electrophysiologic effects on the immature heart at the atrial level when compared to the adult, and similar effects on the refractory period of AV node and ventricle.     

The non-catecholamine-mediated electrophysiological effects of intravenous bethanidine sulfate on the immature mammalian heart

In a preliminary study, we found that bethanidine sulfate had important electrophysiologic effects on the neonatal canine heart, specifically that bethanidine increased atrial effective and functional refractory periods. Other effects (increase in heart rate blood pressure and enhanced atrioventricular conduction) were thought to be due to a release of endogenous catecholamines. To investigate the non-catecholamine-mediated effects of bethanidine, we administered 10 mg/kg i.v. bethanidine to eight neonatal puppies ages 6-14 days pretreated with 0.6 mg/kg of propranolol and compared them with a control group of six neonates that received propranolol followed by a placebo. In the bethanidine group, the mean atrial effective and functional refractory periods increased significantly from 58 to 109 ms and from 108 to 185 ms, respectively (p less than 0.0001). Bethanidine also caused a decrease in resting heart rate (from 154 beats/min postpropranolol to 144 beats/min postbethanidine, p less than 0.002). These effects were not observed in the placebo group. Wenckebach periodicity during incremental atrial pacing did not change significantly. There was a modest increase in the ventricular refractory periods following bethanidine. Thus, the direct electrophysiologic effects of bethanidine in the neonate include a significant prolongation of atrial refractoriness and a decrease in sinus node automaticity. Ventricular refractory periods, while increased, did not show the dramatic prolongation exhibited by the atrium. The atrial specificity of bethanidine is unique and may prove useful in the treatment of supraventricular arrhythmias in the neonatal period.     

Comparisons of the electrophysiological effects of intravenous sotalol and propranolol on the immature mammalian heart

Sotalol is a beta blocker that has also been reported to exert class III antiarrhythmic effects. To evaluate the effects of sotalol on the immature heart, and specifically to assess the relative importance of its class III action, the electrophysiologic effects of incremental doses of intravenous dl-sotalol (cumulative dose of 8 mg/kg) were studied in 11 intact canines (ages 4-15 days) utilizing intracardiac programmed stimulation and electrogram recording techniques. These results were compared to the electrophysiologic effects obtained in an additional 14 neonatal canines given 0.6 mg/kg of the beta blocker propranolol intravenously. Sotalol caused a greater increase than propranolol in the resting sinus cycle length (45 vs. 4%). Importantly, sotalol resulted in greater increases in atrial and ventricular muscle refractoriness than did propranolol (AERP--77 vs. 4%, AFRP--57 vs. 6%; VERP--53 vs. 4%, VFRP--51 vs. 7%). Thus, the electrophysiologic effects of sotalol include large changes in myocardial refractoriness that are not observed with simple beta blockade induced by propranolol. These results suggest that sotalol exerts a significant class III effect in the immature mammalian heart, and thus may be useful as an antiarrhythmic agent in the neonate.     

The cardiodynamic and metabolic effects of verapamil on the isolated dog heart

Summary The cardiodynamic and metabolic effects of verapamil were studied in isolated heart-lung preparations from dogs, modified to measure coronary outflow and myocardial oxygen consumption. An infusion of verapamil of 0.033 mg/min produced initially a decrease in heart rate (–5.7%) and some degree of myocardial failure 10 min after the start of the infusion, followed 10 min later by an increase in coronary outflow (+119.3%), a decrease in heart rate (–16.1%) and in myocardial oxygen consumption (–10.6%) and accentuation of the state of failure (dp/dt –34.6%, left atrial pressure +48.2%, systolic time +25.5%). Continuation of the infusion to a total dose of 1.21 ±0.12 mg of verapamil produced a severe grade of myocardial failure reflected by a decrease in cardiac output (–45.2%) and in dp/dt (–50.0%). This was accompanied by a decrease in heart rate (–26.3%) and in myocardial oxygen consumption (–27.0%). In a separate series, when the decrease in heart rate was prevented by pacing, verapamil did not lead to a significant change in myocardial oxygen consumption at any period during the infusion. Myocardial failure produced either with verapamil at constant heart rate or with pentobarbital sodium was characterized by similar changes in the cardiodynamic parameters and in both instances no significant change in myocardial oxygen consumption occurred. It may be concluded from this study that verapamil, in appropriate doses, increased coronary outflow, decreased heart rate and depressed myocardial contractile force. It also reduced myocardial oxygen consumption but this was found only when a proportionate decrease in heart rate occurred. Verapamil, therefore, in concentrations which are sufficient to produce a marked degree of myocardial failure, as reflected by a reduction in cardiac output of about 50%, does not possess a direct myocardial metabolic effect with consequent reduction in myocardial oxygen requirement.     

Electrophysiologic effects of verapamil metabolites in the isolated heart.

The electrophysiologic effects of the metabolites of verapamil are unknown and may contribute to the observed differences between intravenous and oral verapamil. We examined the electrophysiologic effects of verapamil and its metabolites (norverapamil, N-dealkylverapamil (D617), and N-dealkylnorverapamil (D620)) at estimated, free therapeutic concentrations, in the retrogradely perfused, isolated rabbit heart. Verapamil at 5 and 10 ng/ml significantly prolonged anterograde (11 and 27%, respectively) and retrograde (10 and 25%, respectively) atrioventricular (AV) nodal block cycle lengths. Anterograde and retrograde AV nodal conduction times and refractory periods were also prolonged. Norverapamil at 100 ng/ml had qualitatively similar effects equivalent to 20-50% that observed with verapamil at 10 ng/ml. D620 had small but statistically significant effects on some AV nodal parameters. D617 had no effect. The combination of verapamil plus its principal metabolite, norverapamil, had additive effects. None of the compounds had any measurable effect on atrial conduction, His-Purkinje conduction, or atrial refractoriness. Ventricular refractoriness was significantly prolonged only by norverapamil. In conclusion, some of the metabolites of verapamil have important electrophysiologic AV nodal effects and may contribute to the clinical effects observed during chronic oral verapamil dosing.     

Acute and chronic effects of ethanol on sinoatrial electrophysiology in the rat heart

The influence of moderate chronic ethanol ingestion (CEI) on the acute effects of ethanol upon sinoatrial electrophysiology was studied in rats maintained on a liquid diet for 24 weeks. Rats on ethanol (E-R) received 14% of the caloric intake as ethanol. Controls (N-R) received the same diet, except for isocaloric substitution of carbohydrates for ethanol. The rats were sacrificed at the end of the 24 weeks and sinoatrial preparations were isolated and superfused with Tyrode's solution at 36 degrees C. Intracellular microelectrodes were used to monitor: (a) sinus node automaticity (SNA) in preparations spontaneously active; (b) atrial membrane potentials (AMP) in preparations driven at a constant rate. Ethanol 40-80 mg/100 ml enhanced SNA in N-R, while 240 mg/100 ml were required to obtain a similar effect in E-R. This positive chronotropic effect was not blocked by propranolol. CEI did no modify the effects of carbachol or isoproterenol on SNA. Ethanol 240 mg/100 ml shortened the atrial action potentials in N-R. CEI did not modify the effects of ethanol, carbachol, or isoproterenol on AMP. In summary, small concentrations of ethanol enhanced the SNA in vitro. CEI resulted in development of tolerance to the chronotropic effect of ethanol, without modifying: (a) the acute in vitro effects of carbachol or isoproterenol on SNA and AMP; and (b) the effects of ethanol on AMP.     

Inotropic effects of l-lysine in the mammalian heart

We studied the effects of l-lysine in cardiac preparations of mice and men. Of note, l-lysine increased force of contraction in a concentration- and time-dependent manner in isolated electrically paced left atrium of mouse and in human right atrium. It further increased heart rate and left ventricular pressure in the isolated perfused mouse heart. In isolated adult mouse cardiomyocytes, the contractility as assessed by edge detection was increased as well as the Ca²⁺ transients after electrically pacing by field stimulation. However, using the patch clamp technique, no effect of l-lysine on action potential duration from a constant holding potential or on current through l-type calcium channels could be observed. However, l-lysine led to a depolarization of unclamped cells. Furthermore, effects of l-lysine were stereospecific, as they were not elicited by d-lysine. The inotropic effects of l-lysine were not abrogated by additionally applied l-ornithine or l-arginine (known inhibitors of lysine transport). However, l-lysine (5 mM) shifted the concentration–response curve for a positive inotropic effect of 5-hydroxytryptamine (5-HT; serotonin) in atrium of transgenic mice (with cardiac specific overexpression of 5-HT₄ receptors) to higher concentrations. In summary, we describe a novel positive inotropic effect of an essential amino acid, l-lysine, in the mammalian heart. One might speculate that l-lysine treatment under certain conditions could sustain cardiac performance. Moreover, l-lysine is able to block, at least in part, cardiac 5-HT₄ receptors.     

Inotropic effects of ivabradine in the mammalian heart

Ivabradine represents a novel heart-rate-lowering agent that acts on the sino-atrial node supposedly by selectively inhibiting the 'funny' current (I(f) current). In clinical studies, it was reported that ivabradine effectively reduced resting heart rate and was well tolerated. The aim of this study was to evaluate potential effects of ivabradine on cardiac contractility. Contractile effects of ivabradine were studied in isolated electrically driven atrial preparations from patients undergoing cardiac bypass surgery and for comparison in isolated spontaneously beating right atria and electrically driven left atria from mice. In human trabeculae, a concentration-dependent negative inotropic effect was noted in 7 from 10 patients. However, in 3 patients from 10, a pronounced positive inotropic effect of ivabradine was noted. As expected, in spontaneously beating mouse right atria ivabradine exerted a concentration-dependent negative chronotropic effect. Unexpectedly, contractile effects in mouse and man seem to disagree. In mouse left atria, ivabradine and cilobradine, another hyperpolarization-activated cyclic-nucleotide-gated blocker, always exerted a pronounced positive inotropic effect. These positive inotropic effects were converted to negative inotropic effects in the additional presence of the L-type Ca2+ channel blocker verapamil. The present study demonstrates that ivabradine at high concentrations can affect the force of contraction in atrial preparations from the human heart.     

维拉帕米对心肌细胞的保护与毒性作用

目的研究维拉帕米（verapamil,Ver）对心肌细胞的保护作用与毒性。方法体外培养心肌细胞,测定培养液中乳酸脱氢酶（LDH）、肌酸磷酸激酶（CK）的活性;观察不同浓度维拉帕米对心肌细胞的毒性作用及对缺氧再复氧模拟“缺血再灌注”细胞的保护作用。结果连续培养96h的结果与正常对照组相比,Ver10．0mg／L以上各浓度组存活细胞代谢比色值A540减少、LDH活性增高具有明显的意义;比色值A540与细胞释放的LDH、CK活性呈高度相关（r=-0．986、-0．989,P〈0．01）;维拉帕米可使缺血再灌注损伤的心肌细胞A540显著升高、CK显著降低。结论维拉帕米在缺氧再复氧时有明显的细胞保护作用,但是高浓度特别是超过10mg／L时的直接细胞毒性作用值得关注。     

Electrophysiological effects of verapamil on primary and transitional pacemaker cells of the frog heart

1. In spontaneously beating preparations of sinus venosus of the frog Caudiverbera caudiverbera the electro-physiologic effects of verapamil on action potential parameters of both primary and transitional pacemaker cells were investigated. 2. Verapamil in concentrations ranging from 5 x 10(-8)M to 2 x 10(-6)M slowed the sinus rate and blocked impulse initiation. Action potential blockade was accompanied by oscillations of membrane potential and depolarization. 3. During blockade of primary pacemaker cells, pacemaker shift originated the activation of transitional or atrial contractile fibres. 4. Subthreshold concentrations of the drug to induce complete blockade (5 x 10(-8)M) allowed to observe a greater depression of bioelectric cell characteristics in primary than in transitional fibres. 5. Verapamil-induced blockade of transitional pacemaker action potentials was preceded by the appearance of a notch in their upstroke and the persistence of a fast depolarizing section that remained unblocked. This fast verapamil-resistant section of the upstroke was absent in preparations treated with tetrodotoxin (TTX). 6. The results confirmed most previously described actions of verapamil on mammalian sinoatrial preparations and provided a pharmacological dissection of the two slow and fast bio-electric components contributing to the upstroke of transitional pacemaker cells of the frog sinus venosus.     

The effects of sparteine on membrane potential and contraction of mammalian heart muscle

Summary Membrane and action potentials, electrical thresholds and isometric contractions of isolated guinea-pig papillary muscles were measured before and during exposure to sparteine in concentrations of 10^–5 to 10^–3 M. The rates of rise and fall of the action potential were slowed, the duration prolonged, the overshoot decreased. The resting potential decreased at concentrations of >5×10^–4 M. Electrical threshold for eliciting a contraction was increased. Isometric force and rate of force development were increased, the time to peak of contraction and the relaxation time remained almost unchanged. All drug effects progressed the faster the higher the concentration and were reversible on washout.This work was supported by the Deutsche Forschungsgemeinschaft     

The effects of verapamil on the pharmacokinetics of curculigoside in rats

Context: Clarifying the potential mechanism of the poor oral bioavailability of curculigoside would be helpful for for investigating pharmacological effects and clinical applications.

Objective: To clarify the main mechanism for poor oral bioavailability.

Materials and methods: First, the pharmacokinetics of curculigoside (20?mg/kg) in rats with and without pretreatment with verapamil (10?mg/kg) was determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of curculigoside were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems.

Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 60.17?ng/mL to 93.66?ng/mL) and AUC_0?t (from 289.57 to 764.02?ng·h/mL) of curculigoside. The Caco-2 cell experiments indicated that the efflux ratio of curculigoside was 3.92 (P_appAB 6.43?±?0.57?×?10?^?7?cm/s; P_appBA 2.52?±?0.37?×?10?^?36?cm/s), P-gp might be involved in the transport of curculigoside, and verapamil could inhibit the efflux of curculigoside and increase the absorption of curculigoside significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly decrease the intrinsic clearance rate of curculigoside (from 38.8 to 23.6?μL/min/mg protein).

Discussion and conclusion: These results indicated that verapamil could significantly change the pharmacokinetic profiles of curculigoside in rats, the poor absorption due to P-gp mediated efflux in intestine and high intrinsic clearance rate in rat liver may be the main reason for the poor oral absolute bioavailability of curculigoside.     

Optical isomers of verapamil on canine heart

Effects of optical isomers of verapamil on the canine heart were measured with a pressure catheter in the left ventricle and with the electrocardiogram. 1. Both isomers of verapamil caused impaired atrioventricular conduction. slowed the rate of the sinus pacemaker and depressed the contractile state of the myocardium. (-)-Verapamil was consistently more potent than (+)-verapamil in producing these effects. (-)/(+) potency ratios of 10 and 3 were estimated for atrioventricular blockade and for the negative chronotropic effect, respectively. 2. Negative inotropic effects of 0.06-2.0 mg/kg of (+)-verapamil were determined on hearts paced at constant rate. A similar dose-response relationship could not be established with (-)-verapamil because at concentration higher than 0.06 mg/kg the hearts did not follow the supraventricular driving stimulus. With doses of (-)- and (+)-verapamil which produced the same slowing of the sinus pacemaker rate in spontaneously beating hearts, (-)-verapamil caused greater negative inotropic effects than (+)-verapamil. 3. The following doses of isomers of verapamil reduced the incidence of ventricular fibrillation induced by coronary artery ligation: 0.2 mg/kg (-)-verapamil (P less than 0.001), 0.6 mg/kg (-)-verapamil (P less than 0.001) and 0.6 mg (+)-verapamil (P less than 0.01). 4. Intravenous administration of CaCl2 to dogs treated with either isomer of verapamil restored the contractile state and reversed atrioventricular blockade to sinus rhythm. Dog ventricles under the influence of concentrations of isomers of verapamil which, with normal plasmatic Ca2+-content, prevent fibrillation, consistently fibrillated after coronary artery occlusion when high doses of CaCl2 were administered. 5. The effects of the optical isomers of verapamil may occur predominantly via a blockade of the slow inward Ca2+-current.     

Effects of verapamil on synaptic transmission in mammalian sympathetic ganglia

Effects of verapamil (Ver) on the synaptic transmission of isolated superior cervical ganglia (SCG) were investigated by means of intracellular recording techniques. In the neurons of SCG of rabbits and guinea pigs, Ver (100-400 mumol/L) depressed both the synaptic responses (f-EPSPs and/or evoked action potentials) elicited by orthodromic stimulation and the acetylcholine (ACh) potentials induced by pressure ejection of ACh. 4-Aminopyridine (4-AP, 100 mumol/L) and BaCl2 (5 mmol/L) facilitated the f-EPSPs inhibited by Ver, but had no notable effect on the ACh potentials depressed by Ver. Ver suppressed the ACh potentials enhanced by pyridostigmine (1 mumol/L). The potentiating effect of soman (1 mumol/L) on the ACh potentials was prevented by Ver. It is suggested that Ver can block the synaptic transmission of mammalian SCG by both the pre- and postganglionic mechanisms.     

The influence of verapamil on the gastric effects of stress in rats

The influence of verapamil on stress- or bethanechol-induced gastric effects was investigated in rats. Intraperitoneally injected verapamil (1, 2 or 4 mg/kg), given 30 min beforehand, dose-dependently prevented gastric glandular ulceration, mast cell degranulation and the increased stomach wall contractions evoked by restraint at 4 degrees C for 1 h. Gastric acid secretion, as well as ulceration in both the forestomach and glandular segment, produced by subcutaneously-injected bethanechol (3.2 mg/kg) were also inhibited. It is concluded that decreased amine release from the mast cells, stomach wall relaxation and reduced gastric acid were responsible for the ulcer-antagonising effects of the calcium-entry blocker. The possible antiulcer actions of verapamil are discussed in the light of present knowledge regarding calcium involvement in the various mechanisms thought to contribute to the pathophysiology of stress ulceration in rat stomachs.     

Mechanisms of the contractile effects of 2,3-butanedione-monoxime in the mammalian heart

We studied the mechanisms of action of a negative inotropic compound, 2,3-butanedione-monoxime (BDM), which has been suggested to be a cardioprotective agent.In guinea-pig papillary muscles the negative inotropic effect of BDM started at 100 mol/l amounting to 18.32±2.09% of predrug value at 10 mmol/l without any effects on time parameters (n = 12, each). 30 mmol/l BDM totally abolished force of contraction; this effect was reversible after washout. In the presence of the phosphatase-inhibitor cantharidin (30 mol/l) the concentration response curve on force of contraction was shifted to higher concentrations of BDM.100 mmol/l BDM decreased the phosphorylation state of the inhibitory subunit of troponin (TnI) and phospholamban (PLB) in [³²P]-labeled guinea-pig ventricular myocytes to 76.5±4.7% and 49.7±4.2%, respectively (n = 7). Furthermore, BDM enhanced the activity of phosphorylase phosphatases in guinea-pig ventricular homogenates amounting to a stimulation to 203.5±10.4% at 100 mmol/l whereas type 1 phosphorylase phosphatase activity increased only by 24.5% (n = 5). PLB phosphatase activity was enhanced to 155.9±11.7% by 100 mmol/l BDM (n = 5).It is concluded that the effects of BDM on contractile parameters are accompanied by decreased phosphorylation of the cardiac regulatory proteins TnI and PLB which could in part be due to activation of type 1 or 2A phosphatase activity. Hence, it is suggested that BDM affects the phosphorylation state of TnI and PLB not directly, but via activation of their phosphatases.     

Comparison of Ca2+ channel inhibitory effects of cibenzoline with verapamil on guinea-pig heart

1. Cibenzoline, a class 1 antiarrhythmic drug, was studied on the effects upon the myocardial slow inward Ca2+ current (ICa) and the contractile force, and was compared with verapamil. 2. In voltage-clamp experiments with guinea-pig ventricular myocytes, cibenzoline caused a concentration-related inhibition of ICa (IC50 = 30 microM), whereas verapamil exerts a stronger effect (IC50 = 0.6 microM). 3. Cibenzoline also produced a concentration-related decrease in contractile force of isolated papillary muscle preparation (IC50 = 30 microM), while IC50 of verapamil was 0.8 microM. 4. Although the myocardial Ca2+ channel blocking effect of cibenzoline is about 1/50 compared to verapamil, cibenzoline possesses an inhibitory action on Ca2+ channel as well as on Na+ channel.     

阿斯匹林与维拉帕米单用和合用对兔血液流变性的影响

观察阿斯匹林（Ａｓｐ）与维拉帕米（Ｖｅｒ）单用及合用对免血液流变性的影响。结果表明：ｉｖ生理盐水，Ａｓｐ１．２５ｍｇ·ｋｇ－１和Ｖｅｒ０．０５ｍｇ·ｋｇ－１对兔血液流变性各项指标均无明显影响；ｉｖＡｓｐ２．５、５ｍｇ·ｋｇ－１和Ｖｅｒ０．１、０．２ｍｇ·ｋｇ－１后，血液粘度（ＢＶ），血浆粘度（ＰＶ）和红细胞比积（ＨＣＴ）明显降低，红细胞电泳率（ＥＥＭ）显著提高，且呈明显量效关系；Ａｓｐ１．２５，２．５ｍｇ·ｋｇ－１和Ｖｅｒ０．０５，０．１ｍｇ·ｋｇ－１合用，呈明显协同效应。推测ＡｓＰ，Ｖｅｒ降低ＢＶ可能与ＰＶ，ＨＣＴ下降和ＥＥＭ提高有关。     

The effects of deanol on cognitive performance and electrophysiology in elderly humans

Deanol (900 mg/day for 21 days) had no effect on learning a list of words when tested at weekly intervals. Tests of simple and complex reaction time and a test of continuous serial decoding of digits showed no enhancement with the drug. Several components of evoked potentials recorded from several scalp sites did show enhanced amplitude under drug treatment. These changes were not accompanied by changes in the EEG spectrum as are seen with some other psychoactive drugs. Deanol seems to be an ineffective treatment for the normal slowing of cognitive function seen in the normal elderly person or those elderly with only minimal cognitive decline and free of symptoms of dementia. Contrary to earlier reports, elderly persons were found to be able to benefit from warning signals in a complex reaction time task.