Failure of lidocaine to suppress lethal ischemic ventricular arrhythmias in a canine model of previous myocardial infarction.

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiarrhythmic and arrhythmogenic actions of methyl lidocaine during the recovery phase after canine myocardial infarction

Programmed electrical stimulation was used to evaluate the electrophysiologic and antiarrhythmic actions of methyl lidocaine in both conscious and anesthetized dogs, 4-7 days after myocardial infarction. When administered to animals demonstrating sustained ventricular tachycardia (n = 6), methyl lidocaine (5 and 10 mg/kg i.v.) prevented the induction of the original ventricular tachycardia in 2 dogs, and in the remaining 4 dogs slowed the tachycardia (cycle length 163 +/- 18 ms vs. 198 +/- 11 and 219 +/- 11 ms, respectively, p less than 0.05). New morphologic forms of sustained tachycardia were observed after drug administration in 4 of 6 experiments. When administered to animals developing only nonsustained ventricular tachycardia or no arrhythmias with programmed stimulation, methyl lidocaine administration enabled programmed stimulation to produce monomorphic sustained ventricular tachycardia in 10 of 13 experiments. The drug increased activation delays in both normal and ischemically injured epicardium, with larger activation delays always observed in ischemically injured tissue. The drug increased refractoriness in ischemically injured myocardium without altering refractoriness in normal tissue. The data suggest that the depression of conduction and prolonged refractoriness produced by methyl lidocaine in ischemically injured tissue may extinguish or slow some forms of ventricular arrhythmia while promoting the formation of new reentry pathways.     

Electrophysiologic actions of dibenzepin, a tricyclic antidepressant, on canine Purkinje fibers

Electrophysiologic effects of dibenzepin, a tricyclic antidepressant drug known experimentally to defibrillate the ventricles, were studied in canine Purkinje fibers with glass microelectrodes. In 11 normally perfused preparations the dose-response curve (10(-8)-10(-5) g/ml) revealed that the threshold concentration of this drug was 10(-7) g/ml, reducing the maximal rate of depolarization (MRD) from 930 to 876 V/s and overshoot from 32 to 30 mV, respectively (p less than 0.05). At 10(-6) g/ml, dibenzepin shortened action potential duration (APD) at 50 and 90% repolarization (APD50, APD90), respectively, from 290 to 248 ms and from 385 to 363 ms (p less than 0.001). At 10(-5) g/ml, it decreased the maximal diastolic potential (MDP) from -92 to -85 mV and further reduced MRD, overshoot and APD50 (p less than 0.01). The membrane responsiveness curve was shifted to more negative potentials, but its normalized curve (h infinity curve) remained unchanged. This drug did not alter slow response action potentials produced by 22 mM K+ and 10(-7) M isoproterenol. In six Purkinje fibers, hypoxia (100% N2) reduced MDP and MRD. Subsequent addition of dibenzepin further decreased MRD and shortened APD50. These results indicate that (a) dibezepin inhibits the fast Na+ current without changing its inactivation kinetics, thus suggesting a class 1 antiarrhythmic action; (b) it does not affect the slow inward current; and (c) the former action appears enhanced during hypoxia, possibly contributing to ventricular defibrillation.     

慢性心肌缺血动物模型制备方法

慢性心肌缺血动物模型更加符合缺血性心肌病的临床病理生理过程,适宜多次给药和长时间进行心功能观察。制备方法主要有慢性机械压迫冠状动脉法、冠状动脉内栓塞法、冠状动脉结扎法和高脂饮食法。应根据不同动物的生理特点选用不同的动物和方法。     

Electrophysiologic effects of encainide on acutely ischemic rabbit myocardial cells

The electrophysiologic effects of encainide were determined in normal and acutely ischemic (30 min) rabbit ventricular muscle cells. Encainide (10^?6, 5 × 10^?5 M) had no effect on resting potential (RP); 10^?6 encainide reduced overshoot and action potential (AP) amplitude of cells in normal left ventricles and cells in normal areas of ischemic ventricles. Encainide, 5 × 10^?6 M and 10^?5M, depressed V?_max and prolonged AP duration of normalcells. Surviving cells within ischemic areas displayed AP with reduced RP, overshoot, AP amplitude, V?_max and shorterned AP duration. All encainide concentrations reduced overshoot, AP amplitude and V?_max of depressed AP. Encainide's lengthening of AP duration was greater in cells within ischemic areas than in surrounding normal cells. Encainide (10^?6 M) prolonged effective refractory period and often AP in ischematic cells. Encanides also caused depression in membrane responsiveness. Encainide's differential effect upon AP may significantly contribute to its antiarrhythmic activity in ischemic heart disease.     

Electrophysiologic actions of d,l-sotalol and GLG-V-13 in ischemically injured canine epicardium

The electrophysiologic actions of the class III antiarrhythmic agents, GLG-V-13 and d,l-sotalol, were examined in superfused normal and ischemically injured epicardium. Both drugs produced concentration and reverse-use dependent prolongation of the action potential duration in normal myocardium without altering resting potential, action potential amplitude, or Vmax. Both drugs increased the slope of restitution curves in normal epicardium but prevented action potential alternans at short cycle lengths. The response of superfused ischemically injured left ventricular epicardium to drug 4 days after coronary artery ligation was determined by the extent of ischemic injury, with no electrophysiologic changes produced within epicardial cells characterized by prominent action potential shortening and no further action potential shortening with pacing. Cells demonstrating less severe injury (as evidenced by less severely depressed action potential amplitudes, Vmax, and action potential durations) retained a limited ability to respond to drug administration with action potential prolongation. A concentration-dependent, increased disparity of action potential duration was observed concurrent with the ability of single premature stimuli to induce monomorphic tachycardia. The present data demonstrate a variable response of ischemically injured canine epicardial cells to action potential prolongation with GLG-V-13 and d,l-sotalol, facilitating localized reentry in vitro, despite a failure of the same drugs to facilitate reentrant tachycardia in vivo.     

Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication

OBJECTIVE: Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade. Because of cocaine's ability to block cardiac sodium channels, sodium bicarbonate (NaHCO3) has been proposed as an antidote. The hypothesis of this study was that NaHCO3 would correct cocaine-induced conduction abnormalities and resultant hemodynamic compromise in an animal model simulating severe cocaine intoxication. METHODS: Design: Prospective, controlled, experimental study in which 15 anesthetized dogs were given three successive boluses of cocaine (7 mg/kg) and then randomized to receive NaHCO3, 2 mEq/kg (n = 8) or placebo (n =7). Measurements: Arterial, left ventricular, and pulmonary artery pressures; cardiac output (CO); electrocardiogram (ECG); blood gases; and serum concentrations of cocaine were measured at baseline, at fixed time intervals after each bolus of cocaine, and then after administration of NaHCO3 or placebo. Statistical significance was determined by analysis of variance (ANOVA) for repeated measures. RESULTS: Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block; 2 of these dogs expired prior to receiving NaHCO3 and were excluded. Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group. This effect was associated with a brief 30% decrease in MAP (p = NS). After NaHCO3, CO increased 78% and remained increased for 5 min (p < 0.007). One dog converted from complete heart block to sinus rhythm shortly after NaHCO3 administration. CONCLUSIONS: NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function.     

Electrophysiologic, cardiohemodynamic and beta-blocking actions of a new ultra-short-acting beta-blocker, ONO-1101, assessed by the in vivo canine model in comparison with esmolol.

The purpose of this study was to assess the cardiovascular effects of an ultra-short-acting beta-blocker, ONO-1101, by using halothane-anesthetized beagle dogs in comparison with esmolol. ONO-1101 (n = 6) or esmolol (n = 6) was administered at four infusion rates of 0.3, 3, 30, and 300 microg/ kg/min. Each infusion was performed over a 30-min period, and the parameters were measured at 20-30 min after the start of each infusion. ONO-1101 significantly decreased the heart rate, rate-pressure product, left ventricular contraction, cardiac output, and relative refractory period of the right ventricle, suppressed the AV nodal conduction, and increased the effective refractory period of the right ventricle, whereas no significant change was observed in the preload and afterload of the left ventricle, intrinsic sinus nodal automaticity, His-Purkinje-ventricular conduction, and the monophasic action-potential duration of the right ventricle. The cardiovascular effects of esmolol were comparable to those of ONO-1101, except that the preload of the left ventricle was significantly increased, and the ventricular repolarization phase was shortened by 300 microg/kg/min of esmolol infusion. Meanwhile, ONO-1101 as well as esmolol significantly reduced the isoproterenol-induced increase in heart rate and ventricular contraction, but the inhibitory action of ONO-1101 was 6-8 times greater than that of esmolol. These results suggest that the suppressive effects of ONO-1101 on cardiovascular performance are significantly less potent than those of esmolol at equipotent beta-blocking doses.     

Norepinephrine release is increased in the hibernating heart, studied in a chronic canine model of myocardial hibernation

We examined the change in cardiac sympathetic function in the hibernating heart. To induce hibernating hearts in dogs, we placed a nylon tube via the carotid artery in the left circumflex artery (LCx) and obstructed the LCx flow. The plasma norepinephrine (NE) and epinephrine (E) concentrations in the coronary sinus and the aorta were measured before and 1 week after the tube placement to evaluate the catecholamine release from the heart. The wall motion was followed by echocardiography and. 1 week after the tube placement, regional myocardial blood flow (RBF) was measured using colored microspheres. Also. the restorability of myocardial dysfunction was examined in other dogs by extracting the LCx tube 1 week after the placement. Finally, the heart was removed for pathological observation and dogs showing myocardial infarction were excluded. One week after placing the tube, wall thickening was reduced in the LCx area, but was not in the left anterior descending (LAD) area. Compared with the LAD area, RBF in the LCx area was decreased in the endocardium (p < 0.05), but was not in the epicardium. In other dogs, the reduced wall thickening in the LCx area was restored to normal levels 1 or 2 weeks after the tube extraction. Thereby, our dogs with the tube placed were considered to be models of myocardial hibernation. The plasma NE and E concentrations were not significantly changed by placing the tube, but NE release from the heart was increased after the tube placement (p < 0.05). E uptake from the heart did not differ. Therefore, it is suggested that NE release is increased in the hibernating heart and may contribute to its mechanism.     

Electrophysiologic actions of aprindine in rabbit atrioventricular node

Summary Aprindine hydrochloride is a potent antiarrhythmic agent against various atrial and ventricular tachyarrhythmias. To elucidate its pharmacological actions in the atrioventricular node, electrophysiologic experiments were conducted by applying microelectrode and voltage clamp methods to small preparations of the rabbit atrioventricular node.At a concentration 1 mol/l, aprindine decreased the spontaneous firing frequency, maximal rate of depolarization, action potential amplitude, and take-off potential (P < 0.05, n = 7). The spontaneous and rate-controlled action potential durations at 50 and 100% repolarization were prolonged by aprindine. Voltage-clamp experiments using the double microelectrode method revealed that aprindine blocked the slow inward current (I_si) in a voltage-dependent manner with a dissociation constant of 10 mol/l and Hill coefficient of 0.8. The steady-state inactivation curve for I_si was shifted toward more negative potentials by 2.5 ± 0.9 mV (P < 0.05, n = 5) without a significant change in the slope factor. This finding suggests that aprindine has a higher affinity for inactivated slow inward (or Ca²⁺) channels than for resting channels. Aprindine caused use-dependent block of I_si, a result consistent with the drug's slow dissociation from inactivated Ca²⁺ channels. The delayed rectifying K⁺ current (I_K) tail obtained on repolarization from +10 mV to –60 mV was significantly decreased from 15.4 ± 2.4 to 6.8 ± 1.4 nA (P < 0.01, n = 6) and the deactivation time constant significantly increased by 20.7% (P < 0.01, n = 6). The steady-state activation curve for I_K was shifted in the hyperpolarized direction by 6.9 ± 2.9 mV, suggesting a potent voltage-dependent block of this current by aprindine. The hyperpolarization-activated inward current (1_h) was decreased from 14.4 ± 5.4 to 12.0 ± 5.5 nA (P < 0.05, n = 5). The transient outward and inward currents induced by 1 mol/l acetylstrophanthidin were almost completely suppressed after the addition of 1 mol/l aprindine.These results suggest that aprindine exerts a negative chronotropic action both by slowing deactivation of I_K and by reducing Is; and Ih, and delays atrioventricular nodal conduction by reducing Is; and IK. These blocking actions of aprindine together with its inhibition of the transient outward and inward currents may explain its antiarrhythmic effects on the atrioventricular node. Send offprint requests to Yoshio Watanabe at the above address     

Tedisamil in a chronic canine model of atrial flutter.

Tedisamil inhibits several cardiac potassium channels including Ito, Ikr, and the adenosine triphosphate (ATP)-sensitive potassium channel (I(KATP)), which may be important in the initiation and maintenance of atrial arrhythmias. We herein report the efficacy of tedisamil in terminating and protecting against the reinduction of atrial flutter (AFL) in a conscious canine model. Sustained AFL (> 15 min) was induced in eight of 10 mongrel dogs by programmed atrial stimulation (PAS) 2-41 days after producing a surgical barrier to conduction in the right atrium. At the time of surgery, an epicardial electrode was attached to the right atrial appendage for pacing and recording. Normal saline, 1 ml/kg, was infused after 15 min of AFL as placebo. Tedisamil (1.0 mg/kg) was given intravenously after 30 min of sustained AFL while recording surface ECGs and atrial electrograms. Conversion to sinus rhythm was achieved in 10 of 10 trials (eight dogs) in a mean time of 20.5 s (SD, +/- 11.8 s). Tedisamil had a negative chronotropic effect lasting > or =2 h and was protective against the reinduction of AFL. In five dogs, PAS was able to induce AFL in only two of seven trials 2 h after drug infusion. The corrected QT interval (QTc) was lengthened for the first 15 min after tedisamil administration (mean, +/- 39.3 ms; p < 0.05), but thereafter returned to baseline. The QRS interval was not altered by tedisamil. Saline alone, given after 15 min of sustained AFL, converted AFL in one of 11 trials (eight dogs) but did not alter the RR interval, QTc, or QRS interval compared with values measured during AFL. No significant adverse effects of tedisamil were observed. The results indicate that tedisamil is effective in interrupting and/or preventing reinduction of canine AFL, possibly by prolonging atrial refractoriness through inhibition of one or more potassium ion repolarizing currents in atrial muscle. Further studies are required to address the exact mechanism by which tedisamil exerts its antiarrhythmic effect.     

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.     

Time-dependence of inducible ventricular tachycardia in a chronic canine model.

The natural history of inducible ventricular tachycardia in post-infarction dogs was followed with serial programmed electrical stimulation (PES: 1-3 extrastimuli, 4 msec duration, 2 x diastolic threshold). Arrhythmia inducibility was defined as a minimum of four unstimulated ventricular ectopic beats. Of 119 dogs prepared for chronic electrophysiological study, 87 (73.1%) were ambulant 24 hours after surgery. Mean infarct size was 11.1 +/- 1.5% of left ventricular (LV) mass for animals dying in the first week, before stimulation. 92.4% of 66 animals were inducible when stimulated at one week, 66.7% at two weeks and 64.3% and 55.6% at the third and fourth weeks respectively (p less than 0.01, Chi-square analysis). Infarct sizes fell from 7.0 +/- 0.5% LV mass at first stimulation to 4.6 +/- 0.8% at third stimulation and could not be visualized thereafter (p less than 0.01,ANOVA). There was no statistical difference between infarct sizes for inducible and non-inducible animals, but in both cases infarcts were smaller (p less than 0.01) than for those animals which died suddenly during the first week. This time-dependent decrease in arrhythmia inducibility, which may be related to infarct size, should be considered when similar models are employed for chronic electrophysiological studies.     

Antifibrillatory actions of d,l-nadolol in a conscious canine model of sudden coronary death

The role of beta-adrenergic receptor blockade in preventing ventricular fibrillation in a conscious canine model of sudden coronary death was examined using d,l-nadolol and the non-beta-adrenergic receptor blocking isomer, d-nadolol. On day 4, after a temporary 90-min occlusion of the left anterior descending coronary artery, an anodal current of 150 microA was applied to the intimal surface of the left circumflex coronary artery. Occlusive or nonocclusive thrombosis of the artery was accompanied by ST-segment changes. In saline-treated animals (n = 15), ST-segment changes were followed by sinus tachycardia and QT-segment prolongation, with development of ventricular premature beats. Ventricular fibrillation developed in 14 animals (93%). Pretreatment with 1 (n = 9) or 8 mg/kg d,l-nadolol (n = 13) did not alter the development of left circumflex coronary artery thrombosis and ischemic ST-segment changes, but decreased the incidence of ventricular fibrillation and increased survival at 24 h (56% and 63%, respectively) (p less than 0.01 versus saline). d,l-Nadolol also attenuated the sinus tachycardia and QT-interval prolongation accompanying acute ischemia. d-Nadolol (1 mg/kg), the non-beta-adrenergic receptor blocking isomer, failed to prevent development of ST-segment changes. Sinus tachycardia and QT-interval prolongation were not prevented, and ventricular fibrillation developed in all eight animals (100%). In animals without previously induced anterior myocardial ischemic injury (n = 10), left circumflex coronary artery thrombosis failed to produce sinus tachycardia and QT-interval prolongation and was associated with a lower incidence of ventricular fibrillation (20%, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction.

The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.     

The central actions of lidocaine and a pesticide, chlordimeform

The injection of 300–1000 μg of lidocaine or chlordimeform (CDM) into the lateral ventricles of rats lightly anaesthetized with urethane produced similar dose-dependent pressor (or depressor) responses. Stimulation of the dorsal raphe nucleus caused suppression of the spontaneous EEG recorded from bipolar electrodes implanted in the amygdala. Intraventricular lidocaine and CDM blocked the raphe-mediated suppression of the amygdala EEG activity.

Higher doses (3–4 mg) of intraventricular lidocaine or CDM resulted in clonic limb movements, spikes in the amygdala EEG and blood pressure oscillation. All seizure manifestations could be blocked by intense raphe stimulation or by intravenous diazepam (1 mg/kg).

These studies indicate a central origin for the secondary pressor response that is observed with higher intravenous doses (10–50 mg/kg) of lidocaine or CDM.     

卡托普利对犬实验性围手术期心肌缺血的影响

目的探讨肾素－血管紧张素系统（ＲＡＳ）在围手术期心肌缺血中的作用。方法杂种犬４０只均分为４组：Ⅰ组：对照组；Ⅱ组：心肌梗塞模型组；Ⅲ组：心梗＋胃大部切除组；Ⅳ组：心梗＋卡托普利＋胃大部切除组。取不同部位心脏测肾素和ＡｎｇⅡ，测Ⅲ、Ⅳ组基础、术前和术后的血流动力学和生化指标。结果在Ⅲ组，手术引起左室压最大上升速率及心脏指数下降，致左室舒张末期压、肺动脉嵌压、左室舒张压力下降时间常数（Ｔ值）、总外周阻力（ＴＰＲ）及内皮素、肾素、α－颗粒膜蛋白和ＡｎｇⅡ升高；在Ⅳ组，用药后４０ｍｉｎ，ＴＰＲ和ＡｎｇⅡ下降，Ｔ值和肾素升高；手术使血流动力学回降，其余指标不变。对局部ＲＡＳ、心梗后肾素、ＡｎｇⅡ均增多，手术使ＡｎｇⅡ更多，卡托普利能防止其发生。结论心梗后行胃大部切除术能致左心舒缩功能障碍及激活ＲＡＳ；卡托普利能预防其发生。     

Electrophysiologic effects of cocaine on the canine ventricle

To evaluate the electrophysiologic effects of cocaine on the ventricle, 12 conscious dogs were studied before and after a bolus and infusion of cocaine titrated to maximum tolerance or to an increase in the mean blood pressure by at least 15%. Plasma cocaine levels, blood pressure, and surface and intracardiac electrograms were recorded. Programmed electrical stimulation was performed from the right ventricle at drive cycle lengths of 400 and 350 ms with introduction of up to three extrastimuli. The right ventricular effective refractory period decreased by 10% (p less than or equal to 0.01) and the mean blood pressure increased by 19% (p less than or equal to 0.01). No sustained spontaneous or induced ventricular arrhythmias were recorded after cocaine administration. There were no significant changes in pacing threshold, intraventricular conduction, heart rate, QRS or QTc intervals. The cocaine dose infused was 2.1 +/- 1.0 mg/kg; cocaine plasma levels were 1969 +/- 959 ng/ml immediately after the bolus and 508 +/- 234 ng/ml at the end of the study. It is concluded that in a presumably normal canine heart and at the doses given that cocaine decreases right ventricular effective refractory period, does not change intraventricular conduction, and does not result in sustained spontaneous or induced ventricular arrhythmias.     

Somatostatin analogue mimics acute ischemic preconditioning in a rat model of myocardial infarction

We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation.     

Electrophysiologic effects of bepridil in normal and infarcted canine myocardium

The electrophysiologic effects of bepridil, 10 mg/kg i.v., were determined in normal noninfarcted and in infarcted ventricular myocardium in 8 urethane-anesthetized dogs 4-6 days after anterior myocardial infarction. At drive cycle lengths of 400 and 333 ms, bepridil significantly increased relative (RRP) and effective (ERP) refractory periods in both normal ventricular tissue (mean increases, RRP 7-14%, ERP 5-6%, p less than 0.05-0.01) and in infarcted ventricular tissue (mean increases, RRP 12-15%, ERP 13-14%, p less than 0.01). Bepridil also selectively prolonged the local activation delay in infarcted ventricular myocardium (mean increases 37.5-45.1%, p less than 0.01), while ventricular excitation thresholds were not altered by bepridil in either normal or infarcted myocardium. Before bepridil administration, programmed ventricular stimulation initiated sustained ventricular tachycardias in 6 of the 8 postinfarction dogs tested. After bepridil, 2 of the 6 previously responsive animals were rendered noninducible, 3 animals responded to programmed stimulation with nonsustained tachyarrhythmias of relatively slower rates, and the one remaining dog responded with sustained ventricular tachycardia (VT). These data suggest that increases in refractoriness in both normal noninjured and in ischemically injured ventricular tissue, with a selective delay in conduction in ischemically injured tissue, contribute to the antiarrhythmic actions of bepridil in the setting of myocardial infarction.