Prevention of myocardial electrical activity during ischemic arrest with verapamil cardioplegia

The effect of potassium cardioplegia and potassium cardioplegia containing verapamil hydrochloride on myocardial preservation and electrical activity during prolonged aortic occlusion was examined in 40 adult mongrel dogs. Twenty-four animals (Group 1) received potassium cardioplegia, and 16 animals (Group 2) received potassium verapamil cardioplegia. Potassium or potassium verapamil cardioplegia, 10 ml per kilogram of body weight, was administered after application of the aortic cross-clamp and at 30-minute intervals during the 90-minute arrest. Myocardial temperature was maintained within a range of 8 degrees to 10 degrees C with topical ice saline solution, and electrical activity was monitored with specially designed plunge electrodes. Plunge electrode activity was recorded from the myocardium during arrest in 16 of the 24 animals in Group 1; no electrical activity was present in the animals in Group 2 (p less than .001). The addition of verapamil to potassium cardioplegia increased the tolerance of the myocardium to prolonged ischemia and resulted in less depletion of high-energy phosphate stores and better preservation of mitochondrial ultrastructure and left ventricular function. These data suggest that verapamil augments the preservation provided by potassium cardioplegia by initiating and maintaining a more complete electrical arrest.     

Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine

The cardiovascular and neuromuscular interactions of verapamil and dantrolene were evaluated in 20 chloralose-anesthetized swine. The animals were randomly divided into three groups. Group I, ten animals, received a bolus intravenous injection of 0.1 mg . kg-1 of verapamil followed by the continuous infusion of 5 micrograms . kg-1 . min-1. This group was then randomly divided into two equal subgroups. Five of these animals, Group Ia, continued to receive the verapamil infusion alone. The other five animals, Group Ib, received dantrolene in incremental doses of 1.0, 3.3, and 5.6 mg . kg-1 while the verapamil infusion was continued. An additional group of five animals, Group II, received the same incremental doses of dantrolene but did not receive verapamil. Five control animals, Group III, received the alpha-chloralose anesthetic without dantrolene or verapamil. Neuromuscular function, as measured by twitch height, was affected only by dantrolene, which produced a dose-dependent depression. Verapamil resulted in initial decreases in heart rate, arterial blood pressure, cardiac output, left ventricular dP/dt, and an increase in PR interval. Dantrolene alone produced a mild increase in arterial blood pressure. Dantrolene administration to verapamil-pretreated animals resulted in a profound depression in cardiac function, marked elevation in serum K+ (8.0 +/- 0.7 mEq . l-1), and no change in arterial pH (7.39 +/- 0.02). Cardiac arrest preceded by complete atrioventricular heart block occurred in one animal before and in four animals after the final dantrolene dose was given to animals pretreated with verapamil. Although we cannot extrapolate data from our porcine model to humans, further studies are indicated to help evaluate a possible fatal drug interaction before verapamil and dantrolene are used concomitantly in a clinical setting.     

Superior action of magnesium-lidocaine-1-aspartate cardioplegia to glucose-insulin-potassium cardioplegia in experimental myocardial protection

The effect of 2 hours of hypothermic Mg-lidocaine cardioplegia upon left ventricular function, myocardial high-energy stores, edema, and ultrastructure was studied as compared to glucose-insulin-potassium (GIK) cardioplegia in 12 mongrel dogs. The myocardial temperature recorded in the ventricular septum was kept at 20 degrees C during the cardioplegia. The heart was re-warmed up to 37 degrees C by the support of cardiopulmonary bypass, then, observations were made during a 60 minutes reperfusion. Left ventricular function was preserved at a more physiological level in cases of Mg-lidocaine cardioplegia. Myocardial ATP as preserved at significantly higher levels following Mg-lidocaine cardioplegia than in cases of GIK cardioplegia (p < 0.05). However, content of myocardial creatine phosphate was higher in the GIK cardioplegia group than that in Mg-lidocaine group in the subendocardium and the ventricular septum. Myocardial edema was significantly suppressed following Mg-lidocaine cardioplegia, and such was significantly lower than in cases of GIK cardioplegia (p < 0.05). The myocardial ultrastructure was protected from ischemic insult in the Mg-lidocaine cardioplegia group. These data suggest that Mg-lidocaine-1-aspartate solution is superior to GIK solution as a cardioplegic solution, and that such will feasibly provide myocardial protection for 2 hours of hypothermic cardiac arrest, in an experimental reperfused model.     

异丙酚预先给药对糖尿病大鼠心肌缺血再灌注损伤的影响

目的 探讨异丙酚预先给药对糖尿病大鼠心肌缺血再灌注损伤的影响.方法 健康雄性SD大鼠84只,体重230～280 g,随机分为7组(n=12),假手术组(Ⅰ组);Ⅱ组采用结扎左冠状动脉前降支30 min,再灌注120 min制备心肌缺血再灌注模型;糖尿病大鼠假手术组(Ⅲ组)采用腹腔注射链脲左菌素(STZ)55 mg/kg制备糖尿病模型;糖尿病大鼠心肌缺血再灌注组(Ⅳ组)腹腔注射STZ 3周后制备心肌缺血再灌注模型;Ⅴ组、Ⅵ组和Ⅶ组糖尿病大鼠分别于缺血前10 min至再灌注120 min时静脉输注异丙酚3、6、12 mg·kg-1·h-1.记录再灌注120 min时心率(HR)、左心室收缩峰压、左心室舒张末压(LVDEP)及左心室内压上升,下降最大速率(±dp/dtmax),计算左心室发展压(LVDP);测定血清肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)活性、心肌组织超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、心肌线粒体肿胀度、总ATP酶和谷胱苷肽过氧化物酶(GSH-Px)活性;透射电镜观察心肌组织超微结构.结果 与Ⅲ组比较,Ⅳ组HR、LVDP和±dp/dtmax、心肌组织SOD活性、线粒体总ATP酶及GSH-Px活性降低,LVEDP、血清LDH、CK-MB活性、心肌组织MDA含量及线粒体肿胀度升高(P<0.05或0.01);与Ⅳ组比较,Ⅵ组和Ⅶ组HR、LVDP和±dp/dtmax、心肌组织SOD活性、线粒体总ATP酶及GSH-Px活性升高,LVEDP、血清LDH、CK-MB活性、心肌组织MDA含量和线粒体肿胀度降低,Ⅴ组+dp/dtmax及线粒体总ATP酶活性升高,血清CK-MB活性降低(P<0.05).Ⅵ组和Ⅷ组心肌组织超微结构损伤减轻.结论 异丙酚6、12 mg·kg-1·h-1预先给药可减轻糖尿病大鼠心肌缺血再灌注损伤,可能与其抑制心肌组织脂质过氧化反应,改善心肌细胞线粒体膜通透性有关.     

Antidepressant effects of tricyclic antidepressants and selective serotonin-uptake blockers in diabetic rats

Because it was reported that diabetic rodents were resistant to the effects of several tricyclic antidepressants in various psychopharmacological models, we decided to test the hypothesis that the serotonergic dysfunction seen in diabetes might participate in this phenomenon. The ability of three serotonin-uptake blockers to reverse the performance deficit in learning induced by previous uncontrollable stress (learned-helplessness paradigm) was investigated in streptozocin-induced diabetic rats. Three weeks after induction of diabetes, rats were subjected to a session of 60 inescapable electric foot shocks and, after 48 h, to three daily sessions of two-way shuttle-box training. Three serotonin-uptake blockers were given intraperitoneally over 5 consecutive days. As with nondiabetic rats, citalopram (1 mg.kg-1. day-1), fluoxetine (2 and 4 mg.kg-1. day-1), and fluvoxamine (4 mg.kg-1.day-1) reduced the number of escape failures in diabetic rats. From these data, we suggest that it is unlikely that the impaired response of diabetic rats to tricyclic antidepressants is caused by serotonergic dysfunction.     

Increase in [3H]PN 200-110 binding to cardiac muscle membrane in streptozocin-induced diabetic rats

Voltage-sensitive Ca2+ channels in cardiac left ventricular muscle membranes isolated from nondiabetic control and diabetic rats were measured with [3H]PN 200-110, a dihydropyridine derivative, as a ligand. The binding site (Bmax) of [3H]PN 200-110 in cardiac membranes isolated from streptozocin-induced diabetic (STZ-D) rats (128 +/- 10 fmol/mg protein) significantly (P less than 0.01) increased by 64% compared with that of control rats (78 +/- 4 fmol/mg protein) 10 wk after STZ administration without a significant change in Kd. However, the significant increase in Bmax of [3H]PN 200-110 binding in diabetic rats depended on the duration of diabetes such that the increase was not found until 6 wk after STZ injection. An 8-wk intensive insulin treatment, which was initiated 2 wk after STZ injection, normalized the increase in [3H]PN 200-110 binding in STZ-D rats to control levels (85 +/- 4 fmol/mg protein). Furthermore, [3H]PN 200-110 binding to control cardiac membranes was dose-dependently inhibited in the presence of verapamil, a phenylalkylamine Ca2+ antagonist, but that was not the case in cardiac membranes isolated from STZ-D rats. These results indicate that voltage-sensitive Ca2+ channels in cardiac muscle isolated from STZ-D rats are quantitatively and qualitatively altered, because the course of diabetes and the increase in the channels can be prevented by treatment with insulin.     

A functional and ultrastructural analysis of experimental diabetic rat myocardium. Manifestation of a cardiomyopathy

The effects of experimental diabetes on cardiac function and ultrastructure were studied in rats that had been diabetic for 6-24 wk. Experimental diabetes was produced by the intravenous (i.v.) injection of 65 mg/kg streptozocin (STZ) into rats 42-43 days old. Diabetic rat hearts perfused at 15 cm H2O on the working heart apparatus demonstrated depressed cardiac function (i.e., lower left ventricular pressure and +/- dP/dt) at 6, 12, and 24 wk of diabetes. Electron microscopic analysis of ventricular myocardium revealed increased lipid deposition from 6 to 24 wk of diabetes and progressive deterioration of the myocardial cell integrity at 12 and 24 wk of diabetes. This deterioration was characterized by loss of contractile protein, vacuolization (swollen sarcoplasmic reticulum), myelin formations, myocytolysis, and contracture bands. These alterations paralleled the depression of cardiac function at 12 and 24 wk of diabetes. There was, however, depressed function at 6 wk of diabetes but no observable alterations in myocardial ultrastructure. Therefore, experimental diabetes produced ultrastructural alterations in the rat heart that manifested themselves only after a demonstrable depression in cardiac function.     

Substrate Cardioplegia during Hypothermic Arrest in the Alloxan Diabetic Dog

In an experimental study, 26 mongrel dogs were treated with alloxan (50 mg per kilogram) to induce fasting hyperglycemia and diabetes. The animals were randomly subdivided into two groups, one of which received 100 mg of propranolol in divided doses for two weeks. The animals underwent sternotomy and were placed on total cardiopulmonary bypass. After aortic cross-clamping, each animal received 10 ml per kilogram of cardioplegic solution. Two different solutions were used, a standard hyperkalemic solution and a high-energy glucose-insulin-potassium (GIK) substrate. Baseline studies were made on the four groups of diabetic animals.Animals given potassium cardioplegia but no propranolol showed statistically significant decreases in cardiac index, heart rate, mean arterial pressure, and minute left ventricular stroke work index after bypass. In contrast, animals given GIK cardioplegia but no propranolol showed no changes in any of these measurements. Animals administered propranolol and potassium cardioplegia experienced decrease in mean arterial pressure from 77.5 ± 14.1 mm Hg before bypass to 57.5 ± 17.8 mm Hg after bypass. A similar reduction occurred in animals given propranolol and GIK cardioplegia. However, in this group, the cardiac index increased from 1.78 ± 0.38 L/min/m² before bypass to 2.96 ± 0.73 L/min/m² after bypass (p < .006). Similarly, the minute left ventricular stroke work index increased after bypass in these animals. This study demonstrates the protective effect against myocardial ischemia of the addition of substrate to the cardioplegic solution in diabetic animals subjected to aortic cross-clamping during cardiopulmonary bypass, one group receiving propranolol and one group not receiving it.     

Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart

In view of the depressed sarcoplasmic reticulum (SR) Ca2+-pump and Ca2+-release activities in the diabetic heart and the critical role of phosphorylation in regulating the SR function, we examined the status of Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA)-mediated phosphorylations in the diabetic heart. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (65 mg/kg i.v.), and the animals were killed 6 weeks later for assessment of the ventricular SR function. Depressed cardiac performance and SR Ca2+-uptake and -release activities in diabetic animals were accompanied by a significant decrease in the level of SR Ca2+-cycling proteins, such as ryanodine receptor, Ca2+-pump ATPase, and phospholamban. On the other hand, the CaMK- and PKA-mediated phosphorylations of these Ca2+-cycling proteins, the endogenous SR CaMK and PKA activities, and the endogenous SR and cytosolic phosphatase activities were increased in the diabetic heart. Treatment of 3-week diabetic animals with insulin partially or fully prevented the diabetes-induced changes in cardiac performance, SR Ca2+-uptake and -release activites, and SR protein content, whereas the diabetes-induced changes in SR CaMK- and PKA-mediated phosphorylations and activities, as well as phosphatase activities, were not significantly affected. These results suggest that the reduced content of the Ca2+-cycling proteins, unlike alterations in PKA and phosphatase activities, appear to be the major defect underlying SR dysfunction in the diabetic heart.     

The effect of diltiazem and dobutamine on myocardial ischemia

The effect of diltiazem and dobutamine on cardiac function and metabolism of the myocardium rendered ischemic for 40 min by occlusion of the left anterior descending coronary artery followed by 15 min reperfusion were studied in 22 dogs. In group D, diltiazem was administered in 8 dogs by a 0.1 mg/kg iv bolus followed by 30 micrograms/kg/min continuous infusion. In D-D group, dobutamine was infused at 5 micrograms/kg/min during reperfusion in 8 dogs. Diltiazem was used in the same manner as group D. Cardiac output was much higher in group D than in the non-treated group C, and heart rate, double product, SVR were reduced but coronary flow was increased in group D. Myocardial tissue Ca2+ in group D was significantly lowered level as compared to group C. Myocardial ATP and CP content were much better preserved in group D than in group C. In group D-D, dobutamine enhanced cardiac function without depletion of myocardial high-energy phosphate but tissue Ca2+ was slightly increased. Myocardial ischemic changes in the ultrastructure were much better protected in group D and D-D than in group C. In group C and D-D, reperfusion-induced arrhythmias were significantly reduced.     

Na+-K+-ATPase pumping activity is not directly linked to myo-inositol levels after sorbinil treatment in lenses of diabetic rats

Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular metabolite and enzyme-activity levels in the streptozocin-induced diabetic rat was examined to determine what, if any, relationship exists between these changes. Two weeks of untreated diabetes did not change ouabain-inhibitable ATPase enzyme activity assayed in lens homogenates but did result in a decrease in the Na+-K+-ATPase transport activity as measured by 86Rb uptake in the intact lens. This was accompanied by a 100-fold increase in the levels of sorbitol and significant decreases in the levels of myo-inositol, ATP, and glutathione in the lens. Whereas all of these changes could be reversed by sorbinil treatment, the dose required for restoration of the depleted myo-inositol level (ED50 greater than 20 mg.kg-1.day-1) was much higher than the dose required to reverse the other changes (ED50 range 2-5 mg.kg-1.day-1). These results suggest that the restoration of lenticular Na+ -K+ -ATPase activity is not secondary to a normalization of myo-inositol levels and may provide evidence that the two parameters are not strictly associated in diabetic tissues.     

Effect of various low-dose concentrations of verapamil cardioplegia on small-amplitude electrical activity during cardioplegic arrest

The effect of verapamil cardioplegia on atrioventricular conduction was examined in 19 dogs. During 90 minutes of ischemic arrest, five dogs received multidose potassium cardioplegia, containing 1.2 mg/L of verapamil (group 1), five received potassium cardioplegia containing 600 micrograms/L of verapamil (group 2) and nine animals received cardioplegia containing 300 micrograms/L of verapamil (group 3). Atrioventricular conduction was measured in all groups before bypass, after 90 minutes of ischemia and after 45 minutes of reperfusion. Specially designed plunge electrodes were used to monitor the electrical status of the heart during arrest in group 3 and, in addition, left ventricular function and concentration of high-energy phosphates were determined before and after ischemic arrest. Conduction was prolonged in four group 1 dogs and in two group 2. Atrioventricular conduction was measured in six group 3 dogs; five had prolonged conduction and one experienced second-degree heart block. Small-amplitude electrical potentials were recorded from the myocardium in two of nine dogs in group 3. Persistent electrical activity was associated with continued use of high-energy phosphates and resulted in decreased left ventricular function after 90 minutes of ischemic arrest. Our data indicate that small doses of verapamil will delay atrioventricular conduction and will not prevent small-amplitude electrical activity.     

Effect of FK 506 on spontaneous diabetes in BB rats.

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.     

Prevention by tetrandrine of spontaneous development of diabetes mellitus in BB rats.

Treatment of BB rats with the plant alkaloid tetrandrine (20 mg.kg-1.day-1), a novel anti-inflammatory compound, from 35 to 120 days of age reduced the cumulative incidence of spontaneous diabetes from 75.5 to 10.9% (P less than 0.001). Dose-response studies with 0, 5, 10, and 20 mg.kg-1.day-1 of tetrandrine from 35 to 130 days resulted in spontaneous diabetes in 84.2, 63.1, 31.6, and 5.3% of the rats, respectively. When the start of treatment with 20 mg.kg-1.day-1 tetrandrine was delayed until 70 days of age, there was a significant reduction of the incidence of diabetes from 63.1 to 28.6% (P less than 0.01). Histological examination of the pancreases from tetrandrine-treated rats showed a lesser degree of insulitis than controls (P less than 0.01). Drug toxicity was not seen in the rats, as assessed by appearance, behavioral change, organ histology, and blood chemistry. These results provide some hope that tetrandrine may be of value in preventing diabetes and treating newly diagnosed diabetic subjects, either by itself or in combination with a more potent immunosuppressive agent.     

Decreased myo-inositol content and Na+-K+-ATPase activity in superior cervical ganglion of STZ-diabetic rat and prevention by aldose reductase inhibition

Decreased sciatic nerve myo-inositol content and Na+-K+-ATPase activity have been associated with slowing of motor nerve conduction in the acutely diabetic rat and have been invoked as possible pathogenic factors in diabetic peripheral neuropathy. Aldose reductase inhibitors prevent these abnormalities in peripheral nerves of the streptozocin (STZ)-diabetic rat. Whether an analogous biochemical abnormality occurs in the autonomic nervous system and plays a role in the development of diabetic autonomic dysfunction is unknown. Therefore we examined the effect of 8 wk of untreated STZ diabetes and administration of 20 mg X kg-1 X day-1 of the aldose reductase inhibitor sorbinil on myo-inositol level and Na+-K+-ATPase activity in rat superior cervical ganglia. Both myo-inositol concentration and Na+-K+-ATPase activity were reduced in ganglia from untreated STZ-diabetic rats, and sorbinil administration prevented these abnormalities. Thus, a sorbinil-responsive metabolic defect involving myotional abnormalities in the somatic and autonomic nervous systems in diabetes.     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. VI. Verapamil and fentanyl-pancuronium

To assess the interaction between verapamil and fentanyl-pancuronium, dogs were chronically instrumented to measure heart rate; PR interval; aortic, left ventricular, and left atrial pressures; and coronary, carotid, and renal blood flows. The effect of fentanyl citrate infusion on single-dose verapamil pharmacokinetics was examined in six animals. The effects of verapamil infusion (3 micrograms.kg-1.min-1 and 6 micrograms.kg-1.min-1) were examined in the conscious state and during fentanyl infusion plus pancuronium on two separate occasions in nine dogs. In addition, the effects of fentanyl citrate (500 micrograms.kg-1 followed by 1.5 micrograms.kg-1.min-1) were examined over 1 h of infusion. Fentanyl infusion did not affect single-dose verapamil pharmacokinetics. In the conscious animals, verapamil increased heart rate and PR interval, and slightly decreased LV dP/dt. Fentanyl combined with pancuronium increased mean arterial pressure and LV dP/dt. During fentanyl infusion, verapamil decreased mean arterial pressure and LV dP/dt, increased PR interval, and did not change heart rate. The hemodynamic effects of fentanyl infusion were steady over 1 h. In contrast to the inhalational anesthetics, which alter verapamil pharmacokinetics and have mainly additive effects with verapamil on left ventricular contractility, cardiac conduction, and regional blood flows, fentanyl-pancuronium had no effect on verapamil pharmacokinetics and minimal effect on verapamil pharmacodynamics in healthy dogs.     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. I. Verapamil and halothane

In order to assess the interaction between halothane and verapamil on the cardiovascular system, mongrel dogs were instrumented so that the following measurements could be made awake and under the influence of the drugs: aortic, left ventricular, and left atrial blood pressures; myocardial segment length shortening; heart rate and rhythm; and coronary, carotid, and renal blood flows. The effect of two infusion doses of verapamil (3 micrograms X kg-1 X min-1 and 6 micrograms X kg-1 X min-1 after 200 micrograms X kg-1 bolus) were examined awake. On a different day in the same dogs, two concentrations of halothane (1.2-low and 2.4-high % end-tidal) and the effect of the two infusion doses of verapamil during low and high halothane were studied. Thirty minutes of either infusion dose of verapamil produced only heart rate and electrocardiographic P-R interval increases in conscious dogs. Halothane produced dose-related decreases in mean aortic pressure, left ventricular maximum rate of tension development (dP/dt), and segment length shortening and increases in heart rate and left atrial pressure. Carotid blood flow was increased by low halothane concentrations and returned to control with high halothane concentrations. There were no significant changes in coronary or renal blood flow produced by halothane. Verapamil infusion during low halothane concentration produced minimal effects. However, both the 3 and 6 micrograms X kg-1 X min-1 verapamil doses further depressed hearts already depressed by the high concentrations of halothane and decreased renal and carotid blood flows.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic verapamil treatment depresses automaticity and contractility in isolated cardiac tissues

Chronically administered verapamil can accumulate in cardiac tissues and may depress cardiac function despite low plasma concentration. To examine this, two groups of rabbits were injected intraperitoneally twice a day with either 1 mg/kg verapamil or saline for 28 days. Fourteen hours after the last dose, right atrial tissue and right ventricular papillary muscle were isolated. Plasma and myocardial tissue concentrations of verapamil were determined. Plasma samples contained no detectable amounts of verapamil, but the myocardium contained 2.1 +/- 0.6 (mean +/- SE) ng of verapamil per gram of wet tissue. Spontaneous action potentials recorded from the sinoatrial node in the verapamil-treated group showed decreases in the phase 0 and phase 4 depolarization rates, a slower pacemaker rate, and an attenuated response to epinephrine compared with the saline-treated group. Papillary muscle in the verapamil-treated group exhibited a significantly lower force of contraction and a depressed contractile response to epinephrine compared with the control group. There were no differences in rate or contractile responses the day after single injection with 2 mg/kg verapamil or saline twice a day. Myocardial verapamil concentration increased with the duration of treatment and with the doses given; myocardial verapamil concentration was 3.0 +/- 0.6 ng/g wet tissue in the group treated for 28 days with 2 mg/kg verapamil. Our study shows that chronic treatment of rabbits with verapamil decreases cardiac chronotropic and inotropic responses to adrenergic stimuli despite no detectable verapamil in plasma, and that accumulation of verapamil in the myocardium is probably associated with these effects.     

Droperidol Inhibits Intracellular Ca2+, Myofilament Ca2+ Sensitivity, and Contraction in Rat Ventricular Myocytes

Background: Droperidol has recently been associated with cardiac arrhythmias and sudden cardiac death. Changes in action potential duration seem to be the cause of the arrhythmic behavior, which can lead to alterations in intracellular free Ca2+ concentration ([Ca2+]i). Because [Ca2+]i and myofilament Ca2+ sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca2+]i or myofilament Ca2+ sensitivity in rat ventricular myocytes and to identify the cellular mechanisms responsible for these effects.

Methods: Freshly isolated rat ventricular myocytes were obtained from adult rat hearts. Myocyte shortening, [Ca2+]i, nitric oxide production, intracellular pH, and action potentials were monitored in cardiomyocytes exposed to droperidol. Langendorff perfused hearts were used to assess overall cardiac function.

Results: Droperidol (0.03-1 [mu]m) caused concentration-dependent decreases in peak [Ca2+]i and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca2+]i, with little direct effect on sarcoplasmic reticulum Ca2+ stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca2+ for shortening, with no concomitant effect on peak [Ca2+]i. Droperidol decreased pHi and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts.     

Effect of creatine monohydrate on cardiac function in a rat model of endotoxemia

BACKGROUND: Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia. METHODS: Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals. RESULTS: High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia. CONCLUSIONS: Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies.