Effects of Losartan on acute atrial electrical remodeling

Background Atrial electrical remodeling (AER) contributes to the maintainance of atrial fibrillation (AF). This study was to compare the effects of Losartan with those of Diltiazem on tachycardia-induced acute AER in rabbits.Methods Twenty-one rabbits paced with maximal atrial capture rate for 3 hours in the right atrium (RA) were randomly divided into saline group, Diltiazem group and Losartan group. After autonomic blockage, we measured atrial effective refractory period (AERP), AERP rate adapting feature, AERP dispersion and RA conduction time at basic cycle lengths (BCLs) of 200 ms and 150 ms at baseline, 0.5 hour, 1 hour, 2 and 3 hours after rapid atrial pacing. Results In the saline group, there was a prompt decrease in AERP as a result of rapid atrial pacing, and AERP200 and AERP150 were shortened sharply within 0.5 hour of pacing （30.2±10.5 ms and 24.1±9.1 ms, respectively）. The AERP did not change dramatically in the Diltiazem and Losartan groups. In the saline group, the value of （AERP200-AERP150）/50 ms in high RA was 0.17±0.08 at baseline and became significantly smaller at 0.5 hour (0.08±0.06), 1 hour (0.09±0.06), 2 hours (0.08±0.04) and 3 hours (0.09±0.05) (all P<0.05), suggesting a reduction of rate adaptation of AERP. The value of （AERP200-AERP150）/50 ms in high RA did not change during the 3 hours of pacing in both Diltiazem and Losartan groups. In the saline group, AERP dispersion increased significantly at 2 and 3 hours (P<0.05). However, Diltiazem could not prevent the increase of AERP dispersion at 3 hours (P<0.05). During Losartan infusion, the AERP dispersion was no longer increased after rapid atrial pacing. There was no significant difference in RA conduction time among the three groups.Conclusion Like calcium antagonist Diltiazem, Losartan could prevent AERP shortening and preserve rate adaptation of AERP after rapid atrial pacing. Losartan is more effective than Diltiazem in inhibiting the increase of AERP dispersion.     

钙拮抗剂对心血管系统的作用及临床应用

对钙拮抗剂对心血管系统的作用及治疗心绞痛、高血压中的有关注意事项 ,临床疗效及其不良反应等方面作一概述。     

地尔硫卓联合地高辛治疗心力衰竭并慢性快速房颤分析

目的观察地尔硫卓联合小剂量地高辛对心力衰竭并慢性快速房颤患者血压、心室率和心功能的影响。方法 :心功能Ⅱ～Ⅲ级慢性房颤患者 10 6例 ,随机分为二组 ,对照组 5 0例 ,单用地高辛 ,治疗组 5 6例 ,地尔硫卓与地高辛联用 ,其余治疗二组相同 ,7～ 10d为一疗程 ,观察治疗前后血压、心率、左室射血分数 (LVEF)、心输出量 (CO)。结果 :治疗组较对照组心室率明显下降 ,控制满意 ,血压、LVEF及CO变化二组相似。结论 :地尔硫卓联合小剂量地高辛治疗心衰并慢性快速房颤患者心室率较单用地高辛效果更好 ,且较为安全。     

Die Beeinflussung der Organperfusion durch Kalziumblocker und Converting-Enzyminhibitor an der herzinsuffizienten,wachen Ratte

Summary The present study examined the regional vascular effects (radioactive microspheres) of converting-enzyme inhibition (captopril, 1mg/kg) and calcium-antagonism (diltiazem, 1 mg/kg) in a rat model of cardiac failure due to large myocardial infarction (n=18, infarct size 40% of the left ventricle) both at rest and during submaximal tread-mill exercise. Diltiazem increased renal, gastrointestinal, coronary and cutaneous blood flow at rest by 29%, 28%, 26% and 37% (p<0.05 each) and enhanced skeletal muscle blood flow during exercise by 16% (p<0.05). Captopril improved primarily renal and coronary blood flow at rest (by 59% and 23%, respectively,p<0.05) and reduced vascular resistance in the gastrointestinal bed by 25% (p<0.05) without significant effects in other circulatory beds. We conclude that the regional vascular effects elicited by converting-enzyme inhibition and calcium antagonism differ considerably in this animal model of congestive heart failure and may be clinically important. The favourable regional vascular profile of diltiazem deserves further clinical investigation.

Mit Unterstützung der Deutschen Forschungsgemeinschaft Dr 148/2-1     

钙通道拮抗剂恬尔心在肾移植中的应用

供体取肾时，在肾灌注液中临时加入恬尔心针剂，受体自术日起长期口服恬尔心片剂，治疗６４例肾移植患者，同时与６４例对照组比较。结果表明，肾移植中应用恬尔心能减少急性肾小管坏死发生率和急性排斥发生率，并能提高环孢素Ａ（ＣｓＡ）的血浓度，减少其用量，并且对心血管及肝脏影响有不大。     

Paralytic ileus as a result of diltiazem treatment

Abstract. Diltiazem is a widely used calcium channel blocker, and has been found to be effective in the treatment of hypertension, stable, variant and unstable angina, as well as oesophageal spasm. Calcium channel antagonists have been shown to diminish the contractility of gut smooth muscle, but have not as yet been reported to cause clinically significant inhibition of gut motility when used alone. We report a case of reversible functional intestinal obstruction, immediately following diltiazem treatment in a patient with ischaemic heart disease.     

Effect of diltiazem on hypoxic pulmonary vasoconstriction in dogs

We have examined the effect of diltiazem upon the pulmonary vascular response to the left lower lobe (LLL) hypoxia in dogs.Without diltiazem, the fraction of cardiac output perfusing the LLL (Q_LLL/Q_T) measured by the ultrasonic doppler rheometer in the hypoxic phase was 21.0 ± 11.7(%) of the ratio in the first normoxic phase. When diltiazem was given as a 0.48mg/kg intravenous bolus followed by an intravenous infusion of 0.48mg/kg/hr and 0.96mg/kg intravenous bolus followed by an intravenous infusion of 0.96mg/kg/hr, Q_LLL/Q_T in the hypoxic phase were 34.0 ± 14.0, 48.6 ± 16.1(%) of the ratio in the first normoxic phase respectively. Significant difference was observed at all diltiazem concentrations.With respect to Pa_{O 2}, significant difference was not observed at all diltiazem concentrations in the ratio of the hypoxic phase to the first control phase.So we concluded that diltiazem obviously attenuated hypoxic pulmonary vasoconstriction (HPV) response but did not decrease Pa_{O 2} because of keeping myocardial oxygen balance and better ventilation/perfusing relationship.(Okutomi T, Wakabayashi C, Ikeda K: Effect of diltiazem on hypoxic pulmonary vasoconstriction in dogs. J Anesth 3: 138–144, 1989)     

Effects of halothane and calcium entry blockers on atrioventricular conduction

The effects of halothane on AV nodal function were evaluated in dogs with verapamil, diltiazem, or nifedipine during atrial pacing using the technique of Hisbundle electrocardiography. Fifty-one mongrel dogs were divided into six groups. Anesthesia was induced with ketamine 100mg im. and thiamylal 25mg/kg iv. The animals were intubated and mechanically ventilated at normocapneic levels. Anesthesia was maintained with 50% nitrous-oxide in oxygen with pancuronium 2mg im. Dogs in groups I, III, and V were anesthetized with 0.8% halothane and 50% nitrous-oxide in oxygen. We observed interactions between halothane and intravenous administration of either verapamil 0.1mg/kg, diltiazem 0.15mg/kg, or nifedipine 0.01mg/kg respectively. Dogs in groups II, IV, and VI were administered either verapamil, diltiazem, or nifedipine iv without halothane. There were prolongations of sinus cycle length (SCL) (414 ± 10 to 542 ± 19msec.), atrium-His (AH) interval (73 ± 3 to 97 ± 5msec.), and functional refractory period (FRP) of the AV-node (227 ± 5 to 260 ± 5msec.) in halothane anesthesia in groups I, III, and V. There were more prolongations of these variables after iv administration of verapamil (SCL; 617 ± 35, AH; 118 ± 7, FRP of the AV node; 311 ± 4) and diltiazem (SCL; 554 ± 19, AH; 118 ± 12, FRP of the AV node; 283 ± 12) but no prolongations after nifedipine (SCL; 533 ± 19, AH; 99 ± 8, FRP of the AV node; 272 ± 9). Comparing effects of calcium entry blockers with and without halothane in groups I and II, III and IV, or V and VI, there were additive depressing effects of halothane with either verapamil or diltiazem on AV nodal function. And there is a difference between the effects of nifedipine on SCL with and without halothane.(Yokota S, Harada K, Takigawa C et al.: Effects of halothane and calcium entry blockers on atrioventricular conduction; A comparative study of verapamil, diltiazem, and nifedipine. J Anesth 2: 219–226, 1998)     

Glibenclamide suppresses stretch-activated ANP secretion: involvements of K+ ATP channels and L-type Ca2+ channel modulation

 The mechanism by which glibenclamide regulates mechanically activated atrial natriuretic peptide (ANP) secretion was investigated using isolated perfused rat atria. A reduction in atrial pressure from an experimentally imposed distending pressure stimulated the secretion of ANP and caused concomitant translocation of extracellular fluid (ECF) into the atrial lumen. The activation of ANP secretion and ECF translocation were closely correlated with atrial volume changes and the increase in ANP secretion was a function of the ECF translocation. Glibenclamide (1, 10, 100 μM), an ATP-sensitive K⁺ (K⁺ _ATP) channel blocker, had no effect on the basal secretion of ANP, suppressed the stimulation of stretch-activated ANP secretion in a dose-dependent manner, but not the translocation of the ECF. Glipizide (100 μM) and tolbutamide (100 μM), other K⁺ _ATP channel blockers, had similar effects to those of glibenclamide. Suppression by glibenclamide (100 μM) of the stretch-induced ANP secretion was not observed in atria that had been pretreated with pinacidil (200 μM), an ATP-sensitive K⁺ channel opener: pinacidil alone had no effect on ECF translocation and ANP secretion. Furthermore, blocking Ca²⁺ influx by using the Ca²⁺ channel blocker diltiazem (10 nM), or a Ca²⁺-depleted medium prevented the suppression of stretch-induced ANP secretion by glibenclamide. In other experiments, atrial distension produced a slight membrane depolarization of cardiomyocytes; this was accentuated in the presence of glibenclamide. Furthermore, in single cardiomyocytes, glibenclamide increased the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in a dose-dependent manner. From these results, we suggest that glibenclamide suppresses atrial release of ANP by blocking K⁺ _ATP channels and increasing Ca²⁺ influx and that the K⁺ _ATP channels are associated with the regulation of the mechanically activated ANP secretion from the atria. Received: 13 May 1996 / Received after revision: 10 February 1997 / Accepted: 5 March 1997     

Antifertility effect of calcium channel blockers on male rats: association with oxidative stress

PurposeCalcium ions are vital in many biologic processes including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, haemostasis, bone metabolism and sperm functions. Calcium channel blockers (CCB) appear to have a reversible anti-fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis. While the effects of CCB on male reproductive function have been investigated, less information is available regarding other reproductive indices and the underlying mechanism in the pathogenesis of male reproductive dysfunction. Therefore, the involvement of oxidative mechanisms in the adverse manifestation induced by CCB on male reproductive functions is investigated in this study.MethodsFor this purpose, lipid peroxidation; enzymatic antioxidants such as superoxide dismutase, catalase and glutathione reduced; epididymal sperm count, motility; histopathology of the testes, epididymis, seminal vesicle, prostate glands; and reproductive performance were determined.ResultsCCB administration in rats causes significant oxidative stress in the male reproductive milieu in term of increase in malondialdehyde (MDA) level and a concomitant decrease in catalase, superoxide dismutase and reduced glutathione enzyme activities in the testes. In addition, CCB treatment significantly decreased the sperm count, sperm motility, fertility index, implantation count, and litter size in this study.ConclusionThere is substantial evidence that CCB induces significant oxidative stress in the testes, which appears to be responsible for the adverse effects of decreased sperm count and motility ultimately leading to reduced fertility in rats.