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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats
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Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats

机译：正常和梗死大鼠低流量缺血后，赖诺普利和（或）螺内酯慢性治疗对离体心脏的潜在有益和有害作用

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摘要

This study was designed to demonstrate potential beneficial as well as detrimental effects of lisinopril and spironolactone given in combination. In patients with congestive heart failure or myocardial infarction, the use of angiotensin-converting enzyme (ACE) inhibitors may inhibit aldosterone production. Spironolactone, a specific aldo sterone receptor antagonist may exert other independent and additive effects to those of ACE inhibitors. Given the consequences of aldosterone on ischemic hearts, we evaluated the protective effects of spironolactone or lisinopril and combined spironolactone–lisinopril therapy during low-flow ischemia and reperfusion in isolated rat hearts. Normal and infarcted (left coronary artery ligature) male Wistar rats were submitted to chronic action of drugs (0.8 mg·kg–1·day–1 for lisinopril and 8 or 50 mg·kg–1·day–1 for spironolactone) for 1 month. Hearts were rapidly excised and perfused (constant pressure) for a 40-min period of stabilization followed by a 25-min period of global low-flow ischemia and a 30-min reperfusion. In normal rats, spironolactone decreased ischemic and reperfusion contracture, reduced ventricular tachycardia, suppressed action-potential duration dispersion, and increased reactive hyperemia leading to an improvement of contractile recovery. Lisinopril also decreased ventricular tachycardia and action-potential duration dispersion concomitantly with increased reactive hyperemia and better contractile recovery. These beneficial effects of the drugs were lost when the two treatments were combined (lisinopril and 50 mg·kg–1·day–1 spironolactone), despite a synergistic effect on plasmatic K+ and Mg2+. However, an interaction between the ACE inhibitor and spironolactone potentiating the effects of either drug alone was observed with a lower dose of spironolactone (lisinopril and 8 mg·kg–1·day–1 spironolactone). Similar beneficial effects have been noted in infarcted rat hearts on reactive hyperemia, ventricular tachycardia, and contractile recovery with the combined treatment and for both spironolactone concentrations (8 or 50 mg). Chronic spironolactone treatment produces similar beneficial effects to ACE inhibitor treatment on normal rat hearts during an ischemia-reperfusion protocol. Synergistic effects have been observed with the combined therapy when a lower dose of spironolactone was utilized in normal and infarcted rats. However, in the case of a high dose of spironolactone, the two effective drugs seem to cancel each other but only in normal rats.Key words: spironolactone, ACE inhibitors, ischemia–reperfusion, ventricular arrhythmia, action potentials, coronary flow, congestive heart failure.La présente étude visait à démontrer les effets bénéfiques et néfastes potentiels d'un traitement combiné au lisinopril et à la spironolactone. L'utilisation d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ACE) chez les patients souffrant d'insuffisance cardiaque congestive ou chez les victimes d'infarctus du myocarde peut inhiber la production de l'aldostérone. La spironolactone, un antagoniste spécifique des récepteurs de l'aldostérone, peut produire non seulement une synergie additive, mais aussi d'autres effets indépendants à ceux des inhibiteurs de l'ACE. Compte tenu des effets de l'aldostérone sur les curs ischémiques, nous avons évalué les effets protecteurs individuels et combinés de la spironolactone et du lisinopril lors d'ischémies à débit réduit et de reperfusion chez les curs de rats isolés. Des rats mâles Wistar normaux et des rats mâles Wistar présentant un infarctus du myocarde (ligature de l'artère coronaire gauche) ont été soumis à l'action prolongée de médicaments (0,8 mg·kg–1·jour–1 de lisinopril et 8 ou 50 mg·kg–1·jour–1 de spironolactone) pendant 1 mois. Les curs ont été rapidement prélevés et reperfusés (pression constante) pendant 40 min (période de stabilisation), puis soumis à une ischémie globale à débit réduit de 25 min et à une reperfusion de 30 min. Chez les rats normaux, la spironolactone a entraîné une diminution de la contracture ischémique et de la contracture de repe
机译：本研究旨在证明赖诺普利和螺内酯组合使用可能产生的有益作用以及有害作用。对于充血性心力衰竭或心肌梗塞的患者，使用血管紧张素转换酶（ACE）抑制剂可能会抑制醛固酮的产生。螺内酯，一种特定的醛固酮受体拮抗剂，可能对ACE抑制剂产生其他独立的累加作用。考虑到醛固酮对缺血性心脏的影响，我们评估了螺内酯或赖诺普利以及螺内酯-赖诺普利联合治疗在低流量缺血和离体大鼠心脏再灌注中的保护作用。正常和梗死的（左冠状动脉结扎）雄性Wistar大鼠均接受慢性作用药物（赖诺普利0.8 mg·kg –1 ·day -1 ）和8或50螺内酯的剂量为mg·kg –1 ·day –1 ），持续1个月。快速切除心脏并进行灌注（恒压），持续40分钟，然后进行25分钟的整体低流量缺血再灌注30分钟。在正常大鼠中，螺内酯可减少缺血性和再灌注性挛缩，减少心室性心动过速，抑制动作电位持续时间分散，并增加反应性充血，从而改善收缩恢复。利诺普利还减少了室性心动过速和动作电位持续时间的分散，并伴有反应性充血增加和更好的收缩恢复。尽管两种药物对血浆药物有协同作用，但联合使用两种药物（赖诺普利和50 mg·kg –1 ·天 –1 螺内酯）时，这些药物的这些有益作用消失了。 K + 和Mg 2 + 。但是，在较低剂量的螺内酯（赖诺普利和8 mg·kg –1 ·天 –1 螺内酯）。在合并治疗的情况下，对于螺内酯浓度（8或50 mg），在梗死的大鼠心脏中，对反应性充血，室性心动过速和收缩恢复都有类似的有益作用。在缺血/再灌注方案中，慢性螺内酯治疗对正常大鼠心脏产生与ACE抑制剂治疗相似的有益作用。当在正常和梗塞的大鼠中使用较低剂量的螺内酯时，在联合疗法中已观察到协同作用。然而，在大剂量螺内酯的情况下，这两种有效药物似乎互相抵消，但仅在正常大鼠中起作用。关键词：螺内酯，ACEI抑制剂，缺血-再灌注，室性心律不齐，动作电位，冠状动脉血流，充血性心脏失败的原因包括：既有特征性又有螺内酯的螺内酯和螺内酯。血管紧张素转换酶（ACE）的使用对患者的抵抗力充血，心肌梗塞或心肌梗塞患者体内的充血性醛固酮缺乏症。螺内酯，醛固酮拮抗药，非生产性和协同作用的非专利药，有效抑癌的独立药房。补充法医学的个人概论，保护个人和反螺旋内酯和反义​​齿酸内酯合用药，以及再灌注后的鼠类补充剂。 Wistar normaux et al大鼠的心肌梗塞（0,8 mg·kg –1 ） ·jour –1 de lisinopril等8 ou 50 mg·kg –1 ·jour –1 de spironolactone）1悬垂。静压和持续灌注（恒定压力）悬挂器40分钟（稳定压力），全球局部冰激凌25分钟和重新灌注30分钟。 Chez les rat normaux，螺内酯，缩小和缩小缺血再狭窄

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