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Halogenated Anesthetics and Human Myocardium

Riou, Bruno M.D., Ph.D.

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Accepted for publication September 10, 1999.
THE effects of halogenated anesthetics on the myocardium have been studied extensively in vivo and in vitro in various animal species. In the past, investigators have focused their efforts on heart function, myocardial mechanics, and electrophysiology. 1 During recent years, considerable knowledge has been obtained by new investigative methodologies, including molecular and cellular biology 2–4 and animal models of disease. 5,6 Important interaction of halogenated anesthetics with pharmacologic agents on the myocardium have also been recently emphasized, 7,8 leading to a better knowledge of their effects on signal transduction, particularly through G-proteins. 7 In the current issue of ANESTHESIOLOGY, Hanouz et al.9 make an important contribution to our knowledge on the myocardial effects of halogenated anesthetics, although they have used a simple methodology (isolated atrial trabeculae in isometric conditions). Why is this work important to us? This is the first study to compare the inotropic effects of the four main halogenated anesthetics (halothane, isoflurane, sevoflurane, and desflurane) in human myocardium. This work must be considered as important as that from Gelissen et al., 10 who first compared the inotropic effects of the main intravenous anesthetic agents in human myocardium.
The clinical relevance of experimental research is an important issue. Indeed, species differences have been emphasized as long as animals have been used in research. Although molecular and cellular biology have shown the high degree of conservation of myocardial protein structure and function across numerous mammalian species, and although animal models of cardiac human disease have also shown their close relationship to human pathophysiology, 11 species differences remain a critical issue in cardiac physiology. For example, considerable differences exist between rat and human myocardium: heart rate (250–300 beats/min in the rat), force–frequency relationship (an increased frequency decreases force in the rat in contrast humans), action potential, participation of the sarcoplasmic reticulum versus calcium exchange to the calcium influx to the myofilaments (higher in the rat), isomyosin isoform predominance (fast V1 in the rat vs. slow V3 type in humans), response to inotropic agents (e.g., the positive inotropic effect of α-adrenoceptor stimulation is increased in the rat). 8 These species differences in cardiac physiology explain why ketamine induces a positive inotropic effect in the rat but a negative inotropic effect in the guinea pig. 12 Thus, the study by Hanouz et al.9 provides important information on the negative inotropic effect of halogenated anesthetics (halothane > sevoflurane, isoflurane > desflurane), confirming the previous results obtained in various animal species. These results also suggest that species differences in the myocardial effects is less important for halogenated anesthetics than for intravenous anesthetics.
Hanouz et al.9 suggest that desflurane releases intramyocardial catecholamine stores in human myocardium as it was observed in rat myocardium. 13 This effect explains why desflurane induces a less pronounced negative inotropic effect compared with other halogenated anesthetics and probably participates to the preserved hemodynamic conditions or the sympathetic activation that occurs with desflurane administration. However, this effect deserves further study to elucidate the origin of these catecholamines (nerve endings of extracardiac neurons, intrinsic cardiac neurons, non-neuronal adrenergic cardiac cells) and, overall, the beneficial or deleterious consequences of this release in healthy and diseased myocardium. Indeed, intramyocardial catecholamines play a role in the maintenance of cardiac function and may interfere with ischemic preconditioning.
By following the lead of Hanouz et al., 9 we can develop the use of human myocardial tissue to understand better the effects of anesthetic agents and their interactions with endogenous and exogenous pharmacologic agents encountered during anesthesia. Several recommendations should be followed for future research. First, no single experimental approach is uniquely suited for this evaluation. 11 Integration of data derived from complementary methodologies, using subcellular, cellular, and organ studies, with clinical studies will provide the best approach. Second, human myocardial tissues are usually obtained in nonhealthy humans, and thus the possible interference with cardiac disease may occur, requiring careful selection of patients. 9 Even if cardiac tissues are obtained from brain-dead patients without known cardiac disease, we cannot rule out the possibility of brain death–related cardiac damage. 14 Conversely, it could be a unique opportunity to understand better the effects of anesthetics on diseased myocardium. Third, ethical issues must kept in mind. Conducting research in human tissue required ethical guidelines (ethical committee approval and informed consent, particularly when genetic analysis is performed). There are some ethical difficulties in obtaining tissue in brain-dead patients because they are not capable of giving approval with regard to the scientific use of their tissues, and because there is no clear and direct benefit for another patient compared with transplantation. 15 Scientists should be prepared to deal with these obstacles to be able to conduct fruitful research in human tissues.
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References

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Keywords:
Inotropic effects; myocardial relaxation; volatile anesthetics.

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