Morphology and Function of Myocardium and Skin Microcirculation 24 Hours after Clozapine Poisoning

И А Рыжков ,В В Антонова ,Anastasiya S Babkina ,З И Цоколаева ,М В Сергеева ,S Kalabushev ,А В Ершов

doi:10.15360/1813-9779-2020-5-56-64

Abstract

Aim of the study: to evaluate the effect of sublethal dose of clozapine on the rat cardiovascular system 24 hours after administration of the drug.Materials and methods. The experiments were carried out on 17 male Wistar rats weighing 220-270 g. Under general anesthesia with sevoflurane, the animals of Group I were enterally given 0.9% NaCl solution, Group II animals received clozapine in a dose of 150 mg/kg diluted in 2.0 ml of NaCl solution 0.9%, Group III animals were given clozapine in a dose of 150 mg/kg diluted in 2.0 ml of 40% ethanol. Blood pressure (BP), heart rate (HR), skin microcirculation using laser Doppler flowmetry (LDF), NADH and FAD+ fluorescence were estimated 24 hours after the drug administration. After euthanasia, autopsy with sampling of internal organs for morphological study was done. Then paraffin heart sections with subsequent H&E staining were made, which were studied using the Nikon Eclipse Ni-U light microscope.Results. Spectral analysis of local skin blood flow fluctuations showed that clozapine reduced Amax and amplitude in all frequency ranges of active microcirculation regulatory system in comparison with the controls. No differences in blood gases and acid-base status were seen between the groups of animals 24 hours after administration of the drugs. However, the animals from clozapine groups (II and III) had lower hemoglobin and hematocrit than in the control group.Histological examination of rat hearts in groups II and III revealed congested venules, haemorrhages by dia-pedeses, perivascular and interstitial edema. The signs of blood stasis and marginalization of granulocytes were noted in the vascular lumen. Irregular staining of myocardium due to cardiomyocytes with hypereosinophilic and occasionally homogeneous cytoplasm, fragmentation and deformations of cardiac cells were revealed. Car-diomyocytic nuclei were polymorphic and irregularly stained, and perinuclear edema was observed.Conclusions. The results of the study demonstrate the toxic effect of clozapine manifesting as progressive myocardial alteration and disordered central and peripheral circulation. However, control of bradycardia, restored skin perfusion and metabolic improvement (diagnosed by NADH fluorescence and blood acid-base status) after 24 hours may be due to the activation of compensatory mechanisms, particularly through changes in neurogenic and humoral regulation of homeostasis.

Highlights

При остром отравлении нейролептиками токсические эффекты проявляются не только угнетением сознания и развитием других неврологических нарушений, но и нарушением функций сердечно-сосудистой системы, печени, легких [1,2,3,4,5,6]
In the experimental study of the toxic effect of clozapine on the rat cardiovascular system, we showed that 4 hours after the enteric administration of the drug the signs of circulatory disturbance appeared, such as hypotension, reduced blood flow in the skin and abnormal oxidative metabolism in peripheral tissues [6]
Min-1 Blood pressure, mm Hg Mean skin perfusion, PU Mean square deviation of the blood flow oscillations amplitude, PU Perfusion variation coefficient, PU Maximal amplitude of microvascular blood flow, endothelial origin, PU Maximal amplitude of microvascular blood flow, neurogenic origin, PU Maximal amplitude of microvascular blood flow, muscular origin, PU Maximal amplitude of microvascular blood flow ranging 0.01–0.4 Hz, PU Frequency corresponding to Аmax, Hz NADH fluorescence FAD fluorescence+ Redox ratio

Summary

Introduction

При остром отравлении нейролептиками токсические эффекты проявляются не только угнетением сознания и развитием других неврологических нарушений, но и нарушением функций сердечно-сосудистой системы, печени, легких [1,2,3,4,5,6]. Токсические эффекты клозапина и его метаболитов неспецифичны и включают в себя снижение уровня сознания вплоть до комы, угнетение дыхания и кровообращения [9]. Ранее при экспериментальном изучении токсического действия клозапина на сердечно-сосудистую систему крысы нами было показано, что через 4 часа после энтерального введения препарата выявлялись признаки нарушения кровообращения, что проявлялось артериальной гипотензией, снижением кровотока в сосудах кожи и нарушениями окислительного метаболизма в периферических тканях (изменение флуоресценции кофермента НАДН) [6]. При сравнении эффектов клозапина и его комбинации с алкоголем существенных различий не было выявлено, за исключением брадикардии в группе животных, которым клозапин вводили в изотоническом солевом растворе

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