The effects of chronic FAAH inhibition on myocardial lipid metabolism in normotensive and DOCA-salt hypertensive rats

Polak, Agnieszka; Harasim-Symbor, Ewa; Malinowska, Barbara; Kasacka, Irena; Pędzińska-Betiuk, Anna; Weresa, Jolanta; Chabowski, Adrian

doi:10.1016/j.lfs.2017.06.019

Cited by 11 publications

(18 citation statements)

References 46 publications

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“…It is not surprising because 10% more ATP is generated from glycolysis than fatty acid oxidation per mole of oxygen [42]. Thus, glucose is more effective source of energy when heart is subjected to higher work (such as in hypertension), especially in hypertrophied heart [43], which was also present in our model and described previously [29]. Moreover, elevated myocardial expression of PDH in our study might reveal that in hypertension, pyruvate was mainly converted into acetyl-Co-A linking the glycolysis pathway to the Krebs cycle, which takes place only in aerobic conditions.…”

Section: Discussionmentioning

confidence: 55%

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The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

Polak

Harasim-Symbor

Malinowska

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recent interest in the use of cannabinoids as therapeutic agents has revealed the involvement of the endogenous cannabinoid system (ECS) in the regulation of the cardiovascular system in hypertension. Abnormalities in glucose metabolism and insulin action are commonly detected in hypertensive animals. Thus, potential antihypertensive drugs should be investigated with respect to modulation of glucose homeostasis. Therefore, the aim of the present study was to evaluate the effects of the ECS activation after chronic fatty acid amide hydrolase inhibitor (URB597) administration on plasma glucose and insulin concentrations as well as parameters of myocardial glucose metabolism in the deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of secondary hypertension. Methods: Hypertension was induced by DOCA (25mg/kg) injections and addition of 1% NaCl in the drinking water for six weeks. Chronic activation of the ECS was performed by URB597 (1mg/kg) injections for two weeks. We examined fasting plasma levels of insulin (ELISA), glucose and intramyocardial glycogen (colorimetric method). Expressions of glucose transporters (GLUT1, 4) and selected proteins engaged in GLUT translocation as well as glucose metabolism were determined using Western blotting. Results: Hypertension induced hypoinsulinemia with concomitant lack of significant changes in glycemia, reduced intramyocardial glycogen content and increased pyruvate dehydrogenase (PDH) expression in the cardiac muscle. Importantly, chronic URB597 administration in the hypertensive rats increased insulin concentration, elevated plasmalemmal GLUT1 and GLUT4 expression and concomitantly improved myocardial glycogen storage. Conclusion: Chronic administration of fatty acid amide hydrolase (FAAH) inhibitor has potential protective properties on myocardial glucose metabolism in hypertension.

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Section: Discussionmentioning

confidence: 55%

“…Moreover, hemodynamic parameters, body and heart weights as well as cardiomyocytes dimension were monitored throughout the study and included in our previous article [29]. Briefly, induction of DOCA-salt hypertension caused a significant increase in mean blood pressure (MBP, +42.9% vs control group) value.…”

Section: Methodsmentioning

confidence: 99%

The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

Polak

Harasim-Symbor

Malinowska

et al. 2018

Cell Physiol Biochem

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“…Moreover, URB597 reduced cardiac and renal hypertrophy in younger and hypertrophy of aorta and coronary vessels (but not mesenteric artery) in older DOCA‐salt rats. However, it did not diminish organ hypertrophy in SHR as well as cardiomyocyte dimension and density of coronary blood vessels in DOCA‐salt animals (Toczek et al ., and unpublished; Polak et al ., ).…”

Section: Effects Of Chronic Cannabinoid Administration On Cardiovascumentioning

confidence: 97%

“…By contrast, in SHR, only normalization of the positive inotropic effect of isoprenaline was observed (Pędzińska‐Betiuk et al ., ). Moreover, chronic FAAH inhibition improved the morphology of coronary vessels and myocardial glucose metabolism and slightly modified lipid metabolism in DOCA‐salt hypertension (Polak et al ., ,b).…”

Section: Potential Mechanisms Involved In the Cardiovascular Effects mentioning

confidence: 97%

Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

Malinowska

Toczek

Pędzińska-Betiuk

et al. 2018

British J Pharmacology

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The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. We discuss pleiotropic effects of cannabinoids on the cardiovascular system mediated via numerous neuronal and non‐neuronal mechanisms both in normotension and in hypertension. The final results are dependent on the model of hypertension, age, sex, the cannabinoid ligands used or the action via endocannabinoid metabolites. More experimental and clinical studies are needed to clarify the role of endocannabinoids in hypertension, not only in the search for new therapeutic strategies but also in the context of cardiovascular effects of cannabinoids and the steadily increasing legalization of cannabis use for recreational and medical purposes. Linked Articles This article is part of a themed section on 8 th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc

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“…Extensive studies have proven that this inner lipid signaling system has significant influence on the whole body by interfering energetic homeostasis, central nervous system functions, immune responses, gastrointestinal motility and blood pressure as well [15][16][17]. Moreover, we and others [18][19][20][21] have shown in animal models of primary (SHRs) and secondary (DOCA salt) hypertension that elevated tone of ECS in 2-week time frame can be a beneficial in markedly declining both systolic and mean blood pressures. Importantly, we have also reported that upregulation of ECS significantly alters intramyocardial fatty acid and glucose metabolism in hypertensive state [20][21][22].…”

Section: Introductionmentioning

confidence: 94%

Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes

Harasim-Symbor

Polak-Iwaniuk

Konstantynowicz-Nowicka

et al. 2020

Molecules

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Hypertension coincides with myocardial alternations in lipid (including sphingolipids) and glucose metabolism. The latest data indicate that accumulation of metabolically active lipids, especially ceramide (CER) and diacylglycerol (DAG) significantly influences intracellular signaling pathways along with inducing insulin resistance. Since, it was demonstrated that the endocannabinoid system (ECS) affects myocardial metabolism it seems to be a relevant tool in alleviating metabolic disturbances within the cardiac muscle due to hypertension. All designed experiments were conducted on the animal model of primary hypertension, i.e., spontaneously hypertensive rat (SHR) with chronic ECS activation by injections of fatty acid amide hydrolase (FAAH) inhibitor—URB597. Lipid analyses were performed using chromatography techniques (gas liquid, thin layer, and high performance liquid chromatography). Colorimetric and immunoenzymatic testes were applied in order to determine plasma concentrations of insulin and glucose. Total myocardial expression of selected proteins was measured by Western blotting and/or immunohistochemistry methods. SHRs exhibited significantly intensified myocardial de novo pathway of CER synthesis as well as DAG accumulation compared to the control Wistar Kyoto rats. Besides, intramyocardial level of potentially cardioprotective sphingolipid, i.e., sphingosine-1-phosphate was considerably decreased in SHRs, whereas URB597 treatment restored the level of this derivative. Unexpectedly, ECS upregulation protected overloaded cardiac muscle against CER and DAG accumulation. Moreover, chronic URB597 treatment improved intramyocardial insulin signaling pathways in both normotensive and hypertensive conditions. It seems that the enhanced ECS triggers protective mechanisms in the heart due to decreasing the level of lipid mediators of insulin resistance.

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The effects of chronic FAAH inhibition on myocardial lipid metabolism in normotensive and DOCA-salt hypertensive rats

Cited by 11 publications

References 46 publications

The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes

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