Endogenous cannabinoids: A new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat

doi:10.1053/gast.2002.30305

Gastroenterology

Volume 122, Issue 1, January 2002, Pages 85-93

https://doi.org/10.1053/gast.2002.30305 Get rights and content

Abstract

Background & Aims: Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis. Methods: Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry. Results: CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals. Conclusions: Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.

GASTROENTEROLOGY 2002;122:85-93

Section snippets

Induction of cirrhosis in rats

This study was performed in cirrhotic adult male Wistar rats with ascites and in control Wistar rats (Charles-River, Saint Aubin les Elseuf, France). Both groups were fed ad libitum with standard chow and phenobarbital (0.3 g/L). Cirrhosis was induced as described elsewhere.⁸ CCl₄ was used as hepatotoxin and phenobarbital was administered to shorten the time required to induce cirrhosis. After 1 week of receiving phenobarbital, inhalation of CCl₄ was started. Rats were placed in a gas chamber

Results

The liver histology of all animals treated with CCl₄ included in the study had a finely granulated surface and histological examination showed marked architectural distortion leading to fully developed cirrhosis.⁸ At the time of the study, all cirrhotic rats had ascites, which were evacuated aseptically by paracentesis to measure ascites volume and tested for bacterial culture. Ascites volume ranged between 12 and 80 mL and data from those cirrhotic rats in which the ascites culture was

Discussion

Endocannabinoids are a family of lipid-derived substances of which anandamide is the most prominent member. Interest in this agent emerged after the realization that anandamide reproduces most of the biological effects of plant-derived cannabinoids, including the cardiovascular actions of these recreational drugs.¹² Exogenous administration of anandamide to anesthetized rats results in a transient hypertension followed by a long-lasting hypotension.¹³ This vasodepressor effect is mediated by

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Cited by (195)

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Hepatorenal syndrome (HRS) is a form of kidney dysfunction that characteristically occurs in liver cirrhosis. It is characterized by a marked impairment of kidney function in response to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, aggravated by systemic inflammation and bacterial translocation. The classical definitions of the types of HRS have been recently revisited and 2 forms of HRS have been redefined: the acute form, referred to as acute kidney injury (HRS-AKI), and the chronic form, referred to as chronic kidney disease. HRS-AKI is one of the most severe forms of AKI in patients with cirrhosis and it consists of an abrupt impairment of kidney function, frequently triggered by an infection, appearing in the setting of advanced decompensated cirrhosis. Differential diagnosis with other causes of AKI is crucial because HRS-AKI requires a specific treatment. Differential diagnosis with AKI–acute tubular necrosis may be challenging and kidney biomarkers may be useful in this setting. Treatment of HRS-AKI is based on the administration of vasoconstrictor drugs in combination with volume expansion with albumin. Prognosis of HRS-AKI is poor, and the ideal definitive treatment consists of liver transplantation or simultaneous liver-kidney transplantation. HRS-AKI has a big impact on patients’ quality of life. Management of HRS-AKI remains challenging in specific situations such as alcohol-associated hepatitis or metabolic-associated steatotic liver disease cirrhosis. Developing preventive measures for HRS-AKI, improving its early identification, discovering new biomarkers for differential diagnosis, and improving the response to therapy are some of the unmet needs in the field of HRS-AKI.
Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities
2023, Progress in Lipid Research
N-acylethanolamines (NAEs), including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), N-arachidonoylethanolamine (AEA, anandamide), N-docosahexaenoylethanolamine (DHEA, synaptamide) and their oxygenated metabolites are a lipid messenger family with numerous functions in health and disease, including inflammation, anxiety and energy metabolism. The NAEs exert their signaling role through activation of various G protein-coupled receptors (cannabinoid CB₁ and CB₂ receptors, GPR55, GPR110, GPR119), ion channels (TRPV1) and nuclear receptors (PPAR-α and PPAR-γ) in the brain and periphery. The biological role of the oxygenated NAEs, such as prostamides, hydroxylated anandamide and DHEA derivatives, are less studied. Evidence is accumulating that NAEs and their oxidative metabolites may be aberrantly regulated or are associated with disease severity in obesity, metabolic syndrome, cancer, neuroinflammation and liver cirrhosis. Here, we comprehensively review NAE biosynthesis and degradation, their metabolism by lipoxygenases, cyclooxygenases and cytochrome P450s and the biological functions of these signaling lipids. We discuss the latest findings and therapeutic potential of modulating endogenous NAE levels by inhibition of their degradation, which is currently under clinical evaluation for neuropsychiatric disorders. We also highlight NAE biosynthesis inhibition as an emerging topic with therapeutic opportunities in endocannabinoid and NAE signaling.
Peripheral vasculature in portal hypertension
2022, Cardio-Hepatology: Connections Between Hepatic and Cardiovascular Disease
Peripheral vasculature in portal hypertension is characterized by hyperdynamic circulation, decreased effective circulating volume, the peripheral venous ‘sump’ effect, and arterial splenic vasodilation. Also, the autonomic nervous system plays a key role in modulation of vasomotor activity. Pathogenetic mechanisms associated with hyperdynamic circulation are known as nitric oxide, endocannabinoids, humoral agents, bile acids, central neural activation, and inflammation. Several studies have reported strategies to reverse the abnormal change of peripheral vasculature in patients with portal hypertension.
Management of cannabinoid hyperemesis syndrome—is it more than just avoiding cannabis use?
2022, Cyclic Vomiting Syndrome and Cannabinoid Hyperemesis
Cannabinoid hyperemesis syndrome (CHS) presents after prolonged use of cannabis with stereotypical episodes of emesis similar to cyclic vomiting syndrome (CVS). The best accepted treatment of CHS is abstinence from cannabis intake; recurrent CHS is reported after restarting its use. Initial management to abort CHS episodes involves supportive measures, including intravenous fluids. The current belief that antiemetic therapies employed for CVS have little utility in CHS is based on limited study. Measures specifically reported to relieve acute CHS attacks include hot showers, cutaneous application of capsaicin, and intravenous administration of benzodiazepines and the dopamine antagonist haloperidol. The benefits of agents accepted for CVS prophylaxis have not been defined for CHS. Special considerations are given for pediatric CHS and for pregnant women with CHS.
The therapeutic potential of second and third generation CB<inf>1</inf>R antagonists
2020, Pharmacology and Therapeutics
Citation Excerpt :
These are negatively affecting disease progression and the quality of life. CB1R antagonism with rimonabant was found to attenuate cirrhosis related vascular complications (Batkai et al., 2001; Batkai et al., 2007; Domenicali et al., 2009; Ros et al., 2002) Furthermore, CB1R antagonism attenuates hepatocellular carcinoma via downregulating multiple critical pathways involved in cancer initiation and progression (Mukhopadhyay et al., 2015). iNOS is expressed by most cell types in the liver such as macrophages (Lowenstein, Glatt, Bredt, & Snyder, 1992), sinusoidal endothelial cells (Rockey & Chung, 1996), hepatocytes (Geller et al., 1993), hepatic stellate cells (Rockey & Chung, 1995) and cholangiocytes (Jaiswal, LaRusso, Shapiro, Billiar, & Gores, 2001).
Endocannabinoids acting via CB₁ receptors (CB₁R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB₁R antagonists for the treatment of obesity. Although the first-in-class CB₁R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB₁Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by ‘second generation’ peripherally restricted CB₁R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB₁R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel ‘third generation’ hybrid inhibitors of peripheral CB₁R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB₁R antagonists and their potential therapeutic uses.
Endocannabinoid-mediated modulation of Gq protein-coupled receptor mediates vascular hyporeactivity to nor-adrenaline during polymicrobial sepsis
2018, Pharmacological Reports
Endocannabinoids level are reported to increase in sepsis, however, the role of vascular cannabinoid receptor-1 (CB1R) in sepsis-induced vascular hyporeactivity is yet to be unravelled.
Polymicrobial sepsis was induced by caecal ligation and puncture in mice. Isometric tension in isolated aortic rings during early (6 h) and late (20 h) phases of sepsis was recorded and expression of mRNA of monoacylglycerol lipase (MAGL) and cannabinoid receptor-1 (CB1R) was investigated.
Sepsis significantly (p < 0.001) reduced the mean survival time in mice along with increase in bacterial load in blood and peritoneal lavage. Compared to Sham-operated (SO) mice, vascular reactivity to nor-adrenaline (NA) was significantly (p < 0.05) attenuated in both early and late phases of sepsis. NA-induced vasoconstriction was significantly (p < 0.05) potentiated by inhibition of diacylglycerol lipase (DAGL) and attenuated by inhibition of MAGL in SO mice. Pre-incubation with KT 109, a DAGL inhibitor, significantly (p < 0.05) improved the vascular hypo-reactivity to NA during both the phases of sepsis. mRNA expression of MAGL in aorta was significantly (p < 0.05) attenuated during both the phases of sepsis. But in the presence of AM 251, specific antagonist of CB1R, vascular reactivity to NA was significantly (p < 0.05) restored along with significant (p < 0.05) increase in mRNA expression of CB1R in aortic rings from both early and late phases of septic mice.
2-AG regulates vascular response to NA and increased aortic expression of CB1R is responsible for vascular hyporeactivity to NA in sepsis, and in vitro inhibition of this receptor by AM 251 restored the vascular reactivity.

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^*: Address requests for reprints to: Wladimiro Jiménez, Ph.D., Laboratorio Hormonal, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain. e-mail: [email protected]; fax: (34) 93 4515272.

^**: Supported by grants from the Dirección General de Investigación Científica y Técnica (SAF99-0016, to W. Jiménez) and from Fondo de Investigación Sanitaria (FIS 00/0398 and FIS 00/0616 to J. Ros and V. Arroyo, respectively). P. Cejudo and A. Planagumà received a grant from IDIBAPS and G. Fernández-Varo from DGICYT (SAF99-0016). SR141716A was a generous gift from Dr. M. Mossé, Sanofi Recherche, Montpellier, France.

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Basic ResearchEndogenous cannabinoids: A new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat*,**

Abstract

Section snippets

Induction of cirrhosis in rats

Results

Discussion

Biochim Biophys Acta

Trends Pharmacol Sci

FEBS Lett

Eur J Pharmacol

Chem Phys Lipids

J Hepatol

Renal dysfunction in cirrhosis

Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide (NO)

Hepatology

Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis

N Engl J Med

Activation of peripheral CB1 receptors in hemorrhagic shock

Nature

Platelet and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension

FASEB J

Renal dysfunction and ascites in Carbon-Tetrachloride-induced cirhosis in rats

Basic Research
Endogenous cannabinoids: A new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat*,**