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Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats
Sándor Bátkai1, Partha Mukhopadhyay, Judith Harvey-White
1Section on Neuroendocrinology, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, MSC 9413, Rm. 2N17, 5625 Fishers Lane, Bethesda, MD 20892-9413, USA. sbatkai@mail.nih.gov
Insights
Endocannabinoid system activation contributes to cardiac contractile dysfunction in advanced liver cirrhosis. CB(1) receptor antagonists may improve heart function in cirrhotic cardiomyopathy.
Area of Science:
- Cardiovascular Physiology
- Hepatology
- Endocannabinoid System Pharmacology
Background:
- Advanced liver cirrhosis presents with hyperdynamic circulation, systemic hypotension, and cardiac dysfunction, known as cirrhotic cardiomyopathy.
- Endocannabinoids and vascular CB(1) receptors are implicated in hypotension and vasodilation in liver cirrhosis models.
- CB(1) receptors may also mediate decreased beta-adrenergic responsiveness in cirrhotic rat heart tissue.
Purpose of the Study:
- To document cardiac contractile dysfunction in vivo in liver cirrhosis.
- To explore the role of the endocannabinoid system in the development of cirrhotic cardiomyopathy.
Main Methods:
- Carbon tetrachloride (CCl(4))-induced liver cirrhosis in rats.
- Millar pressure-volume microcatheter system for assessing cardiac contractility and hemodynamics.
- Administration of CB(1) receptor antagonist AM251 and measurement of cardiac function and blood pressure.
- Quantification of endocannabinoid levels (anandamide, 2-arachidonoylglycerol) in heart and liver tissue.
- Western blotting to assess CB(1)-receptor expression in the heart.
Main Results:
- Rats with cirrhosis exhibited decreased cardiac contractility, low blood pressure, and tachycardia.
- AM251 administration acutely increased blood pressure and systolic function indexes in cirrhotic rats, but not in controls.
- Cardiac anandamide levels were significantly increased in cirrhotic rats compared to controls.
- Cirrhotic livers showed marked increases in both anandamide and 2-arachidonoylglycerol.
- CB(1)-receptor expression in the heart remained unchanged in cirrhotic rats.
Conclusions:
- Activation of cardiac CB(1) receptors by endogenous anandamide contributes to reduced cardiac contractility in liver cirrhosis.
- CB(1)-receptor antagonists represent a potential therapeutic strategy for improving contractile function in cirrhotic cardiomyopathy.
- These findings may also have implications for other forms of heart failure.
Abstract:
Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB(1) receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB(1) receptors have also been implicated in the decreased beta-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl(4)-induced cirrhosis developed decreased cardiac contractility, as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, and tachycardia. Bolus intravenous injection of the CB(1) antagonist AM251 (3 mg/kg) acutely increased mean blood pressure, as well as both load-dependent and -independent indexes of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB(1)-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB(1) receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB(1)-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.
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