Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 293, Issue 3, Pages H1689-H1695Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00538.2007
Keywords
cirrhosis; cannabinoid CB1 receptors; endocannabinoids; cardiac contractility; pressure-volume loops
Funding
- Intramural NIH HHS [Z01 AA000351-07, Z01 AA000375-02] Funding Source: Medline
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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 CB1 receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB1 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 CCl4-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 CB1 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. CB1-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB1 receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB1-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.
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