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Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats
Published on: August 1, 2018
Hemodynamic effects of one week of carvedilol administration on cirrhotic rats
Han-Chieh Lin1, Yi-Tsau Huang, Hung-Chi Wei
1Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan.
Insights
Carvedilol effectively reduces portal pressure in cirrhotic rats by decreasing splanchnic blood flow and hepatocollateral resistance. This mechanism involves a reduction in endothelial-derived vasodilatory factors, impacting nitric oxide and prostacyclin pathways.
Area of Science:
- Pharmacology
- Hepatology
- Cardiovascular Physiology
Background:
- Carvedilol, a nonselective beta-blocker with alpha(1)-adrenergic activity, is known to reduce portal pressure in cirrhosis.
- Portal hypertension in cirrhosis is a critical factor leading to complications.
Purpose of the Study:
- To investigate the hemodynamic mechanisms by which carvedilol reduces portal pressure in a rat model of cirrhosis.
- To evaluate the impact of carvedilol on endothelial-related vasodilatory pathways.
Main Methods:
- Common bile duct ligation induced portal hypertension in male Sprague-Dawley rats.
- Rats received either vehicle or carvedilol (5 mg/kg) for one week.
- Hemodynamic parameters, serum biochemistry, and aortic mRNA expression of eNOS and COX-1 were assessed.
Main Results:
- Carvedilol significantly decreased cardiac index, portal pressure, heart rate, and splanchnic blood flow in cirrhotic rats.
- Systemic and portal vascular resistances increased, while hepatocollateral resistance decreased.
- Serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, along with eNOS and COX-1 mRNA expression, were reduced.
Conclusions:
- Carvedilol lowers portal pressure by reducing splanchnic blood flow and hepatocollateral resistance.
- The drug diminishes endothelial-derived vasodilatory activities, indicated by decreased nitric oxide and prostacyclin markers.
Background:
Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. The current study was undertaken to evaluate the possible mechanism of carvedilol on hemodynamics in cirrhotic rats with portal hypertension produced by common bile duct ligation.
Methods:
Male Sprague-Dawley rats received either a sham operation or common bile duct ligation. Three weeks after surgery, both sham-operated and cirrhotic rats were randomly assigned to receive vehicle or carvedilol 5 mg.kg(-1).12 h(-1) by gastric gavage for 1 week. Hemodynamic measurements, serum biochemistry, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, and aortic mRNA expression of eNOS and COX-1 were performed on the eighth day after drug administration.
Results:
Carvedilol treatment did not affect serum biochemistry in either sham-operated or cirrhotic rats. In sham-operated rats, administration of carvedilol significantly decreased the heart rate without affecting other hemodynamic values. In contrast, in cirrhotic rats, administration of carvedilol significantly decreased the cardiac index, portal pressure, heart rate, and portal territory blood flow, and it significantly increased systemic and portal territory vascular resistances. The hepatocollateral resistance was significantly decreased, but the hepatic arterial blood showed no significant changes. In sham-operated rats treated with carvedilol, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels were not affected. In contrast, cirrhotic rats receiving carvedilol showed a significant decrease in serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, associated with a decrease in aortic mRNA expression of eNOS and COX-1 compared with those receiving vehicle.
Conclusions:
Carvedilol decreased portal pressure through a reduction of splanchnic blood flow associated with a decrease in hepatocollateral resistance. Additionally, administration of carvedilol decreased endothelial-related vasodilatory activities.
