The Hemodynamic Effects of AT-112, an Analog of Ketanserin, in Portal Hypertensive Rats

Abstract

A serotonin mechanism has been reported to contribute to the hyperdynamic circulation of portal hypertension. Different studies have demonstrated that serotonin antagonists decrease portal pressure in portal hypertensive patients and animals. The present study was undertaken to investigate the effect of AT-112, an analog of ketanserin, on portal hypertension induced by partial portal vein ligation in rats. Since ketanserin is known to possess alpha 1-adrenergic antagonistic activity, the effect of AT-112 was compared to that of prazosin. A single dose (prazosin 4.2 micrograms/kg, AT-112 1 mg/kg) was chosen to produce a similar hypotensive effect (-20 +/- 4% for prazosin and -24 +/- 4% for AT-112). At this dose, prazosin significantly decreased total peripheral resistance whereas AT-112 significantly decreased cardiac index and heart rate. Both agents significantly decreased the portal tributary blood flow and portal pressure. In rats receiving AT-112, a significant correlation was found between the magnitudes of decrease in cardiac index and the decrease in portal tributary blood flow. We also found that the magnitude of reduction in portal pressure was greater following AT-112 administration. This study suggested that AT-112 may have more beneficial hemodynamic effects than prazosin in portal hypertensive rats. Our results provide further support for the serotonergic mechanism in the pathogenesis of hyperdynamic circulation in portal hypertension.