Cardiovascular Drugs and Therapy4:33-35 1990
© KluwerAcademicPublishers. Printed in the U.S.A.
PORTALHYPERTENSION:SEROTONINAND PATHOGENESlS
SUMMARY. It has b e e n demonstrated that serotonin (5-hydroxytryptamine; 5HT) can decrease portal vascular resistance in animals and could be a possible mediator for intestinal vasodilatation. Moreover, isolated m e s e n t e r i c v e i n from portal hypertensive rats has b e e n s h o w n to be hyper-responsive to 5HT. Hence 5HT m a y p l a y a role in the pathophysiology of the h y p e r k i n e t i c s y n d r o m e observed in patients w i t h portal hypertension. This hypothesis that serotonin m i g h t increase s p l a n c h n i c blood flow, and h e n c e portal pressure, led us to propose that 5HT receptor antagonists m i g h t decrease portal hypertension. We observed that acute administration of ketanserin, an antagonist of serotonin at 5HT 2 receptors, significantly decreased portal pressure and portal-systemic collateral blood f l o w in patients w i t h cirrhosis, w h e r e a s hepatic blood f l o w w a s not modified. Arterial pressure slightly decreased, w h i l e cardiac output w a s not affected b y ketanserin. These f i n d i n g s w e r e also observed d u r i n g c o n t i n u o u s administration of ketanserin. More recently, it has b e e n s h o w n that ritanserin, a more specific 5HT 2 receptor antagonist, significantly decreased portal pressure in cirrhotic patients. Finally, in rats w i t h portal hypertension, ketanserin as w e l l as ritanserin produced significant reductions in portal pressure but did not m o d i f y portal tributory blood flow. In these portal hypertensive animals, 5HT 2 antagonists m a y act on hepatecollateral vascular resistance. These studies confirm current evid e n c e in favor of a role for the actions of serotonin via 5HT2 receptors in portal h y p e r t e n s i o n and add a n e w group of substances for its treatment. KEY WORDS. serotonin, ketanserin, portal h y p e r t e n s i o n
Different studies have shown that serotonin (5hydroxytryptamine; 5HT) contributes to maintain portal hypertension, and hence 5HT receptor antagonist drugs may decrease portal pressure in patients with cirrhosis. Several experimental studies have demonstrated that 5HT is a mediator for intestinal vasodilatation [1-3]. In different species of healthy animals, administration of 5HT produces an increase in mesenteric or gastric blood flow [2,3] and a decrease in portal vascular resistance [1]. This effect is dose dependent [2]. Moreover, it has been demonstrated that isolated superior mesenteric veins from portal hypertensive rats are 3-10 times more sensitive to 5HT than veins from sham-operated rats [4]. Finally, a clinical study has shown that ketanserin, an antagonist of 5HT at 5HT2 receptors, pre-
Didier Lebrec Unit~ de Recherchesde PhysiopathologieH~patique (INSERM U-24) Hbpital Beaujon, Clichy,France
vented the phenylepinephrine-induced rise in portal pressure in subjects without portal hypertension [5]. In the present paper, experimental and clinical hemodynamic investigations into the effects of 5HT2 receptor antagonists are reviewed.
5HT2 Antagonists and Portal Hypertensive Animals Several hemodynamic studies have been performed in different models of portal hypertension in rats [4,6-8] and one in cirrhotic dogs [9]. The effects of ketanserin (0.3 mg/kg body wt) or ICI 169,369 (1.5 mg/kg body wt) - - novel 5HT 2 receptor antagonists - - in anesthetized portal vein stenosed rats produced significant decreases in portal pressure by 17% and 13%, respectively [4,6]. These reductions were accompanied by decreases in mean arterial pressure and heart rate. In comparison with saline infusion, in portal hypertensive rats, ketanserin infusion produced decreases in portal tributary blood flow and cardiac output, as estimated by the radioactive microsphere method. Hence, vascular resistance in the portal-systemic collateral circulation was not affected in this model. These hemodynamic effects were not observed in sham-operated rats. They were less marked after ICI 169,369 administration. From these studies, the authors concluded that 5HT 2 receptor antagonists produce a venous dilatation and pooling of blood in the portal venous system that could be secondary to the blockade of 5HT2receptors. In conscious, portal hypertensive animals, ketanserin and ritanserin also significantly decreased portal pressure, but the mechanism of this reduction differed from that in anesthetized animals [7-9]. In conscious cirrhotic rats, portal pressure decreased,
Address for correspondenceand reprint requests: Dr. D. Lebrec, INSERM U-24, H6pital Beaujon, 92118 Clichy, France. 33
34
Lebrec
while portal tributary blood flow was not affected by ritanserin (0.60 mg/kg body weight IV); mean arterial pressure did not change, but cardiac output significantly increased by 20% [7]. In conscious cirrhotic dogs, continuous administration of ritanserin (10 mg/day for 5 days) significantly decreased portal pressure but had no effect on systemic circulation and portal tributary blood flow [9]. From these studies it may be hypothesized that the decrease of portal pressure by ritanserin results from a reduction of intrahepatic or portacollateral resistance. This hypothesis has been confirmed in a model of portal hypertension in rats with total portal systemic shunts [8]. This study showed that ketanserin (0.25 mg/kg body weight IV) significantly decreased portal pressure and vascular resistance of portal systemic collaterals by 16% and 17%, respectively. In these animals, neither portal tributary blood flow nor arterial pressure were modified by ketanserin.
decreased significantly. No correlation was found between systemic changes and hepatic venous pressure gradient reduction. However, side effects occurred in some patients, the most significant being a reversible hepatic encephalopathy observed in 3 out of 16 patients who had poor liver function. Although not certainly drug related, the relatively high dosage of ketanserin may explain, at least in part, these side effects. A second long-term study was performed using the 5HT 2 receptor antagonist ritanserin (0.08 mg/kg body weight/day for 7 days) in eight cirrhotic patients [13]. This preliminary hemodynamic investigation showed that continuous administration of ritanserin significantly decreased the hepatic venous pressure gradient by approximately 15%, with no systemic effects. Moreover, ritanserin was well tolerated in all patients.
Conclusion 5HT2 Receptor Antagonists and Cirrhosis Five hemodynamic studies have been reported in patients with portal hypertension due to cirrhosis [10-14]; four studies used ketanserin and one used ritanserin. In the first investigation performed in cirrhotic patients, ketanserin (10 mg IV) moderately but significantly decreased mean arterial pressure; this effect was maximal at 5 minutes and correlated with the severity of cirrhosis [10]. Cardiac output and systemic vascular resistance were unaffected by ketanserin. The hepatic venous pressure gradient - a reflection of portal pressure in patients with cirrhosis - - was significantly decreased by 23% after ketanserin treatment. Azygous blood f l o w - - a reflection of superior portasystemic collateral blood f l o w - was also significantly decreased, by 26%; however, this effect was delayed, progressive, and not correlated with the arterial pressure decrease. Hepatic blood flow was not affected. Similar results were observed with a lower dose of ketanserin (5 mg IV) [14]. A further clinical study also showed that acute administration of ketanserin (0.1 mg/kg body weight) significantly decreased the hepatic venous pressure gradient [11]. The long-term hemodynamic effects of ketanserin (mean dose 51 mg/day for a mean period of 32 days) have been studied in patients with cirrhosis [12]. This trial showed that continuous administration of ketanserin produced a sustained decrease in the hepatic venous pressure gradient. In these cirrhotic patients, cardiac output and mean arterial pressure were also
The portal hypotensive effect of 5HT2 receptor antagonists is well established, but the mechanism of this effect has to be elucidated. Moreover, a beneficial effect of these drugs on complications of portal hypertension has also to be demonstrated.
References 1. Richardson PDI, Withrington PG, Responses of the simultaneously-perfused hepatic arterial and portal venous vascular beds ofthe dog to histamine and 5-hydroxytryptamine. Br J Pharmacol 1978;64:581-588. 2. Schrauwen E, Houvenaghel A. Effect of 5-hydroxytryptamine on mesenteric hemodynamics in the pig. Arch Int de Pharmacodynam et de Thdrap 1980;246:257-263. 3. GrSnstad KO, DahlstrSm A, Jaffe BM, Ahlman H. Regional and selective changes in blood flow of the feline small intestine induced by endoluminal serotonin. Acta Physiol Scand 1986;127:207-213. 4. Cummings SA, Groszmann RJ, Kaumann AJ. Hypersensitivity of mesenteric veins to 5-hydroxytryptamine and ketanserin-induced reduction of portal pressure in portal hypertensive rats. Br J Pharmacol 1986;89:501-513. 5. Gasic S, Eichler HG, Korn A. Effect of ketanserin on phenylephrine-dependent changes in splanchnic hemodynamics and systemic blood pressure in healthy subjects. J Cardiovasc Pharmacol 1985;7:219--223. 6. Kaumann AJ, Morgan JS, Groszmann RJ. ICI 169,369 selectivelyblocks 5-hydroxytryptamine2 receptors and lowers portal pressure in portal hypertensive rats. Gastroenterol 1988;95:1601-1606. 7. Mastai R, Giroux L, Semret M, Huet PM. Mechanism of ritanserin-induced decrease in portal pressure in conscious and unrestrained cirrhotic rats. Hepatology 1988;8:1245.
Serotonin and Portal Hypertension
8. Koshy A, Sekiyama T, Hadengue A, Cerini R, Girod C, Lebrec D. Effects of different vasoactive substances on portal-systemic collateral vascular resistance in conscious portal hypertensive rats. Hepatology 1988;8:1344. 9. Mastai R, Rocheleau B, Huet PM. Serotonin blockade in conscious, unrestrained cirrhotic dogs with portal hypertension. Hepatology 1989;9:265-268. 10. Hadengue A, Lee SS, Moreau R, Braillon A, Lebrec D. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: Possible role of serotonergic mechanisms in portal hypertension, Hepatology 1987;7:644-647. 11. Deflandre J, Pirotte J, Etienne M, Carlier J. Effects d'un antagoniste des r~cepteurs $2 de la s6rotonine sur l'hypertension portale de la cirrhose. R~sultats pr~liminaires
35
d'une 6tude h6modynamique cardiaque et h~patique, Annales de Gastroentdrol et d'Hdpatol 1988;24:103-105. 12. Vorobioff J, Garcia-Tsao G, Groszmann R, Aceves G, Picabea E. Villavicencio R, Hernandez-Ortiz J, Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology1989; 9:88-91. 13. Huet PM, Pomier Layrargues G, Semret M. Effects of ritanserin, a serotonin antagonist, in cirrhotic patients with portal hypertension. Hepatology 1988;8:1422. 14. Hadengue A, Moreau R, Cerini R, Koshy A, Lee SS, Lebrec D. Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: Research for an additive effect. Hepatology 1989;9:83-87.
© KluwerAcademicPublishers. Printed in the U.S.A.
PORTALHYPERTENSION:SEROTONINAND PATHOGENESlS
SUMMARY. It has b e e n demonstrated that serotonin (5-hydroxytryptamine; 5HT) can decrease portal vascular resistance in animals and could be a possible mediator for intestinal vasodilatation. Moreover, isolated m e s e n t e r i c v e i n from portal hypertensive rats has b e e n s h o w n to be hyper-responsive to 5HT. Hence 5HT m a y p l a y a role in the pathophysiology of the h y p e r k i n e t i c s y n d r o m e observed in patients w i t h portal hypertension. This hypothesis that serotonin m i g h t increase s p l a n c h n i c blood flow, and h e n c e portal pressure, led us to propose that 5HT receptor antagonists m i g h t decrease portal hypertension. We observed that acute administration of ketanserin, an antagonist of serotonin at 5HT 2 receptors, significantly decreased portal pressure and portal-systemic collateral blood f l o w in patients w i t h cirrhosis, w h e r e a s hepatic blood f l o w w a s not modified. Arterial pressure slightly decreased, w h i l e cardiac output w a s not affected b y ketanserin. These f i n d i n g s w e r e also observed d u r i n g c o n t i n u o u s administration of ketanserin. More recently, it has b e e n s h o w n that ritanserin, a more specific 5HT 2 receptor antagonist, significantly decreased portal pressure in cirrhotic patients. Finally, in rats w i t h portal hypertension, ketanserin as w e l l as ritanserin produced significant reductions in portal pressure but did not m o d i f y portal tributory blood flow. In these portal hypertensive animals, 5HT 2 antagonists m a y act on hepatecollateral vascular resistance. These studies confirm current evid e n c e in favor of a role for the actions of serotonin via 5HT2 receptors in portal h y p e r t e n s i o n and add a n e w group of substances for its treatment. KEY WORDS. serotonin, ketanserin, portal h y p e r t e n s i o n
Different studies have shown that serotonin (5hydroxytryptamine; 5HT) contributes to maintain portal hypertension, and hence 5HT receptor antagonist drugs may decrease portal pressure in patients with cirrhosis. Several experimental studies have demonstrated that 5HT is a mediator for intestinal vasodilatation [1-3]. In different species of healthy animals, administration of 5HT produces an increase in mesenteric or gastric blood flow [2,3] and a decrease in portal vascular resistance [1]. This effect is dose dependent [2]. Moreover, it has been demonstrated that isolated superior mesenteric veins from portal hypertensive rats are 3-10 times more sensitive to 5HT than veins from sham-operated rats [4]. Finally, a clinical study has shown that ketanserin, an antagonist of 5HT at 5HT2 receptors, pre-
Didier Lebrec Unit~ de Recherchesde PhysiopathologieH~patique (INSERM U-24) Hbpital Beaujon, Clichy,France
vented the phenylepinephrine-induced rise in portal pressure in subjects without portal hypertension [5]. In the present paper, experimental and clinical hemodynamic investigations into the effects of 5HT2 receptor antagonists are reviewed.
5HT2 Antagonists and Portal Hypertensive Animals Several hemodynamic studies have been performed in different models of portal hypertension in rats [4,6-8] and one in cirrhotic dogs [9]. The effects of ketanserin (0.3 mg/kg body wt) or ICI 169,369 (1.5 mg/kg body wt) - - novel 5HT 2 receptor antagonists - - in anesthetized portal vein stenosed rats produced significant decreases in portal pressure by 17% and 13%, respectively [4,6]. These reductions were accompanied by decreases in mean arterial pressure and heart rate. In comparison with saline infusion, in portal hypertensive rats, ketanserin infusion produced decreases in portal tributary blood flow and cardiac output, as estimated by the radioactive microsphere method. Hence, vascular resistance in the portal-systemic collateral circulation was not affected in this model. These hemodynamic effects were not observed in sham-operated rats. They were less marked after ICI 169,369 administration. From these studies, the authors concluded that 5HT 2 receptor antagonists produce a venous dilatation and pooling of blood in the portal venous system that could be secondary to the blockade of 5HT2receptors. In conscious, portal hypertensive animals, ketanserin and ritanserin also significantly decreased portal pressure, but the mechanism of this reduction differed from that in anesthetized animals [7-9]. In conscious cirrhotic rats, portal pressure decreased,
Address for correspondenceand reprint requests: Dr. D. Lebrec, INSERM U-24, H6pital Beaujon, 92118 Clichy, France. 33
34
Lebrec
while portal tributary blood flow was not affected by ritanserin (0.60 mg/kg body weight IV); mean arterial pressure did not change, but cardiac output significantly increased by 20% [7]. In conscious cirrhotic dogs, continuous administration of ritanserin (10 mg/day for 5 days) significantly decreased portal pressure but had no effect on systemic circulation and portal tributary blood flow [9]. From these studies it may be hypothesized that the decrease of portal pressure by ritanserin results from a reduction of intrahepatic or portacollateral resistance. This hypothesis has been confirmed in a model of portal hypertension in rats with total portal systemic shunts [8]. This study showed that ketanserin (0.25 mg/kg body weight IV) significantly decreased portal pressure and vascular resistance of portal systemic collaterals by 16% and 17%, respectively. In these animals, neither portal tributary blood flow nor arterial pressure were modified by ketanserin.
decreased significantly. No correlation was found between systemic changes and hepatic venous pressure gradient reduction. However, side effects occurred in some patients, the most significant being a reversible hepatic encephalopathy observed in 3 out of 16 patients who had poor liver function. Although not certainly drug related, the relatively high dosage of ketanserin may explain, at least in part, these side effects. A second long-term study was performed using the 5HT 2 receptor antagonist ritanserin (0.08 mg/kg body weight/day for 7 days) in eight cirrhotic patients [13]. This preliminary hemodynamic investigation showed that continuous administration of ritanserin significantly decreased the hepatic venous pressure gradient by approximately 15%, with no systemic effects. Moreover, ritanserin was well tolerated in all patients.
Conclusion 5HT2 Receptor Antagonists and Cirrhosis Five hemodynamic studies have been reported in patients with portal hypertension due to cirrhosis [10-14]; four studies used ketanserin and one used ritanserin. In the first investigation performed in cirrhotic patients, ketanserin (10 mg IV) moderately but significantly decreased mean arterial pressure; this effect was maximal at 5 minutes and correlated with the severity of cirrhosis [10]. Cardiac output and systemic vascular resistance were unaffected by ketanserin. The hepatic venous pressure gradient - a reflection of portal pressure in patients with cirrhosis - - was significantly decreased by 23% after ketanserin treatment. Azygous blood f l o w - - a reflection of superior portasystemic collateral blood f l o w - was also significantly decreased, by 26%; however, this effect was delayed, progressive, and not correlated with the arterial pressure decrease. Hepatic blood flow was not affected. Similar results were observed with a lower dose of ketanserin (5 mg IV) [14]. A further clinical study also showed that acute administration of ketanserin (0.1 mg/kg body weight) significantly decreased the hepatic venous pressure gradient [11]. The long-term hemodynamic effects of ketanserin (mean dose 51 mg/day for a mean period of 32 days) have been studied in patients with cirrhosis [12]. This trial showed that continuous administration of ketanserin produced a sustained decrease in the hepatic venous pressure gradient. In these cirrhotic patients, cardiac output and mean arterial pressure were also
The portal hypotensive effect of 5HT2 receptor antagonists is well established, but the mechanism of this effect has to be elucidated. Moreover, a beneficial effect of these drugs on complications of portal hypertension has also to be demonstrated.
References 1. Richardson PDI, Withrington PG, Responses of the simultaneously-perfused hepatic arterial and portal venous vascular beds ofthe dog to histamine and 5-hydroxytryptamine. Br J Pharmacol 1978;64:581-588. 2. Schrauwen E, Houvenaghel A. Effect of 5-hydroxytryptamine on mesenteric hemodynamics in the pig. Arch Int de Pharmacodynam et de Thdrap 1980;246:257-263. 3. GrSnstad KO, DahlstrSm A, Jaffe BM, Ahlman H. Regional and selective changes in blood flow of the feline small intestine induced by endoluminal serotonin. Acta Physiol Scand 1986;127:207-213. 4. Cummings SA, Groszmann RJ, Kaumann AJ. Hypersensitivity of mesenteric veins to 5-hydroxytryptamine and ketanserin-induced reduction of portal pressure in portal hypertensive rats. Br J Pharmacol 1986;89:501-513. 5. Gasic S, Eichler HG, Korn A. Effect of ketanserin on phenylephrine-dependent changes in splanchnic hemodynamics and systemic blood pressure in healthy subjects. J Cardiovasc Pharmacol 1985;7:219--223. 6. Kaumann AJ, Morgan JS, Groszmann RJ. ICI 169,369 selectivelyblocks 5-hydroxytryptamine2 receptors and lowers portal pressure in portal hypertensive rats. Gastroenterol 1988;95:1601-1606. 7. Mastai R, Giroux L, Semret M, Huet PM. Mechanism of ritanserin-induced decrease in portal pressure in conscious and unrestrained cirrhotic rats. Hepatology 1988;8:1245.
Serotonin and Portal Hypertension
8. Koshy A, Sekiyama T, Hadengue A, Cerini R, Girod C, Lebrec D. Effects of different vasoactive substances on portal-systemic collateral vascular resistance in conscious portal hypertensive rats. Hepatology 1988;8:1344. 9. Mastai R, Rocheleau B, Huet PM. Serotonin blockade in conscious, unrestrained cirrhotic dogs with portal hypertension. Hepatology 1989;9:265-268. 10. Hadengue A, Lee SS, Moreau R, Braillon A, Lebrec D. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: Possible role of serotonergic mechanisms in portal hypertension, Hepatology 1987;7:644-647. 11. Deflandre J, Pirotte J, Etienne M, Carlier J. Effects d'un antagoniste des r~cepteurs $2 de la s6rotonine sur l'hypertension portale de la cirrhose. R~sultats pr~liminaires
35
d'une 6tude h6modynamique cardiaque et h~patique, Annales de Gastroentdrol et d'Hdpatol 1988;24:103-105. 12. Vorobioff J, Garcia-Tsao G, Groszmann R, Aceves G, Picabea E. Villavicencio R, Hernandez-Ortiz J, Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients. Hepatology1989; 9:88-91. 13. Huet PM, Pomier Layrargues G, Semret M. Effects of ritanserin, a serotonin antagonist, in cirrhotic patients with portal hypertension. Hepatology 1988;8:1422. 14. Hadengue A, Moreau R, Cerini R, Koshy A, Lee SS, Lebrec D. Combination of ketanserin and verapamil or propranolol in patients with alcoholic cirrhosis: Research for an additive effect. Hepatology 1989;9:83-87.
