European Journal of Clinical Investigation ( I 992) 22, 60-66
Somatostatin does not block the effect of vasoactive intestinal peptide on bile secretion in man B. NYBERG*, B. ANGELIN? & K. EINARSSON?, Departments of *Surgery and ?Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden Received 12 April I99 1 and in revised form 19 June 1991 ; accepted 24 June I99 I
Abstract. The effects of intravenously administered somatostatin and vasoactive intestinal peptide (VIP) on bile secretion were studied in 10 patients with complete biliary fistulas. The two peptides were administered both separately and simultaneously. During the infusion of vasoactive intestinal peptide, bile secretion increased by 85%, whereas during somatostatin infusion it decreased by 40%. When the peptides were administered together, the VIP-induced choleretic effect was not reduced by somatostatin. Vasoactive intestinal peptide infusion increased bicarbonate concentration and output, whereas somatostatin had the opposite effect. The output of chloride also increased following vasoactive intestinal peptide infusion but decreased following somatostatin infusion. The concentration of chloride was unaffected by somatostatin whereas it was decreased by vasoactive intestinal peptide. The output of bile acids was unaffected by vasoactive intestinal peptide and decreased by somatostatin infusion, whereas total lipid concentration increased during somatostatin infusion and decreased when vasoactive intestinal peptide was added. It is concluded that, in man, somatostatin acts on the bile acid-dependent canalicular bile secretion and also, to some extent, on the ductular secretion, whereas vasoactive intestinal peptide acts strictly at the ductular level. The effects of the two peptides on bile secretion are independent of each other.
Keywords. Bicarbonate, bile acids, bile secretion, cholesterol, chloride, phospholipids, somatostatin, vasoactive intestinal peptide. Introduction
The bile acid-dependent fraction of canalicular bile secretion results from osmotic filtration due to active transport of bile acids [I]. The mechanisms of regulation of bile acid-independent canalicular and ductular bile secretion have not yet been fully elucidated. Several gastrointestinal peptides participate in the regulation of bile secretion. Secretin, vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) stimuCorrespondence: Bjorn Nyberg MD. Department of Surgery, Huddinge University Hospital, S-141 86 Huddinge. Sweden.
60
late bile secretion while somatostatin and substance P are inhibitors [2]. The effects of VIP on bile secretion have been studied in several species. In awake dogs with chronic bile fistula, bile secretion increases by up to 200% [3] and in anaesthetized dogs by 45-100% [4-61. In rats, VIP has a mild choleretic effect, 10-17%/;,,which is abolished by bile acid depletion [7]. Recently we reported that VIP stimulates a bicarbonate-rich ductular secretion in humans [8]. The effect of somatostatin on bile secretion has been studied in several experimental models in several species. In intact rat and in isolated perfused liver, somatostatin reduced bile flow and bile acid secretion [9], whereas in another study also using isolated perfused rat liver somatostatin failed to reduce both basal and glucagon-stimulated bile secretion as well as glucagon-induced increased cyclic AMP levels [ 101. In dogs, an anticholeretic effect of somatostatin was first described in 1978 [ I I]. Suppression of bile secretion has been described both with decreased and unchanged bile acid output [ 12- 181. Mechanisms of action both on the canalicular bile acid-independent level [14,16] and on the ductular level [14,17] of bile secretion have been suggested. Somatostatin has been found to inhibit the increased bile flow and the increased portal plasma secretin release caused by duodenal acidification in dogs [ 12,141. The effect of somatostatin on bile secretion, stimulated by exogenously administered secretin, has been studied by several authors. A reduced effect of secretin in lower doses, administered together with somatostatin, has been reported in dogs and rats [17,18]. Other authors, however, have reported that in dogs somatostatin does not affect bile secretion caused by secretin infusion [12-141. So far, no studies have been published on the effects of somatostatin on VIP-stimulated bile secretion. Recently we reported on seven patients with complete bile fistulas, in whom somatostatin reduced bile secretion by 30% and also reduced the output of bile lipids [ 191. It was concluded that, in man, the effect of somatostatin on bile production is mainly at the canalicular level. In another recently published study, in two patients with bile fistulas, somatostatin was found to decrease bile production and bile acid secretion [20], confirming our results.
EFFECTS O F VIP AND SOMATOSTATIN ON BILE
61
Table 1. Basal data of patients and values of liver function tests
Patient
Serum Age Body weight bilirubin (pmol I - ' ) (Years) (kg)
Patients given VIP+SST 1 26 58 2 79 46 3 77 75 4 58 72 5 65 73 6 25 57 Patients given 7 8 9 10
Normal range
SST+VIP 43 60 44 78 76 73 52 68
Serum ALP (pkat I-
I)
Serum AST (pkat I - ' )
Serum ALT (pkat I - ' )
17 7 8 8 5 33
7.3 4. I 10.2 5.1 4.4 7.5
0.97 0.70 0.60 0.38 2.32 I .42
5.8 I 0.59 0.73 0.50 0.60 1.85
6 9 7 45
5.0 12.2 4.6 14.0
0.83 4.22 0.60 4.27
I .46 9.28 0.80 3.45
t0.70
Somatostatin does not block the effect of vasoactive intestinal peptide on bile secretion in man B. NYBERG*, B. ANGELIN? & K. EINARSSON?, Departments of *Surgery and ?Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden Received 12 April I99 1 and in revised form 19 June 1991 ; accepted 24 June I99 I
Abstract. The effects of intravenously administered somatostatin and vasoactive intestinal peptide (VIP) on bile secretion were studied in 10 patients with complete biliary fistulas. The two peptides were administered both separately and simultaneously. During the infusion of vasoactive intestinal peptide, bile secretion increased by 85%, whereas during somatostatin infusion it decreased by 40%. When the peptides were administered together, the VIP-induced choleretic effect was not reduced by somatostatin. Vasoactive intestinal peptide infusion increased bicarbonate concentration and output, whereas somatostatin had the opposite effect. The output of chloride also increased following vasoactive intestinal peptide infusion but decreased following somatostatin infusion. The concentration of chloride was unaffected by somatostatin whereas it was decreased by vasoactive intestinal peptide. The output of bile acids was unaffected by vasoactive intestinal peptide and decreased by somatostatin infusion, whereas total lipid concentration increased during somatostatin infusion and decreased when vasoactive intestinal peptide was added. It is concluded that, in man, somatostatin acts on the bile acid-dependent canalicular bile secretion and also, to some extent, on the ductular secretion, whereas vasoactive intestinal peptide acts strictly at the ductular level. The effects of the two peptides on bile secretion are independent of each other.
Keywords. Bicarbonate, bile acids, bile secretion, cholesterol, chloride, phospholipids, somatostatin, vasoactive intestinal peptide. Introduction
The bile acid-dependent fraction of canalicular bile secretion results from osmotic filtration due to active transport of bile acids [I]. The mechanisms of regulation of bile acid-independent canalicular and ductular bile secretion have not yet been fully elucidated. Several gastrointestinal peptides participate in the regulation of bile secretion. Secretin, vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) stimuCorrespondence: Bjorn Nyberg MD. Department of Surgery, Huddinge University Hospital, S-141 86 Huddinge. Sweden.
60
late bile secretion while somatostatin and substance P are inhibitors [2]. The effects of VIP on bile secretion have been studied in several species. In awake dogs with chronic bile fistula, bile secretion increases by up to 200% [3] and in anaesthetized dogs by 45-100% [4-61. In rats, VIP has a mild choleretic effect, 10-17%/;,,which is abolished by bile acid depletion [7]. Recently we reported that VIP stimulates a bicarbonate-rich ductular secretion in humans [8]. The effect of somatostatin on bile secretion has been studied in several experimental models in several species. In intact rat and in isolated perfused liver, somatostatin reduced bile flow and bile acid secretion [9], whereas in another study also using isolated perfused rat liver somatostatin failed to reduce both basal and glucagon-stimulated bile secretion as well as glucagon-induced increased cyclic AMP levels [ 101. In dogs, an anticholeretic effect of somatostatin was first described in 1978 [ I I]. Suppression of bile secretion has been described both with decreased and unchanged bile acid output [ 12- 181. Mechanisms of action both on the canalicular bile acid-independent level [14,16] and on the ductular level [14,17] of bile secretion have been suggested. Somatostatin has been found to inhibit the increased bile flow and the increased portal plasma secretin release caused by duodenal acidification in dogs [ 12,141. The effect of somatostatin on bile secretion, stimulated by exogenously administered secretin, has been studied by several authors. A reduced effect of secretin in lower doses, administered together with somatostatin, has been reported in dogs and rats [17,18]. Other authors, however, have reported that in dogs somatostatin does not affect bile secretion caused by secretin infusion [12-141. So far, no studies have been published on the effects of somatostatin on VIP-stimulated bile secretion. Recently we reported on seven patients with complete bile fistulas, in whom somatostatin reduced bile secretion by 30% and also reduced the output of bile lipids [ 191. It was concluded that, in man, the effect of somatostatin on bile production is mainly at the canalicular level. In another recently published study, in two patients with bile fistulas, somatostatin was found to decrease bile production and bile acid secretion [20], confirming our results.
EFFECTS O F VIP AND SOMATOSTATIN ON BILE
61
Table 1. Basal data of patients and values of liver function tests
Patient
Serum Age Body weight bilirubin (pmol I - ' ) (Years) (kg)
Patients given VIP+SST 1 26 58 2 79 46 3 77 75 4 58 72 5 65 73 6 25 57 Patients given 7 8 9 10
Normal range
SST+VIP 43 60 44 78 76 73 52 68
Serum ALP (pkat I-
I)
Serum AST (pkat I - ' )
Serum ALT (pkat I - ' )
17 7 8 8 5 33
7.3 4. I 10.2 5.1 4.4 7.5
0.97 0.70 0.60 0.38 2.32 I .42
5.8 I 0.59 0.73 0.50 0.60 1.85
6 9 7 45
5.0 12.2 4.6 14.0
0.83 4.22 0.60 4.27
I .46 9.28 0.80 3.45
t0.70
