Circulatory actions of vasopressin in anaesthetized rats with portal hypertension subjected to haemorrhage

328

Journal of Hepatology, 1986; 2:328-339 Elsevier

HEP 0120

Circulatory Actions of Vasopressin in Anaesthetized Rats with Portal Hypertension Subjected to Haemorrhage

D o m i n i q u e Valla, Patrick Geoffroy, Catherine Girod and Didier Lebrec Unit~ de Recherches de Physiopathologie H~patique (INSERM U24), H6pital Beaujon, Clichy (France) (Received 12 September, 1985) (Accepted 16 December, 1985)

Summary To assess the influence of vasopressin on splanchnic and renal circulatory changes induced by haemorrhage in portal hypertension, we studied 4 groups of 7 rats with chronic portal vein stenosis..Two groups received saline (C and H) and two groups vasopressin, 0.01 IU/kg/min (VP and VP-H). Ten minutes after starting drug infusion, group H and VP-H animals were allowed to bleed from the superior mesenteric vein. Both haemorrhage and vasopressin alone, decreased portal venous tributary blood flow and pressure but their association was not additive (as reflected by comparable bleeding rate in groups H and VP-H). By contrast, vasopressin increased renal perfusion in bleeding and non-bleeding animals whereas haemorrhage alone decreased renal perfusion. These results indicate that the effects of vasopressin on the splanchnic circulation in bleeding anaesthetized animals differ from the effects observed when blood volume is normal. Therefore, in patients with cirrhosis the effects of vasopressin during bleeding might also differ from those observed in patients in stable condition.

Dr. D. Valla holds a fellowship from the Fondation pour la Recherche M~dicale. This work was supported by Grant 82 7 018 from Institut National de la Sant6 et de la Recherche M6dicale. This work was presented in part at the 19th Meeting of the European Association for the Study of the Liver in Berne, Switzerland, on 6-8 September, 1984 and is published in abstract form in J. Hepatol. 1984; 1: $144. Address for correspondence and reprints: Dr. D. Valla, INSERM U 24, H6pital Beaujon, 92118 Clichy, France. 0168-8278/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)

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VASOPRESSIN ACTIONS D U R I N G H A E M O R R H A G E

Introduction

In patients with portal hypertension, the efficacy of vasopressin in controlling bleeding from oesphageal varices has not been conclusively demonstrated. Some therapeutic trials have shown superiority over conventional therapies [1,2], but others have not [3,4]. Haemodynamic studies in non bleeding patients have not clearly indicated which mechanism would be responsible for vasopressin efficacy [5-8]. Moreover, in the portal hypertensive state, haemodynamic effects of haemorrhage and their modification by exogenous vasopressin have been investigated neither in patients nor in animals. The purpose of the present study in rats with portal hypertension due to chronic portal vein ligation, was to assess the influence of vasopressin on bleeding from the portal venous bed and to compare the effects of vasopressin in bleeding and non bleeding animals. Materials and Methods Protocol

Portal hypertension was induced by partial portal vein ligation in male SpragueDawley rats weighing 160-180 g, according to a previously reported method [9-11]. The animals were studied 3 wks later, 12-18 h after withdrawal of food. Figure 1 depicts the experimental design. In the first part of the study, 4 experimental groups of 7 animals each, were investigated. Two groups of animals were not bled and received either a control infusion of saline (group C), or a vasopressin infusion (group VP) (Pitressin ®, Parke Davis, Morris Plain, NJ, U.S.A.). The 2 other groups were subjected to bleeding as described below, while receiving either saline (group H) or vasopressin (group VP-H) at rates identical to those in group C and VP, respectively. As depicted in Fig. 1, drug infusions (0.01 ml/min) were beGroup C

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gun after 10 min of baseline observations and terminated 25 min later, at killing. Vasopressin, diluted in saline to a concentration of 0.25-0.35 IU/ml was delivered at a rate 0.01 IU/kg/min after a bolus injection of 0.15 ml. Haemorrhage lasted 5 min and was initiated 10 min after beginning drug infusion. In the second part of the study, we compared the effects of the administration of vasopressin immediately after haemorrhage to those observed when vasopressin was infused before bleeding. Five portal hypertensive rats (group H-VP) were bled by pumping blood from the femoral artery for 5 rain at a rate equal to the mean bleeding rate in group VP-H. Vasopressin was then infused for 10 min in the same conditions as in group VP or VP-H (Fig. 1).

Experimentalpreparation The animals were anaesthetized with intraperitoneal pentobarbital (60 mg/kg). A polyethylene catheter (outside diameter 0.70 mm) was inserted in the left femoral artery for systemic arterial pressure measurement. The abdominal wall was opened through a 10-mm midline incision and a small ileal vein was cannulated using a polyethylene catheter (outside diameter 0.96 mm, inside diameter 0.58 mm; length 16.0 cm) advanced into the cranial portion of the superior mesenteric vein for portal venous monitoring and bleeding from the portal venous bed. The catheter was secured to the mesentery, and the skin was tightly closed around the catheter with surgical suture. The left internal jugular vein was cannulated for drug infusion. A fourth catheter was inserted in the right carotid artery and advanced into the left ventricle according to a technique described elsewhere [10-12]. The trachea was cannulated. Animals in which this experimental preparation had been haemorrhagic were rejected. The rectal.temperature was kept at 37.0 + 0.5 °C by a heating lamp. At the end of these procedures, heparin (50 IU) was administered intravenously. The experimental preparation was completed within 25-40 min. The animals were allowed 10-20 min to recover.

Induction of haemorrhagefrom the portal venous bed A model of haemorrhage from the portal venous bed was developed, producing a reproducible rate of spontaneous bleeding. The procedure is as follows: the distal end of the catheter inserted in the superior mesenteric vein was placed at a level 1.0 cm below the back plane of the animals. Blood was allowed to flow freely into a preweighed container for 5 min. Blood losses were evaluated by weighing. Initial compensation and stabilization of the circulatory state was achieved by 10 min in all animals.

Haemodynamic measurements Mean arterial pressure, heart rate, portal pressure, cardiac output and its distribution, and systemic vascular resistance were determined as described elsewhere [10,11]. For determination of cardiac output and regional blood flows, the reference sample method with intracardiac injection of microspheres labelled with 141Cerium (15 + 3 /~m in diameter) was used [12]. Vascular resistance in the splanchnic organs, except for the hepatic artery and the kidneys, was calculated as

VASOPRESSIN ACTIONS DURING H A E M O R R H A G E

331

the pressure gradient across the organ (mean arterial pressure minus portal pressure) divided by the organ blood flow. In calculating hepatic arterial and renal vascular resistance, pressure gradient was assumed to equal mean arterial pressure.

Statistical analysis Results are expressed as mean + SEM. The statistical significance of the differences between the first 4 groups of animals was assessed by one-way analysis of variance with a Bonferroni correction for multiple comparison [13]. Four comparisons were performed: group C vs groups H, VP and VP-H, and group H vs group VP-H. Accordingly, differences were considered statistically significant when the P-value was < 0.0125 [15]. In the second part of the study, results in groups VP-H and H-VP were compared by means of the Student t-test for unpaired data. Results

Baseline values As shown in Table 1, body weight, duration of portal hypertension, baseline mean arterial and portal pressures, and heart rate were not significantly different among the five groups. Mean arterial pressure, portal pressure, and heart rate did not change significantly during the 10-min baseline period.

Effects of haemorrhage In animals subjected to haemorrhage alone, blood losses averaged 2.2 + 0.2 g. As shown in Fig. 2, immediately after bleeding, mean arterial pressure decreased by 41% as compared to the corresponding values in control animals; 10 min later, mean arterial pressure decreased by 33%, and portal pressure by 23%, on average. At that time, cardiac output significantly decreased by 32% but total systemic vascular resistance was unchanged (Fig. 3). As shown in Figs. 4 and 5, redistribution of cardiac output affected mainly, the hepatic artery (receiving an increased fraction of cardiac output) and t h e mesentery-pancreas (receiving a decreased fraction of TABLE 1 BASELINE D A T A IN THE FIVE GROUPS OF PORTAL-HYPERTENSIVE RAT Results are expressed as mean + SEM. Group C, animals receiving the control saline infusion and not subjected to haemorrhage; group H, animals receiving the control saline infusion and subjected to haemorrhage; group VP, animals receiving the vasopressin infusion (0.01 IU/kg/min) and not subjected to haemorrhage; group VP-H, animals subjected to haemorrhage while receiving vasopressin; group H-VP, animals subjected to haem. orrhage prior to the infusion of vasopressin.

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GroupH (n = 7)

GroupVP (n = 7)

GroupVP-H (n = 7)

GroupH-VP (n = 5)

283 + 119 + 12.0 + 417 +

305 + 11 110+3 13.1 + 0.5 394 + 13

295 + 8 118+3 13.8 + 0.5 437 + 16

288 + 2 116+2 12.1 + 0.8 399 + 8

305 + 11 115+4 11.8 + 0.6 414 + 8

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cardiac output). As a result of redistribution of the decreased cardiac output, total portal venous tributary blood flow and blood flows to spleen, mesentery-pancreas, and kidneys were significantly reduced whereas small bowel and hepatic arterial blood flows were preserved (Figs. 6 and 7). Vascular resistance in splanchnic organs were not significantly different between the 2 groups (Table 2).

Effects of vasopressin As shown in Fig. 2, infusion of vasopressin in group VP animals induced a moderate decrease in portal pressure that was not statistically significant when compared to control animals but was highly significant when compared to the baseline values (average 20% decrease, P < 0.01, Student t-test for paired data). There was no significant change in mean arterial pressure. Cardiac output was decreased by 19% (NS) and systemic vascular resistance was significantly increased by 29% as compared to the corresponding value in group C. As shown in Figs. 4 and 5, redistribution of cardiac output affected mainly the hepatic artery and the renal vascular bed (receiving an increased fraction of cardiac output) and the mesentery-pancreas (receiving a decreased fraction of cardiac output). As a result of redistribution, total portal venous tributary blood flow and blood flows in the caecum and colon, spleen, and mesentery-pancreas were significantly reduced, whereas hepatic arterial blood flow was increased (Figs. 6 and 7), with inverse changes in the vascular resistances of these organs (Table 2).

Effects of vasopressinplus haemorrhage Animals in group VP-H were bled 10 min after starting vasopressin infusion. Blood losses averaged 2.0 + 0.1 g. As shown in Fig. 2, when compared to the correREGIONAL B L O 0 0

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sponding values in group C animals, there was a prompt significant decrease in mean arterial pressure (-32%) and in portal pressure (-43%). Ten minutes after the end of haemorrhage, mean arterial pressure was significantly decreased by 17%, portal pressure was decreased by 37%, (NS). Cardiac output was decreased by 30% and systemic vascular resistance was increased by 17% (Fig. 3). As shown in Figs. 4 and 5, redistribution of cardiac output affected mainly the hepatic artery and, the renal vascular beds (receiving an increased fraction of cardiac output), TABLE 2 S P L A N C H N I C A R T E R I O L A R R E S I S T A N C E IN A N I M A L S R E C E I V I N G A C O N T R O L SALINE I N F U S I O N A N D N O N - B L E D (C) O R B L E D (H), A N D IN A N I M A L S R E C E I V I N G V A S O PRESSIN I N F U S I O N A N D N O N - B L E D (VP) O R B L E D (VP-H) C Kidneys a Hepatic artery ~ Portal venous tributaries b Small bowel a Colon a Spleen" Mesentery-pancreas" Stomach a

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Expressed in m m H g . m l - l - m i n ' g of tissue weight. b Expressed in m m Hg. ml-t-min- 100 g of body weight. c Significantly different from value in group C. d Significantly different from value in group H.

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spleen and mesentery-pancreas (receiving a decreased fraction of cardiac output). As a result, portal venous tributary blood flow and blood flows to caecum and colon, spleen and mesentery-pancreas were significantly reduced whereas blood flow in the hepatic artery was increased (Figs. 6 and 7), with inverse changes in the respective vascular resistance of these organs (Table 2). Because blood losses were very similar in group H and VP-H animals, comparison of these 2 groups was possible. In comparison to group H animals, group VP-H animals, immediately after bleeding, showed a significantly higher mean arterial pressure but similar portal pressure (Fig. 2). Ten minutes after bleeding, differences in mean arterial pressure, portal pressure (Fig. 2) and cardiac output (Fig. 3) were not statistically significant according to the statistical method used; there was a small difference in mean portal pressure, however, suggesting that vasopressin in bled animals caused portal pressure to be decreased for a longer period of time. Systemic vascular resistance was significantly increased in animals receiving vasopressin. As shown in Figs. 4 and 5, differences in the distribution of cardiac output affected mainly the renal vascular bed (receiving a higher fraction of cardiac output in VP-H animals), and mesentery-pancreas (receiving a lower fraction of cardiac output). Portal venous tributary blood flow was not significantly different in the two groups but renal blood flow was greater in animals subjected to haemorrhage while receiving vasopressin (Figs. 6 and 7). Splenic, mesenteric and gastric vascular resistances were significantly increased in animals receiving vasopressin but total vascular resistance in portal venous tributaries was not (Table 2). Comparison of the results between group VP-H and H-VP showed no statistically significant difference (Table 3). TABLE 3 RESULTS OF H A E M O D Y N A M I C STUDIES IN ANIMALS RECEIVING VASOPRESSIN BEFORE (GROUP VP-H) OR AFTER (GROUP H-VP) H A E M O R R H A G E Measurements were performed 10 min after the end of bleeding, during vasopressin infusion. There was no statistically significant difference between the 2 groups. Group VP-H Heart rate (bpm) Mean arterial pressure (mm Hg) Cardiac output (ml/mm/100 gbw) Systemic vascular resistance (dynes.s/cmS/100 gbw) Portal venous pressure (mm Hg) Portal venous tributary blood flow fractional (% of cardiac output) absolute (ml/min/100 bw) Hepatic arterial blood flow fractional (% of cardiac output) absolute (ml/min/g) Renal blood flow fractional (% of cardiac output) absolute (ml/min/g)

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Discussion

The experimental model of chronic portal hypertension used in this study, the anaesthetized portal vein-ligated rat, has been shown to share a number of circulatory alterations with human cirrhosis [10,11,14,15]. Pentobarbital anaesthesia significantly alters portal and systemic haemodynamics in this model, but the qualitative differences between sham-operated and portal vein-ligated animals are present in the conscious as in the anaesthetized states [16]. Finally, pentobarbital anaesthesia [17] as other anaesthetics [18], alters the response to bleeding in normal rats. In this study, the lack of increase in systemic vascular resistance in haemorrhaged rats differs from the findings in conscious animals without portal hypertension. This difference may be explained by the decreased release of catecholamines induced by pentobarbital [17] and to the decreased cardiovascular responsiveness to catecholamines in portal vein-ligated rats [19]. Laparotomy, however, cannot be avoided when portal pressure is to be monitored because a model of chronic cannulation of the portal vein in trained animals is not available at present. Pain and stress due to laparotomy in awake rats may also influence the response to haemorrhage in a different but as significant a manner as anaesthesia. These experimental limitations should be kept in mind when interpreting our data. The primary goal of this study was to compare the rate of 'spontaneous' bleeding from the portal venous territory in animals receiving and not receiving vasopressin and to relate the possible differences to differences in haemodynamic changes. Our results, however, show that the rate of 'spontaneous' bleeding is not significantly different whether or not vasopressin is infused. Moreover, for a similar amount of bleeding, blood flow and pressure in the portal venous tributaries are very comparable. Similar findings have already been reported in dogs without chronic portal hypertension [20-22]. This apparent lack of effect of vasopressin during haemorrhage contrasts with our findings in unbled animals receiving vasopressin. In the latter animals, the expected circulatory effects of vasopressin occurred, i.e. redistribution of cardiac output toward the liver and the kidney at the expense of portal venous tributaries, a small decrease in portal pressure and an increase in systemic vascular resistance as reported in other species of animals with and without portal hypertension [23]. Thus, insufficient dosage of vasopressin was not responsible for its apparent lack of effect on splanchnic haemodynamics during bleeding. In bled animals, as compared to saline infusion, vasopressin did increase mean arterial pressure, systemic vascular resistance and vascular resistance in spleen, mesentery and stomach. Finally, blunted effects of vasopressin on portal venous tributary blood flow and pressure were not related to timing of vasopressin administration in relation to bleeding. It may be argued that pentobarbital anaesthesia explains the failure of vasopressin to affect portal venous haemodynamics in animals subjected to haemorrhage. This explanation is unlikely for 2 reasons: (a) in normovolemic anaesthetized animals, vasopressin clearly affected the systemic and splanchnic haemodynamics in this study as in others [23]; and (b), in bled animals, characteristic effects of vasopressin were observed in systemic haemodynamics and in those splanchnic organs

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which seem to be specific targets for vasopressin vascular actions: spleen, mesentery-pancreas, and stomach. The reason why vasopressin induced no significant change in portal venous tributary blood flow and pressure in bleeding animals cannot be clearly elucidated from our study. A part of the phenomenon may be explained by vasopressin inducing vasoconstriction in vascular beds (spleen, mesentery, stomach) accounting only for a fraction of total splanchnic arterial resistance: vasoconstriction in these tributaries would be sufficient to cause a sizeable decrease in portal venous tributary blood flow in normovolemic animals when cardiac output is normal, but not in bled animals when cardiac output is decreased. On the other hand, response to haemorrhage involves a number of integrated changes: release of endogenous vasoactive substances (among them endogenous vasopressin [17, 24-29]) and autoregulatory escape of various vascular beds [30], all of which may alter the responsiveness to exogenous vasopressin. In conclusion, this study indicates that the effects of vasopressin on the splanchnic circulation differ in magnitude in bleeding and non-bleeding anaesthetized rats with portal hypertension. Although the experimental model used in this study clearly differs from bleeding oesophageal varices in unanaesthetized patients, nevertheless our findings suggest that the results of pharmacodynamic studies of vasoactive drugs iri stable patients with portal hypertension should not be readily extrapolated to bleeding patients.

References 1 Merigan, T.C., Plotkin, G.R. and Davidson, C.S., Effect of intravenously administered posterior pituitary extract on hemorrhage from bleeding esophageal varices. A controlled evaluation, N. Engl. J. Med., 1962; 266: 134-135. 2 Conn, H.O., Ramsby, G.R., Storer, E.H., et al., Intraarterial vasopressin in the treatment of upper gastrointestinal hemorrhage: a prospective, controlled clinical trial, Gastroenterology, 1975; 68: 211-221. 3 Fogel, M.R., Knauer, C.M., Andr/:s, L.L., et al., Continuous intravenous vasopressin in active upper gastrointestinal bleeding. A placebo-controlled trial, Ann. Int. Med., 1982; 96: 565-569. 4 Clanet, J., Tournut, R., Fourtanier, G., et al., Traitement par la pitressine des hrmorragies par rupture de varices oesophagiennes chez le cirrhotique. Etude contrrMe, Acta Gastroentrrol. Belg., 1978; 41: 539-543. 5 Shaldon, S., Dolle, W., Guevara, L., et al., Effect of pitressin on the splanchnic circulation in man, Circulation, 1961; 24: 797-807. 6 Silva, Y.J., Moffat, R.C. and Walt, A.J., Vasopressin effect on portal and systemic hemodynamics. Studies in intact, unanesthetized humans, J. Amer. Med. Ass., 1969; 210: 1065-1068. 7 Thomford, N.R. and Sirinek, K.R., Intravenous vasopressin in patients with portal hypertension. Advantages of continuous infusion, J. Surg. Res., 1975; 18: 113-117. 8 Millette, B., Huet, P.M., Lavoie, P., et al., Portal and systemic effects of selective infusion of vasopressin into the superior mesenteric artery in cirrhotic patients, Gastroenterology, 1975; 69: 6-12. 9 Halvorsen, J.F. and Myking, A.O., Prehepatic portal hypertension in the rat. Immediate and longterm effects on portal vein and aortic pressure of a graded portal vein stenosis, followed by occlusion of the portal vein and spleno-renal collaterals, Europ. Surg. Res., 1979; 11: 889-910. 10 Blanchet, L. and Lebrec, D., Changes in splanchnic blood flow in portal hypertensive rats, Europ. J. Clin. Invest., 1982; 12: 327-330.

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