JOURNAL
OF SURGICAL
RESEARCH
48, 341-344 (1990)
Decreased Mesenteric Vascular Response to Angiotensin II in Portal Hypertension’ JAMES V. SITZMANN, M.D.,* SHAO-SEN LI, M.D.,* Yu-PING, Wu, M.D.,* ROBERTO GROSZMANN, M.D.,t AND GREGORY B. BULKLEY, M.D.* *The Johns Hopkins University, Department of Surgery, Baltimore, Maryland 21205 and t Yale University School of Medicine, New Hauen, Connecticut 06520
Presented at the Annual Meeting of the Association for Academic Surgery, Louisville, Kentucky, November 15-18, 1989
effect of angiotensin II on various vascular beds. For example, angiotensin II has been shown to increase peripheral vascular resistance by directly contracting vascular smooth muscle [l-3]. In the brain, it increases sympathetic outflow and vasopressin release [4,5]. In the mesenteric vascular bed, angiotensin II will cause a direct profound vasoconstriction of the splanchnic resistance vessels, causing a disproportionate increase in splanchnic resistance compared to the increase in total peripheral vascular resistance [2, 31. The mechanism of angiotensin II action on the mesenteric vasculature is not fully understood. While angiotensin II does have a direct vasoconstrictive effect, it may indirectly modulate splanchnic resistance through prostaglandin release [6, 71, through catechol release [3], or by promoting vasopressin release [4, 51. The possible relationship between angiotensin II and other putative agents in the control of splanchnic blood flow is especially interesting in portal hypertension. Chronic portal hypertension is characterized by marked splanchnic hyperemia [8], mediated in part by elevated prostanoid [6] or glucagon production [lo], as well as an abnormal response to sympathetic stimulation [ 111. Therefore, we postulated that in portal hypertension, a splanchnic vascular response to angiotensin II might be reduced. The following experiments were designed to determine whether the splanchnic vascular response to angiotensin infusion is reduced in portal hypertensive animals.
We studied the mesenteric and systemic vascular response to angiotensin II in normotensive and portal hypertensive (PHT) rabbits, because of the documented poor tolerance of hemorrhagic shock in PHT. Normally, the hemodynamic response to angiotensin II (AII) is characterized by selective and disproportionate splanchnic vasoconstriction. We postulated that the response to AI1 could be diminished in PHT. Chronic PHT was induced by partial portal vein ligation 3 weeks prior to graded angiotensin II infusion. Baseline hemodynamic measurements showed markedly elevated portal pressure (I&) and superior mesenteric artery blood flow (QsMA) compared with those of normotensive animals (P < 0.01). Superior mesenteric artery resistance (RSMA) was markedly reduced in PHT compared to that in controls (P < 0.05). Angiotensin II infusion in normals resulted in a marked selective rise in R sMA compared with the rise in systemic resistance (RSYS) (P < 0.01). AI1 infusion in PHT resulted in a rise in RsmA and RsYS, but the disproportionate in RsMA was attenuated. Furthermore, in both normal and PHT, AI1 caused a significant rise in Prv (P < 0.01). We conclude that the findings indicate that the splanchnic vasoconstrictive response to AI1 is substantially impaired in PHT, and that AI1 will paradoxically cause a rise in Ppv, possibly aggravating the tendency to hemorrhage in PHT. o lwso Academic POW, IIIC.
INTRODUCTION
The decreased tolerance of portal hypertensive patients to hypovolemic shock is well known. The usual hemodynamic response to hemorrhage is characterized by selective and disproportionate splanchnic vasoconstriction mediated by angiotensin II [ 11. Angiotensin II is an endogenous released peptide which helps to restore or maintain systemic arterial blood pressure after volume depletion. The mechanism whereby angiotensin maintains arterial blood pressure is variable, as is the relative 1 Supported in part by National Institutes of Health Grant 1 R29 39683-01.
METHODS
Adult male New Zealand white rabbits (2.5 to 3 kg body wt) were used for all experiments. Portal hypertension was induced by partial portal vein ligation to 18 gauge diameter. This produces a greater than 90% portosystemic shunt within 3 weeks of operation [9]. Control animals had no operation prior to hemodynamic studies. Three weeks after portal vein ligation, hemodynamic studies were performed on portal hypertensive rabbits. All hemodynamic studies were performed under 1% Xylocaine local anesthesia and 10 mg/kg ketamine intra-
341
0022.4804/90
$1.50
Copyright 0 1990 by AcademicPress,Inc. All rights of reproduction in any form reserved.
342
JOURNAL
TABLE Hemodynamics
of Portal Normal
PAS
PPV
QSMA &MA
QSYS RSYS
84.0 7.4 64.7 1.2 86.1 0.9
f f + k + +
3.3 0.4 4.6 0.1 3.4 0.07
OF SURGICAL
RESEARCH:
1 Hypertension PHT 83.0 14.5 110.0 0.6 98.0 0.8
f + f f f f
4.0 0.6* 8.6* 0.04* 8.3 0.07
Note. PAS and Ppv expressed in mm Hg. QsMA and Qsys are expressed in ml/min/lOO g intestine or body wt. RsMA and RsYs are expressed in mm Hg/ml/min/lOO g intestine or body wt. * P < 0.01.
venous sedation. The femoral artery and vein were cannulated via groin cutdown for measurement of aortic blood pressure (PAS) and central venous pressure (Pcv). Via laparotomy, Doppler flow probes (Transonic Corp.) were placed on the superior mesenteric artery and supraceliac aorta. Portal pressure (Ppv) was measured directly by placing a silicone catheter through a small mesenteric vein and threading it into the portal vein. Superior mesenteric artery blood flow (QsMA), aortic blood flow (QAo), PAS, PC”, and P~XJwere monitored continuously on a Grass Model 7D polygraph. The abdominal incision was closed and the animal allowed to stabilize for 30 min. Drug infusions were carried out through a separate femoral venous catheter via a contralateral groin incision. At the conclusion of each experiment, rabbits were euthanized with intravenous pentobarbital, Doppler probes were then calibrated in situ, and the gut was excised, blotted, and weighed. Experimental
Protocol
Angiotensin II was dissolved in normal saline solution, and in nine portal hypertensive rabbits and nine normotensive rabbits, it was infused via a femoral venous catheter in a step-wise incremental fashion until no further change in QsMA or QAo was obtained. Data Analysis Superior mesenteric artery resistance (RsM*) was calculated and systemic vascular resistance (J&s) was estimated using QAo. The dose-response curves of both RsMA and Rsvs to angiotensin II infusion were plotted for portal hypertensive and normotensive animals. At each dose, the responses were also expressed as the percentage baseline response, and statistical comparisons were performed using Student’s t test for unpaired data. A difference with a probability less than 0.05 was judged statistically significant. RESULTS
Baseline hemodynamic measurements prior to angiotensin II infusion revealed that portal hypertensive rabbits
VOL. 48, NO. 4, APRIL
1990
had markedly elevated Ppv and QsMA with a concurrent fall in RSMAcompared with those of normotensive animals (Table 1). Although systemic vascular resistance was slightly lower in the portal hypertensive rabbits, this difference was not significant. In normotensive rabbits, graded, incremental, central venous angiotensin II infusion from 0.05 to 2.0 pg/kg/ min produced a threefold rise in splanchnic resistance (1.2 f 0.1 to 4.0 + 0.4 mm Hg/ml/min/lOO g) and a twofold rise in systemic resistance (0.92 f 0.07 to 2.3 k 0.7 mm Hg/mi/min/lOO g). This confirmed previous work in other animal models that splanchnic vascular response to angiotensin II infusion was far greater than the systemic vascular response. The peak response to angiotensin II infusion was achieved at 1.0 pg/kg/min. The RsMA in normotensive rabbits was 330 f 21% higher than the baseline (pre-AI1 infusion), and the Rsvs was 237 & 51% higher than baseline (Fig. 1). At peak angiotensin II infusion, RsMA percentage response was significantly greater than Rsvs response (P < 0.05) (Fig. 4a). Notably, there was a steady increment in portal pressure during the course of angiotensin II infusion with a 50% increment in Ppv from control values (P < 0.01, Fig. 3). In portal hypertensive rabbits, graded central venous infusion of angiotensin II produced an incremental increase in RsMA and Rsvs with peak response occurring at 1.0 pg/kg/min. The RsMA rose from 0.6 + 0.04 to 1.5 + 0.2 mm Hg/ml/min/lOO g (235 f 29% increase), and the RsYs rose from 0.81 + 0.07 to 1.5 + 0.2 mm Hg/ml/min/lOO g (199 ? 21% increase) (Fig. 4b). The percentage rise in RsMA and Rsvs in portal hypertensive animals was significantly less (P < 0.01) (Fig. 2) than that in normotensive rabbits. Furthermore, the expected disproportionate increase in vasoconstrictive response of the splanchnic vascular bed to angiotensin II infusion was diminished. While the percentage rise in RSM~ from baseline was higher than the percentage change from baseline of RWS,
375 350. 325300275-1
00
SYSTEMIC RESISTANCE
e-0 FISHA
l p
OF SURGICAL
RESEARCH
48, 341-344 (1990)
Decreased Mesenteric Vascular Response to Angiotensin II in Portal Hypertension’ JAMES V. SITZMANN, M.D.,* SHAO-SEN LI, M.D.,* Yu-PING, Wu, M.D.,* ROBERTO GROSZMANN, M.D.,t AND GREGORY B. BULKLEY, M.D.* *The Johns Hopkins University, Department of Surgery, Baltimore, Maryland 21205 and t Yale University School of Medicine, New Hauen, Connecticut 06520
Presented at the Annual Meeting of the Association for Academic Surgery, Louisville, Kentucky, November 15-18, 1989
effect of angiotensin II on various vascular beds. For example, angiotensin II has been shown to increase peripheral vascular resistance by directly contracting vascular smooth muscle [l-3]. In the brain, it increases sympathetic outflow and vasopressin release [4,5]. In the mesenteric vascular bed, angiotensin II will cause a direct profound vasoconstriction of the splanchnic resistance vessels, causing a disproportionate increase in splanchnic resistance compared to the increase in total peripheral vascular resistance [2, 31. The mechanism of angiotensin II action on the mesenteric vasculature is not fully understood. While angiotensin II does have a direct vasoconstrictive effect, it may indirectly modulate splanchnic resistance through prostaglandin release [6, 71, through catechol release [3], or by promoting vasopressin release [4, 51. The possible relationship between angiotensin II and other putative agents in the control of splanchnic blood flow is especially interesting in portal hypertension. Chronic portal hypertension is characterized by marked splanchnic hyperemia [8], mediated in part by elevated prostanoid [6] or glucagon production [lo], as well as an abnormal response to sympathetic stimulation [ 111. Therefore, we postulated that in portal hypertension, a splanchnic vascular response to angiotensin II might be reduced. The following experiments were designed to determine whether the splanchnic vascular response to angiotensin infusion is reduced in portal hypertensive animals.
We studied the mesenteric and systemic vascular response to angiotensin II in normotensive and portal hypertensive (PHT) rabbits, because of the documented poor tolerance of hemorrhagic shock in PHT. Normally, the hemodynamic response to angiotensin II (AII) is characterized by selective and disproportionate splanchnic vasoconstriction. We postulated that the response to AI1 could be diminished in PHT. Chronic PHT was induced by partial portal vein ligation 3 weeks prior to graded angiotensin II infusion. Baseline hemodynamic measurements showed markedly elevated portal pressure (I&) and superior mesenteric artery blood flow (QsMA) compared with those of normotensive animals (P < 0.01). Superior mesenteric artery resistance (RSMA) was markedly reduced in PHT compared to that in controls (P < 0.05). Angiotensin II infusion in normals resulted in a marked selective rise in R sMA compared with the rise in systemic resistance (RSYS) (P < 0.01). AI1 infusion in PHT resulted in a rise in RsmA and RsYS, but the disproportionate in RsMA was attenuated. Furthermore, in both normal and PHT, AI1 caused a significant rise in Prv (P < 0.01). We conclude that the findings indicate that the splanchnic vasoconstrictive response to AI1 is substantially impaired in PHT, and that AI1 will paradoxically cause a rise in Ppv, possibly aggravating the tendency to hemorrhage in PHT. o lwso Academic POW, IIIC.
INTRODUCTION
The decreased tolerance of portal hypertensive patients to hypovolemic shock is well known. The usual hemodynamic response to hemorrhage is characterized by selective and disproportionate splanchnic vasoconstriction mediated by angiotensin II [ 11. Angiotensin II is an endogenous released peptide which helps to restore or maintain systemic arterial blood pressure after volume depletion. The mechanism whereby angiotensin maintains arterial blood pressure is variable, as is the relative 1 Supported in part by National Institutes of Health Grant 1 R29 39683-01.
METHODS
Adult male New Zealand white rabbits (2.5 to 3 kg body wt) were used for all experiments. Portal hypertension was induced by partial portal vein ligation to 18 gauge diameter. This produces a greater than 90% portosystemic shunt within 3 weeks of operation [9]. Control animals had no operation prior to hemodynamic studies. Three weeks after portal vein ligation, hemodynamic studies were performed on portal hypertensive rabbits. All hemodynamic studies were performed under 1% Xylocaine local anesthesia and 10 mg/kg ketamine intra-
341
0022.4804/90
$1.50
Copyright 0 1990 by AcademicPress,Inc. All rights of reproduction in any form reserved.
342
JOURNAL
TABLE Hemodynamics
of Portal Normal
PAS
PPV
QSMA &MA
QSYS RSYS
84.0 7.4 64.7 1.2 86.1 0.9
f f + k + +
3.3 0.4 4.6 0.1 3.4 0.07
OF SURGICAL
RESEARCH:
1 Hypertension PHT 83.0 14.5 110.0 0.6 98.0 0.8
f + f f f f
4.0 0.6* 8.6* 0.04* 8.3 0.07
Note. PAS and Ppv expressed in mm Hg. QsMA and Qsys are expressed in ml/min/lOO g intestine or body wt. RsMA and RsYs are expressed in mm Hg/ml/min/lOO g intestine or body wt. * P < 0.01.
venous sedation. The femoral artery and vein were cannulated via groin cutdown for measurement of aortic blood pressure (PAS) and central venous pressure (Pcv). Via laparotomy, Doppler flow probes (Transonic Corp.) were placed on the superior mesenteric artery and supraceliac aorta. Portal pressure (Ppv) was measured directly by placing a silicone catheter through a small mesenteric vein and threading it into the portal vein. Superior mesenteric artery blood flow (QsMA), aortic blood flow (QAo), PAS, PC”, and P~XJwere monitored continuously on a Grass Model 7D polygraph. The abdominal incision was closed and the animal allowed to stabilize for 30 min. Drug infusions were carried out through a separate femoral venous catheter via a contralateral groin incision. At the conclusion of each experiment, rabbits were euthanized with intravenous pentobarbital, Doppler probes were then calibrated in situ, and the gut was excised, blotted, and weighed. Experimental
Protocol
Angiotensin II was dissolved in normal saline solution, and in nine portal hypertensive rabbits and nine normotensive rabbits, it was infused via a femoral venous catheter in a step-wise incremental fashion until no further change in QsMA or QAo was obtained. Data Analysis Superior mesenteric artery resistance (RsM*) was calculated and systemic vascular resistance (J&s) was estimated using QAo. The dose-response curves of both RsMA and Rsvs to angiotensin II infusion were plotted for portal hypertensive and normotensive animals. At each dose, the responses were also expressed as the percentage baseline response, and statistical comparisons were performed using Student’s t test for unpaired data. A difference with a probability less than 0.05 was judged statistically significant. RESULTS
Baseline hemodynamic measurements prior to angiotensin II infusion revealed that portal hypertensive rabbits
VOL. 48, NO. 4, APRIL
1990
had markedly elevated Ppv and QsMA with a concurrent fall in RSMAcompared with those of normotensive animals (Table 1). Although systemic vascular resistance was slightly lower in the portal hypertensive rabbits, this difference was not significant. In normotensive rabbits, graded, incremental, central venous angiotensin II infusion from 0.05 to 2.0 pg/kg/ min produced a threefold rise in splanchnic resistance (1.2 f 0.1 to 4.0 + 0.4 mm Hg/ml/min/lOO g) and a twofold rise in systemic resistance (0.92 f 0.07 to 2.3 k 0.7 mm Hg/mi/min/lOO g). This confirmed previous work in other animal models that splanchnic vascular response to angiotensin II infusion was far greater than the systemic vascular response. The peak response to angiotensin II infusion was achieved at 1.0 pg/kg/min. The RsMA in normotensive rabbits was 330 f 21% higher than the baseline (pre-AI1 infusion), and the Rsvs was 237 & 51% higher than baseline (Fig. 1). At peak angiotensin II infusion, RsMA percentage response was significantly greater than Rsvs response (P < 0.05) (Fig. 4a). Notably, there was a steady increment in portal pressure during the course of angiotensin II infusion with a 50% increment in Ppv from control values (P < 0.01, Fig. 3). In portal hypertensive rabbits, graded central venous infusion of angiotensin II produced an incremental increase in RsMA and Rsvs with peak response occurring at 1.0 pg/kg/min. The RsMA rose from 0.6 + 0.04 to 1.5 + 0.2 mm Hg/ml/min/lOO g (235 f 29% increase), and the RsYs rose from 0.81 + 0.07 to 1.5 + 0.2 mm Hg/ml/min/lOO g (199 ? 21% increase) (Fig. 4b). The percentage rise in RsMA and Rsvs in portal hypertensive animals was significantly less (P < 0.01) (Fig. 2) than that in normotensive rabbits. Furthermore, the expected disproportionate increase in vasoconstrictive response of the splanchnic vascular bed to angiotensin II infusion was diminished. While the percentage rise in RSM~ from baseline was higher than the percentage change from baseline of RWS,
375 350. 325300275-1
00
SYSTEMIC RESISTANCE
e-0 FISHA
l p
