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F4-3 A study of portal and gastric mucosal hemodynamics in cirrhotic patients with portal-hypertensive gastropathy
S14
Clinical and Research Forum/International Hepatology Communications 3 Suppl. (1995) $5-$36
F4-2
INTRAHEPATIC HAEMODYNAMICS IN PORTAL HYPERTENSION Grossman VL, Grossman HJ and Bhathal PS. Pathology Department, The University of Melbourne, Parkville, VIC, 3052, Australia. During the development of cirrhosis, an increased resistance to portal flow develops which has been attributed to mechanical vascular obstruction and to active vasoconstriction. Experimental cvidcncc presented here cnfirms that the relative contribution of active vasoconstriction varies with the activity of the underlying liver disease. In a study of the intrahepatic portal vascular bed in carbon tetrachlnridc (CCl4)-induced cirrhosis in the rat, cirrhnsis was induced with 10 consecutive oral doses of CCI4. Treatment was then stopped and responses to the vasodilator agent sodium nitroprusside (SNP, Ixl0"3M) and pressure-flow curves were compared in isolated perfuscd rat hvor preparations (IPRL) on day 5 (active cirrhosis) and day 20 (inactive cirrhosis). Portal venous pressure in vivo was significantly higher on day 5 compared with day 20 (15.7 + 0.7 vs 11.2 _+0.6 mmHg, p<0.01), as was myofibroblast density determined by immunohistochemical staining of liver sections (5.7 -+ 1.2 vs 0.77 -+ 0.07 cells/104 ~tm2, p<0.001). The fall in perfusion resistance of IPRL induced by SNP was significantly greater at day 5 than day 20 (0.28 _+ 0.10 vs 0.10 + 0.02 mmHg. m1-1.min.g, p<0.05). Pressure-conductance curves were linear (p<0.001) at flow rates below 2 ml.min-l.g -I with a gradient C, but then approached a limiting conductance Gmax. The magnitude of C, was not significantly different on day 5 and 20, but was lower (p<0.01) than the value for normal controls (0.088 + 0.018. 0.127 + 0.020, and 0.23 + 0.02 ml. min'l.g-l.mmHg-I, respectively), as was the case for Gmax (0.97 + 0.11, and 0.93 + 0.07 vs 1.67 + 0.15 mhmin-l.g-l.mmHg -l, p<0.005). The results confirm that intrahepatic portal haemodynamics differ in active and inactive cirrhosis. The increased resistance in inactive cirrhosis appears to be due mainly to mechanical vascular obstruction, while higher pressures are required to fully recruit or distend the portal vascular bed in active cirrhosis due to an increase in vasomotor tone and to reduced vascular compliance.
F4-4 INTESTINAL HEMODYNAMICS IN PORTAL HYPERTENSION Takashi Joh and Makoto Itoh 1st Dept of Internal Med, Nagoya City Univ, Nagya 467, Japan It is well recognized that vascular sensitivity and vascular tone were reduced in portal hypertension. In this study, vascular responsiveness to norepinephrine (NE) and endogenous vasoconstrictor tone were assessed in each level of portal hypertensive intestinal microcirculation. Methods:The intestine of normal and prehepatic portal hypertensive rats were prepared for in vi~-omicroscopic observation 'and 1st, 2nd or 3rd order arteriole (IA, 2A, 3A) was selected for study. Diameter and red cell velocity were continuously monitored and used to calculate blued flow. Once baseline blood flow was obtained, the preparation was exposed to several concentrations of NE for dose-response curve, and antagonists against vasopressin (VP), angiotensin It (AII) or ad-renergic receptors ( a ). Results: Diameter Response to NE (ED50: ~LM) IA 2A 3A C 2.52_+0.24 2.75_+0.41 2.52_+0.23 P 2.99_+0.49 4.53_+0.62* 4.14_+0.56" receptor %Increase in Diameter blocked IA 2A 3A VAA C 8.73 ± 1.98 4.68 _+ 1.68 1.48 ± 1.24 P 5.10_+ 1.32 3.52±0.62 4.84_+ 1.01" AII C 0.02_+ 0.74 0.57-t- 1.59 5.36-+ 1.45 P 3.75±1.39" 2.77--+1.05 6.63-+2.18 a C 1.28_+0.88 1.52± 1.45 14.7-+4.79 P 1.03-+0.75 1.01-+0.75 2.33±0.69* C: Control, P: Portal hypertension, mean-+SE *p<0.05 vs control Conclusions: 1. Intestinal microvascular responsiveness to NE was reduced in portal hypertension, which was mainly due to abnormalities in terminal arterioles. 2. Major changes in vasoregulatorycontrol occur in portal hypertensive intestinal microcirculation. 3. These changes may partly explain hemodynamic abnormalities in portal hypertension.
F4-3
A STUDY OF PORTAL AND GASTRIC MUCOSAL HEMODYNAMICS IN CIRRHOTIC PATIENTS WITH PORTAL-HYPERTENSIVE GASTROPATHY H. Hashizume, M. Ohta, H. Kawanaka, F. Kishihara, M. Tomikawa, K. Tanoue, H. Higashi, K. Sugimachi Dept. of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan To investigate portal hemodynamics and gastric mucosal perfusion in cirrhotic patients with portal-hypertensive gastropathy, 56 cirrhotic patients with portal hypertension were studied by using portal vein catheterization, pneumatic pressure sensor technique, duplex sonography and laser Doppler flowmetry. Thirteen patients had portal-hypertensive gastropathy. The presence of portal-hypertensive gastropathy seemed to be independent of age, sex, cause of cirrhosis or grade be esophageal varices. Portal venous pressure, esophageal variceal pressure, portal venous flow and congestion index in patients with portal-hypertensive gastropathy were not significantly different from the values in those without portal-hypertensive gastropathy. However, portal-variceal pressure gradient (subtracting esophageal variceal pressure from portal venous pressure) (p<0.0 I) and the incidence of palisading-type esophageal varices on portography (p<0.05) was increased in patients with portal-hypertensive gastropathy significantly more than in those without portal-hypertensive gastropathy. In the fundus, gastric macosal blood flow was significantly higher in patients with portal-hypertensive gastropathy than in those without portal hypertensive gastropathy, whereas in the corpus and the antrum the values were not significantlydifferent. We concluded that the mucosa of the upper stomach in patients with portal-hypertensive gasthopathy is congestive and highly perfused. The pathogenesis of portal-hypertensive gastropathy may be related to both congestion and hyperemia in the upper stomach.
F4-5
GASTRIC MICROCIRCULATORY CHANGES IN PORTAL HYPERTENSION, PATHOPHYSIOLOGICAL RATIONALE FOR CLINICAL TREATMENT. Josep M. Piqu6. Gastroenterology Department, Hospital, Clfnic, University of Barcelona.
Po~al hypertension induces morphological and functional changes in gastric microcirculation. Capillary and vein dilatation occur in gastric mueosa and submucosa as a consequence of venous outflow obstruction but also promoted by the increased blood flow, as a pan of a generalized splanchnic hyperdynamic circulatory syndrome. The mechanisms involved in that increment of gastric blood flow are not well known, but endothelial vasoactive factors such as prostaglandin and nitric oxide have been implicated. Acute or chronic diffuse bleeding is a common clinical complication of gastric vascular disturbances in patients with portal hypertension. Hemorrhage arises from a mucosa without any significant inflammatory or erosive lesion and probably related with disruption of the tense capillary wall. Therefore, drugs reducing blood perfusion in the gastric mucosa seems theoretically the most appropriate pharmacological intervention to prevent such complication. In that regard, propranolol, a beta-blocker which reduces both portal pressure and gastric blood flow, has been demonstrated to be useful in preventing rebleeding from portal hypertensive gastropathy in cirrhotic patients. Estrogen-progestagcn treatment, an hormonal combination which also reduces portal pressure and gastric blood flow, could be an alternative therapy to propranolol. In addition, somatostatin, glypressin or vasopressin, because of their effects reducing gastric blood flow, might be useful drags treating over bleeding from portal hypertensive gastropathy.
Clinical and Research Forum/International Hepatology Communications 3 Suppl. (1995) $5-$36
F4-2
INTRAHEPATIC HAEMODYNAMICS IN PORTAL HYPERTENSION Grossman VL, Grossman HJ and Bhathal PS. Pathology Department, The University of Melbourne, Parkville, VIC, 3052, Australia. During the development of cirrhosis, an increased resistance to portal flow develops which has been attributed to mechanical vascular obstruction and to active vasoconstriction. Experimental cvidcncc presented here cnfirms that the relative contribution of active vasoconstriction varies with the activity of the underlying liver disease. In a study of the intrahepatic portal vascular bed in carbon tetrachlnridc (CCl4)-induced cirrhosis in the rat, cirrhnsis was induced with 10 consecutive oral doses of CCI4. Treatment was then stopped and responses to the vasodilator agent sodium nitroprusside (SNP, Ixl0"3M) and pressure-flow curves were compared in isolated perfuscd rat hvor preparations (IPRL) on day 5 (active cirrhosis) and day 20 (inactive cirrhosis). Portal venous pressure in vivo was significantly higher on day 5 compared with day 20 (15.7 + 0.7 vs 11.2 _+0.6 mmHg, p<0.01), as was myofibroblast density determined by immunohistochemical staining of liver sections (5.7 -+ 1.2 vs 0.77 -+ 0.07 cells/104 ~tm2, p<0.001). The fall in perfusion resistance of IPRL induced by SNP was significantly greater at day 5 than day 20 (0.28 _+ 0.10 vs 0.10 + 0.02 mmHg. m1-1.min.g, p<0.05). Pressure-conductance curves were linear (p<0.001) at flow rates below 2 ml.min-l.g -I with a gradient C, but then approached a limiting conductance Gmax. The magnitude of C, was not significantly different on day 5 and 20, but was lower (p<0.01) than the value for normal controls (0.088 + 0.018. 0.127 + 0.020, and 0.23 + 0.02 ml. min'l.g-l.mmHg-I, respectively), as was the case for Gmax (0.97 + 0.11, and 0.93 + 0.07 vs 1.67 + 0.15 mhmin-l.g-l.mmHg -l, p<0.005). The results confirm that intrahepatic portal haemodynamics differ in active and inactive cirrhosis. The increased resistance in inactive cirrhosis appears to be due mainly to mechanical vascular obstruction, while higher pressures are required to fully recruit or distend the portal vascular bed in active cirrhosis due to an increase in vasomotor tone and to reduced vascular compliance.
F4-4 INTESTINAL HEMODYNAMICS IN PORTAL HYPERTENSION Takashi Joh and Makoto Itoh 1st Dept of Internal Med, Nagoya City Univ, Nagya 467, Japan It is well recognized that vascular sensitivity and vascular tone were reduced in portal hypertension. In this study, vascular responsiveness to norepinephrine (NE) and endogenous vasoconstrictor tone were assessed in each level of portal hypertensive intestinal microcirculation. Methods:The intestine of normal and prehepatic portal hypertensive rats were prepared for in vi~-omicroscopic observation 'and 1st, 2nd or 3rd order arteriole (IA, 2A, 3A) was selected for study. Diameter and red cell velocity were continuously monitored and used to calculate blued flow. Once baseline blood flow was obtained, the preparation was exposed to several concentrations of NE for dose-response curve, and antagonists against vasopressin (VP), angiotensin It (AII) or ad-renergic receptors ( a ). Results: Diameter Response to NE (ED50: ~LM) IA 2A 3A C 2.52_+0.24 2.75_+0.41 2.52_+0.23 P 2.99_+0.49 4.53_+0.62* 4.14_+0.56" receptor %Increase in Diameter blocked IA 2A 3A VAA C 8.73 ± 1.98 4.68 _+ 1.68 1.48 ± 1.24 P 5.10_+ 1.32 3.52±0.62 4.84_+ 1.01" AII C 0.02_+ 0.74 0.57-t- 1.59 5.36-+ 1.45 P 3.75±1.39" 2.77--+1.05 6.63-+2.18 a C 1.28_+0.88 1.52± 1.45 14.7-+4.79 P 1.03-+0.75 1.01-+0.75 2.33±0.69* C: Control, P: Portal hypertension, mean-+SE *p<0.05 vs control Conclusions: 1. Intestinal microvascular responsiveness to NE was reduced in portal hypertension, which was mainly due to abnormalities in terminal arterioles. 2. Major changes in vasoregulatorycontrol occur in portal hypertensive intestinal microcirculation. 3. These changes may partly explain hemodynamic abnormalities in portal hypertension.
F4-3
A STUDY OF PORTAL AND GASTRIC MUCOSAL HEMODYNAMICS IN CIRRHOTIC PATIENTS WITH PORTAL-HYPERTENSIVE GASTROPATHY H. Hashizume, M. Ohta, H. Kawanaka, F. Kishihara, M. Tomikawa, K. Tanoue, H. Higashi, K. Sugimachi Dept. of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan To investigate portal hemodynamics and gastric mucosal perfusion in cirrhotic patients with portal-hypertensive gastropathy, 56 cirrhotic patients with portal hypertension were studied by using portal vein catheterization, pneumatic pressure sensor technique, duplex sonography and laser Doppler flowmetry. Thirteen patients had portal-hypertensive gastropathy. The presence of portal-hypertensive gastropathy seemed to be independent of age, sex, cause of cirrhosis or grade be esophageal varices. Portal venous pressure, esophageal variceal pressure, portal venous flow and congestion index in patients with portal-hypertensive gastropathy were not significantly different from the values in those without portal-hypertensive gastropathy. However, portal-variceal pressure gradient (subtracting esophageal variceal pressure from portal venous pressure) (p<0.0 I) and the incidence of palisading-type esophageal varices on portography (p<0.05) was increased in patients with portal-hypertensive gastropathy significantly more than in those without portal-hypertensive gastropathy. In the fundus, gastric macosal blood flow was significantly higher in patients with portal-hypertensive gastropathy than in those without portal hypertensive gastropathy, whereas in the corpus and the antrum the values were not significantlydifferent. We concluded that the mucosa of the upper stomach in patients with portal-hypertensive gasthopathy is congestive and highly perfused. The pathogenesis of portal-hypertensive gastropathy may be related to both congestion and hyperemia in the upper stomach.
F4-5
GASTRIC MICROCIRCULATORY CHANGES IN PORTAL HYPERTENSION, PATHOPHYSIOLOGICAL RATIONALE FOR CLINICAL TREATMENT. Josep M. Piqu6. Gastroenterology Department, Hospital, Clfnic, University of Barcelona.
Po~al hypertension induces morphological and functional changes in gastric microcirculation. Capillary and vein dilatation occur in gastric mueosa and submucosa as a consequence of venous outflow obstruction but also promoted by the increased blood flow, as a pan of a generalized splanchnic hyperdynamic circulatory syndrome. The mechanisms involved in that increment of gastric blood flow are not well known, but endothelial vasoactive factors such as prostaglandin and nitric oxide have been implicated. Acute or chronic diffuse bleeding is a common clinical complication of gastric vascular disturbances in patients with portal hypertension. Hemorrhage arises from a mucosa without any significant inflammatory or erosive lesion and probably related with disruption of the tense capillary wall. Therefore, drugs reducing blood perfusion in the gastric mucosa seems theoretically the most appropriate pharmacological intervention to prevent such complication. In that regard, propranolol, a beta-blocker which reduces both portal pressure and gastric blood flow, has been demonstrated to be useful in preventing rebleeding from portal hypertensive gastropathy in cirrhotic patients. Estrogen-progestagcn treatment, an hormonal combination which also reduces portal pressure and gastric blood flow, could be an alternative therapy to propranolol. In addition, somatostatin, glypressin or vasopressin, because of their effects reducing gastric blood flow, might be useful drags treating over bleeding from portal hypertensive gastropathy.