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188 Reduced baroreceptor reflex sensitivity in cirrhosis. Relations to central haemodynamics and humoral systems
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mesenteric diameter and superior mesenteric artery flow and changed cardiac output of BDL rats. AM630 had no effect on measured cardiovascular markers of both sham and BDL animals. Capsa~zepine administration decreased mesenteric arteriole diameter, cardiac output and superior mesenteric artery flow and increased systemic vascular resistance in BDL rats without any effect in control animals. Expression of CB1 and VR1 receptors was increased in superior mesenteric artery of cirrhotic rats while there was no difference between expression of CB2 receptors in sham and BDL rats. Conclusions: Differential effects of AM251 and capsa~zepine on hemodynamics of BDL rats suggests a possible role of endocannabinoids in the mesenteric circulatory disturbances in cirrhotic rats. The AM251 and capsazepine data suggest a CB1- or VRl-mediated mechanism for this phenomenon.
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DECREASED PULMONARY BLOOD VOLUME AND TRANSIT TIME IN CIRRHOSIS. RELATION TO LUNG FUNCTION
S. Moiler 1, H. Burchardt 3'5, C. Ogard 2, F. Schioedt 4, J.O. Lund 3. 1Dept.
Clinical Physiology, Hvidovre Hospital, Hvidovre, Denmark," 2Dept. Clinical Physiology, Herlev Hospital, Herlev, Denmark," 3Dept. Clinical Physiology, Gentofte Hospital, Gentofie, Denmark," 4Dept. Medical Gastroenterology, Herlev Hospital, Herlev, Denmark," 5Dept. Medical Gastroenterology, Gentofie Hospital, Gentofte, Denmark Introduction: In addition to portal hypertension, patients with cirrhosis
exhibit characteristic changes in their systemic haemodynamics with a hyperdynamic circulation. A systemic vasodilatation leads to an abnormal distribution of the blood volume with a contracted central blood volume i.e. the blood volume in the lungs, heart, and central arterial tree and increased peripheral blood volumes. In addition, the patients have a ventilation/perfusion imbalance and low diffusing capacity leading to a hepatopulmonary syndrome in some patients. Aim: As the size of the blood volume of the lungs has not previously been determined separately and it seems to be involved in the pulmonary dysfunction in cirrhosis, we assessed the pulmonary blood volume (PBV) and pulmonary transit time (PTT) and cardiac volumes in relation to lung function in patients with cirrhosis and in controls. Patients and Methods: Pulmonary and cardiac haemodynamics and transit times were determined by radionuclide techniques in 22 patients with alcoholic cirrhosis and in 12 controls matched for gender and age. The lung function including diffusing capacity for monoxide (DL, CO) was determined by conventional single breath technique. Results: The cirrhotic patients had lower arterial blood pressure and higher heart rate than the controls (p <0.05). In the cirrhotic patients, the PTT was shorter (mean• 3.9• vs 5.7• 0.3 s in the controls, p < 0.001, and the PBV was lower, 362• vs 587• mL, in the controls p < 0.005. DL, CO was significantly reduced in the patients and correlated significantly with PTT (r 0.58, p 0.007), PBV (r 0.49, p <0.03), and total blood volume (r 0.43, p < 0.05). Conclusion: The present results suggest a relation between the reduced PBV and PTT on the one hand and the abnormal diffusing capacity in cirrhosis on the other. This is in agreement with a general reduced central vascular compartment and ventilation/perfusion abnormalities as an important element in the pathophysiology of the lung dysfunction in cirrhosis.
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R E D U C E D B A R O R E C E P T O R REFLEX SENSITIVITY IN CIRRHOSIS. RELATIONS TO C E N T R A L H A E M O D Y N A M I C S AND HUMORAL SYSTEMS
S. Moller 1, J.S. Iversen2, J.H. Henriksen 1, F. Bendtsen2. 1Department of
Clinical Physiology, 2Department of Medical Gastroenterology, Hvidovre Hospital, Denmark In cirrhosis, arterial vasodilatation leads to central hypovolaemia and activation of sympathetic nervous (SNS) and renin angiotensin~ldosterone systems (RAAS) with the development of a hyperdynamic circulation. In addition, an autonomic dysfunction with impaired baroreceptor reflex sensitivity (BRS) has been suggested, but BRS in cirrhosis has only been sparsely studied. Aim: We therefore assessed BRS in a large group of patients with cirrhosis with various liver dysfunction and in controls supine during catheterisation and after passive tilting in relation to central haemodynamics, oxygenation, and activity of the SNS and RAAS. Patients and Methods: In 105 patients (Child class A/B/C: 21/55/29) and 14 controls, BRS was assessed by cross-spectral analysis of variabilities between 5 min recordings of the intra-arterial blood pressure and ECGderived HR time series. All measurements were performed supine. In a subset of 23 patients, BRS, haemodynamics and the activity of SNS and RAAS was additionally assessed after 60 ~ passive head-up tilting. Results: Median BRS was significantly lower in the cirrhotic patients, 3.7 (0.3 30.7) ms/mmHg than in the controls, 6.7 (0.9 31.4), p <0.03 and it correlated with the severity of liver disease, CCT, and ventilation (p < 0.04 0.008). At baseline, BRS in the patients correlated with serum renin activity (r 0.60, p 0.007) and serum aldosterone (r 0.45, p 0.05). A multivariate regression analysis revealed that BRS was determined by serum sodium (p 0.044), heart rate (p 0.027), and central circulation time (p 0.034). After head-up tilting, BRS decreased in the patients to values not dill'erent from the controls (ns) and the short CCT increased after head-up tilting by 30% in only the cirrhotic patients (p <0.001). Conclusion: In cirrhosis, the BRS is reduced in the supine position relating to various aspects of liver dysfunction, the hyperdynamic circulating, and cardiac dysfunction but it normalises in parallel with the amelioration of the hyperdynamic circulation after head-up tilting. The BRS is moreover related to the activated RAAS and impaired cardiac performance reflected by the short CCT which may contribute to the impaired baroreflex function. The results indicate that compensatory mechanisms to vasodilatation and a possible cirrhotic cardiomyopathy may be involved in the low BRS in cirrhosis.
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HEPATIC I N F L A M M A T I O N I N C R E A S E S PORTAL P R E S S U R E T H R O U G H INHIBITION OF e N O S ACTIVITY POTENTIAL M E C H A N I S M S
R.R Mookerjee 1, N.A. Davies 1, S.J. Hodges 1, R.N. Dalton 2, C. Turnel2, A. Wiesenthal 3, K. Schilling 3, A. Icking 3, S. Sen 1, R. Williams 1, W. Muller-Esterl 3, R. Jalan 1. 1Liver Failure Group, Institute of
Hepatology, University College London, UK," 2Wellehild Laboratory, Guys Hospital Medical School, Kings' College, London, UK,"SInstitutefor Biochemistry II, University Hospital, Frankfitrt, Germany Background: Previously we have described an acute and sustained reduction of portal pressure in alcoholic hepatitis (AH) patients following antiTNF a antibody therapy. Animal data suggests inflammation can modulate eNOS activity by reducing the hepatic metabolism of an endogenous inhibitor, ADMA. Aims: (1) To demonstrate reduced eNOS activity in AH compared to cirrhosis alone. (2) To assess hepatic tissue ADMA, and NOSTRIN (NOS traffic-inducing protein) and Caveolin-1 (other mediators believed to modulate eNOS activity).
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mesenteric diameter and superior mesenteric artery flow and changed cardiac output of BDL rats. AM630 had no effect on measured cardiovascular markers of both sham and BDL animals. Capsa~zepine administration decreased mesenteric arteriole diameter, cardiac output and superior mesenteric artery flow and increased systemic vascular resistance in BDL rats without any effect in control animals. Expression of CB1 and VR1 receptors was increased in superior mesenteric artery of cirrhotic rats while there was no difference between expression of CB2 receptors in sham and BDL rats. Conclusions: Differential effects of AM251 and capsa~zepine on hemodynamics of BDL rats suggests a possible role of endocannabinoids in the mesenteric circulatory disturbances in cirrhotic rats. The AM251 and capsazepine data suggest a CB1- or VRl-mediated mechanism for this phenomenon.
I•
DECREASED PULMONARY BLOOD VOLUME AND TRANSIT TIME IN CIRRHOSIS. RELATION TO LUNG FUNCTION
S. Moiler 1, H. Burchardt 3'5, C. Ogard 2, F. Schioedt 4, J.O. Lund 3. 1Dept.
Clinical Physiology, Hvidovre Hospital, Hvidovre, Denmark," 2Dept. Clinical Physiology, Herlev Hospital, Herlev, Denmark," 3Dept. Clinical Physiology, Gentofte Hospital, Gentofie, Denmark," 4Dept. Medical Gastroenterology, Herlev Hospital, Herlev, Denmark," 5Dept. Medical Gastroenterology, Gentofie Hospital, Gentofte, Denmark Introduction: In addition to portal hypertension, patients with cirrhosis
exhibit characteristic changes in their systemic haemodynamics with a hyperdynamic circulation. A systemic vasodilatation leads to an abnormal distribution of the blood volume with a contracted central blood volume i.e. the blood volume in the lungs, heart, and central arterial tree and increased peripheral blood volumes. In addition, the patients have a ventilation/perfusion imbalance and low diffusing capacity leading to a hepatopulmonary syndrome in some patients. Aim: As the size of the blood volume of the lungs has not previously been determined separately and it seems to be involved in the pulmonary dysfunction in cirrhosis, we assessed the pulmonary blood volume (PBV) and pulmonary transit time (PTT) and cardiac volumes in relation to lung function in patients with cirrhosis and in controls. Patients and Methods: Pulmonary and cardiac haemodynamics and transit times were determined by radionuclide techniques in 22 patients with alcoholic cirrhosis and in 12 controls matched for gender and age. The lung function including diffusing capacity for monoxide (DL, CO) was determined by conventional single breath technique. Results: The cirrhotic patients had lower arterial blood pressure and higher heart rate than the controls (p <0.05). In the cirrhotic patients, the PTT was shorter (mean• 3.9• vs 5.7• 0.3 s in the controls, p < 0.001, and the PBV was lower, 362• vs 587• mL, in the controls p < 0.005. DL, CO was significantly reduced in the patients and correlated significantly with PTT (r 0.58, p 0.007), PBV (r 0.49, p <0.03), and total blood volume (r 0.43, p < 0.05). Conclusion: The present results suggest a relation between the reduced PBV and PTT on the one hand and the abnormal diffusing capacity in cirrhosis on the other. This is in agreement with a general reduced central vascular compartment and ventilation/perfusion abnormalities as an important element in the pathophysiology of the lung dysfunction in cirrhosis.
•
R E D U C E D B A R O R E C E P T O R REFLEX SENSITIVITY IN CIRRHOSIS. RELATIONS TO C E N T R A L H A E M O D Y N A M I C S AND HUMORAL SYSTEMS
S. Moller 1, J.S. Iversen2, J.H. Henriksen 1, F. Bendtsen2. 1Department of
Clinical Physiology, 2Department of Medical Gastroenterology, Hvidovre Hospital, Denmark In cirrhosis, arterial vasodilatation leads to central hypovolaemia and activation of sympathetic nervous (SNS) and renin angiotensin~ldosterone systems (RAAS) with the development of a hyperdynamic circulation. In addition, an autonomic dysfunction with impaired baroreceptor reflex sensitivity (BRS) has been suggested, but BRS in cirrhosis has only been sparsely studied. Aim: We therefore assessed BRS in a large group of patients with cirrhosis with various liver dysfunction and in controls supine during catheterisation and after passive tilting in relation to central haemodynamics, oxygenation, and activity of the SNS and RAAS. Patients and Methods: In 105 patients (Child class A/B/C: 21/55/29) and 14 controls, BRS was assessed by cross-spectral analysis of variabilities between 5 min recordings of the intra-arterial blood pressure and ECGderived HR time series. All measurements were performed supine. In a subset of 23 patients, BRS, haemodynamics and the activity of SNS and RAAS was additionally assessed after 60 ~ passive head-up tilting. Results: Median BRS was significantly lower in the cirrhotic patients, 3.7 (0.3 30.7) ms/mmHg than in the controls, 6.7 (0.9 31.4), p <0.03 and it correlated with the severity of liver disease, CCT, and ventilation (p < 0.04 0.008). At baseline, BRS in the patients correlated with serum renin activity (r 0.60, p 0.007) and serum aldosterone (r 0.45, p 0.05). A multivariate regression analysis revealed that BRS was determined by serum sodium (p 0.044), heart rate (p 0.027), and central circulation time (p 0.034). After head-up tilting, BRS decreased in the patients to values not dill'erent from the controls (ns) and the short CCT increased after head-up tilting by 30% in only the cirrhotic patients (p <0.001). Conclusion: In cirrhosis, the BRS is reduced in the supine position relating to various aspects of liver dysfunction, the hyperdynamic circulating, and cardiac dysfunction but it normalises in parallel with the amelioration of the hyperdynamic circulation after head-up tilting. The BRS is moreover related to the activated RAAS and impaired cardiac performance reflected by the short CCT which may contribute to the impaired baroreflex function. The results indicate that compensatory mechanisms to vasodilatation and a possible cirrhotic cardiomyopathy may be involved in the low BRS in cirrhosis.
•
HEPATIC I N F L A M M A T I O N I N C R E A S E S PORTAL P R E S S U R E T H R O U G H INHIBITION OF e N O S ACTIVITY POTENTIAL M E C H A N I S M S
R.R Mookerjee 1, N.A. Davies 1, S.J. Hodges 1, R.N. Dalton 2, C. Turnel2, A. Wiesenthal 3, K. Schilling 3, A. Icking 3, S. Sen 1, R. Williams 1, W. Muller-Esterl 3, R. Jalan 1. 1Liver Failure Group, Institute of
Hepatology, University College London, UK," 2Wellehild Laboratory, Guys Hospital Medical School, Kings' College, London, UK,"SInstitutefor Biochemistry II, University Hospital, Frankfitrt, Germany Background: Previously we have described an acute and sustained reduction of portal pressure in alcoholic hepatitis (AH) patients following antiTNF a antibody therapy. Animal data suggests inflammation can modulate eNOS activity by reducing the hepatic metabolism of an endogenous inhibitor, ADMA. Aims: (1) To demonstrate reduced eNOS activity in AH compared to cirrhosis alone. (2) To assess hepatic tissue ADMA, and NOSTRIN (NOS traffic-inducing protein) and Caveolin-1 (other mediators believed to modulate eNOS activity).