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1.
Kidney Int ; 57(4): 1346-51, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10760065

ABSTRACT

An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1. 9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2. 5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.


Subject(s)
Aldosterone/physiology , Myocardium/metabolism , Ventricular Remodeling/physiology , Aldosterone/biosynthesis , Animals , Fibrosis , Humans , Myocardial Infarction/physiopathology , Myocardium/pathology
2.
Hepatology ; 28(3): 655-9, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9731554

ABSTRACT

In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET(A) and ET(B) endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 microg/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 +/- 1.2 to 12.1 +/- 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 +/- 19 to 101 +/- 9 dyn x s x cm(-5) x 10(-3). Similar results were observed in rats with CCl4-induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 micromol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 +/- 0.6 to 11.4 +/- 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension.


Subject(s)
Antihypertensive Agents/therapeutic use , Endothelin Receptor Antagonists , Hemodynamics/drug effects , Hypertension, Portal/drug therapy , Sulfonamides/therapeutic use , Animals , Bosentan , Endothelin-1/pharmacology , Hypertension, Portal/physiopathology , Liver Cirrhosis, Experimental/drug therapy , Male , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A , Receptor, Endothelin B , Sulfonamides/pharmacology
3.
J Gastroenterol Hepatol ; 13(12): 1254-8, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9918435

ABSTRACT

A substance which increases the entry of extracellular calcium into arterial smooth muscle may decrease cirrhosis-induced vasodilation. The aim of the present study was to measure the effects of the L-type Ca2+ channel activator, Bay K 8644, on the haemodynamics of rats with cirrhosis. Vascular reactivity to this substance was also investigated. Splanchnic and systemic haemodynamic responses to Bay K 8644 (50 microg/kg) were measured in cirrhotic and normal rats. Contraction induced by 0.1 micromol/L Bay K 8644 was measured in arterial rings (aorta and superior mesenteric artery) from cirrhotic and normal rats. In cirrhotic rats, Bay K 8644 significantly decreased portal pressure (15%) and portal tributary blood flow (24%), significantly increased portal territory vascular resistance (54%) and did not significantly change hepatocollateral vascular resistance. Bay K 8644 significantly increased arterial pressure (7%) and systemic vascular resistance (24%) and did not change the cardiac index. In normal rats, Bay K 8644 significantly increased vascular resistance (150%) in portal, hepatocollateral and systemic territories and significantly decreased the cardiac index (44%). Changes in portal territory, hepatocollateral and systemic vascular resistances were significantly less marked in cirrhotic than in normal rats. In rings from the aorta and superior mesenteric artery, Bay K 8644-induced contraction was significantly lower in cirrhotic than in normal rats. In conclusion, in rats with cirrhosis, Bay K 8644 administration reduced vasodilation in splanchnic and systemic arteries and did not affect hepatocollateral vascular resistance. The Bay K 8644-induced reduction in splanchnic vasodilation caused a decrease in portal hypertension. This study also shows that Bay K 8644-induced vascular contraction was less marked in cirrhotic than in normal rats, in systemic and splanchnic vascular beds.


Subject(s)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Aorta/drug effects , Calcium Channel Agonists/pharmacology , Calcium Channels/metabolism , Liver Cirrhosis, Experimental/metabolism , Animals , Aorta/metabolism , Aorta/physiopathology , Calcium/metabolism , Calcium Channels/drug effects , Calcium Channels, L-Type , Hemodynamics/drug effects , In Vitro Techniques , Liver Cirrhosis, Experimental/physiopathology , Male , Mesenteric Artery, Superior/drug effects , Mesenteric Artery, Superior/metabolism , Mesenteric Artery, Superior/physiopathology , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiopathology , Portal Pressure/drug effects , Rats , Rats, Sprague-Dawley
4.
Br J Anaesth ; 81(6): 968-9, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10211029

ABSTRACT

Isoflurane is known to dilate blood vessels and to modulate nitric oxide production. Because cirrhosis is characterized by over production of endothelial nitric oxide, isoflurane-induced vasodilatation may be altered in this situation. We have compared the vasodilator effects of isoflurane in normal rats and rats with secondary biliary cirrhosis. Aortic rings (intact or endothelium denuded) from normal and cirrhotic rats were suspended in HEPES solution and preconstricted with KCl 40 mmol litre-1. Isoflurane dose-dependently relaxed vessels in both groups. Maximal relaxation was comparable between normal and cirrhotic rats in intact (mean 80 (SEM 4) vs 81 (6)%; ns) and in denuded (100 (4) vs 95 (5)%; ns) vessels. Intact vessels relaxed more than denuded vessels in both groups (100 (4) vs 80 (4)% (P = 0.0008) in normal rats and 95 (5) vs 80 (6)% (P = 0.0008) in cirrhotic rats). We conclude that cirrhosis did not modify isoflurane-induced vasodilatation and that the modulator effect of endothelium was conserved.


Subject(s)
Anesthetics, Inhalation/pharmacology , Isoflurane/pharmacology , Liver Cirrhosis, Experimental/physiopathology , Vasodilation/drug effects , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiopathology , Culture Techniques , Dose-Response Relationship, Drug , Male , Rats , Rats, Sprague-Dawley
5.
Aliment Pharmacol Ther ; 11(5): 993-7, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9354212

ABSTRACT

BACKGROUND: An enhancement of the haemodynamic effects of terlipressin by octreotide (and vice versa) may be useful in the treatment of portal hypertension. The aim of this study was to investigate the short-term effects of terlipressin, octreotide or a combination of these substances on splanchnic and systemic haemodynamics in rats with portal vein stenosis. METHODS: Eight rats received an intravenous (i.v.) infusion of isotonic saline (10 microL/min for 15 min). Eight rats received terlipressin first (0.05 mg/kg) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min) 15 min later. Eight other rats first received an i.v. infusion of octreotide and then terlipressin 15 min later. Splanchnic and systemic haemodynamics (radioactive microsphere method) were measured after saline, after terlipressin or octreotide alone, and after the combined treatments. RESULTS: Terlipressin and octreotide alone significantly decreased portal pressure, portal tributary blood flow and cardiac index. Terlipressin, but not octreotide, significantly increased heptocollateral vascular resistance and arterial pressure. Octreotide administration in rats pre-treated with terlipressin did not change portal pressure, caused portal tributary blood flow to increase and decreased hepatocollateral vascular resistance; it also decreased arterial pressure but not cardiac index. Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure, portal tributary blood flow and increased hepatocollateral vascular resistance; terlipressin increased arterial pressure and further decreased cardiac index. CONCLUSIONS: In rats with portal vein stenosis, octreotide decreased short-term splanchnic and systemic vasoconstriction due to terlipressin. In contrast, terlipressin enhanced the splanchnic and systemic vasoconstriction due to octreotide. Thus, the haemodynamic responses to the combination of octreotide and terlipressin depend on the order of administration of these substances.


Subject(s)
Antihypertensive Agents/therapeutic use , Hemodynamics/drug effects , Hormones/therapeutic use , Hypertension, Portal/drug therapy , Lypressin/analogs & derivatives , Octreotide/therapeutic use , Animals , Drug Interactions , Drug Therapy, Combination , Lypressin/therapeutic use , Male , Rats , Rats, Sprague-Dawley , Splanchnic Circulation/drug effects , Terlipressin
6.
Aliment Pharmacol Ther ; 11(4): 775-9, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9305488

ABSTRACT

BACKGROUND: The aim of this study was to investigate short-term effects of propranolol (a non-selective beta-adrenergic antagonist), octreotide (a long-acting somatostatin analogue), or a combination of these substances on splanchnic and systemic haemodynamics and arterial blood gases in rats with portal vein stenosis. METHODS: Splanchnic and systemic haemodynamics were measured using the radioactive microspheres method. Eight rats first received an i.v. infusion of isotonic saline (10 microL/min for 15 min) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min). Eight other rats first received a bolus i.v. injection of propranolol (2 mg) and an i.v. infusion of octreotide 15 min later. RESULTS: Propranolol or octreotide alone significantly decreased portal pressure (both by 23%), portal tributary blood flow (35 and 10%, respectively) and cardiac index (36 and 26%, respectively). Octreotide administration in rats pretreated with propranolol significantly decreased cardiac index but did not change portal and arterial pressures or portal tributary blood flow. Propranolol significantly increased arterial oxygen tension. Octreotide alone or combined with propranolol significantly decreased oxyhaemoglobin saturation and pH and increased carbon dioxide tension. CONCLUSIONS: In rats with portal vein stenosis, the somatostatin analogue, octreotide, accentuates the short-term decrease in cardiac index due to propranolol. In addition, octreotide altered arterial blood gases and acid-base status. In contrast, octreotide does not further decrease portal pressure in animals receiving propranolol.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Hemodynamics/drug effects , Hormones/pharmacology , Hypertension, Portal/physiopathology , Octreotide/pharmacology , Propranolol/pharmacology , Splanchnic Circulation/drug effects , Animals , Blood Pressure/drug effects , Drug Interactions , Heart Rate/drug effects , Male , Rats , Rats, Sprague-Dawley
7.
J Hepatol ; 26(6): 1229-34, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9210608

ABSTRACT

BACKGROUND/AIMS: Refractory ascites, which occurs in certain patients with cirrhosis, is associated with a blunted natriuretic response to exogenous atrial natriuretic peptide (ANP). Since this blunting seems to be related to ANP-induced arterial hypotension, a vasoconstrictor, such as terlipressin (a vasopressin analogue), may restore natriuresis to exogenous ANP. Moreover, since cirrhosis-elicited vasodilation is thought to play a role in sodium retention, a vasoconstriction caused by terlipressin alone may lead to an increase in sodium excretion. This study aimed to evaluate the natriuretic response to either a combination of ANP with terlipressin or terlipressin alone in patients with cirrhosis and refractory ascites. METHODS: Sixteen consecutive patients with cirrhosis and refractory ascites were randomly assigned to receive either a combination of terlipressin (1-2 mg, i.v. bolus) with ANP (35 ng/kg, i.v. bolus followed by 15 ng x kg(-1) x min(-1) for 60 min) (n=8) or terlipressin alone (1-2 mg, i.v. bolus) (n=8). Sodium excretion and urine output, systemic, splanchnic and renal hemodynamics and renal oxygen consumption were measured before and during treatments. RESULTS: Combined therapy did not change arterial pressure but significantly increased urinary sodium excretion and urine output. These effects were associated with a significant increase in glomerular filtration rate and a decrease in renal oxygen consumption. Terlipressin alone significantly increased arterial pressure but did not change urinary sodium excretion or urine output. Moreover, terlipressin did not change either glomerular filtration rate or renal oxygen consumption. CONCLUSIONS: The combination of exogenous ANP with terlipressin, but not terlipressin alone, increases sodium excretion in patients with cirrhosis and refractory ascites.


Subject(s)
Antihypertensive Agents/therapeutic use , Ascites/drug therapy , Atrial Natriuretic Factor/therapeutic use , Liver Cirrhosis, Alcoholic/drug therapy , Lypressin/analogs & derivatives , Natriuresis , Renal Circulation/physiology , Splanchnic Circulation/physiology , Adult , Ascites/physiopathology , Drug Therapy, Combination , Female , Glomerular Filtration Rate/drug effects , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Kidney/blood supply , Liver Cirrhosis, Alcoholic/physiopathology , Lypressin/therapeutic use , Male , Natriuresis/drug effects , Regional Blood Flow/drug effects , Renal Circulation/drug effects , Splanchnic Circulation/drug effects , Terlipressin , p-Aminohippuric Acid/pharmacokinetics
8.
Gastroenterology ; 112(6): 2065-72, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9178700

ABSTRACT

BACKGROUND & AIMS: In cirrhosis, increased amounts of circulating hormones such as angiotensin II may induce vascular tone changes and alter vascular smooth muscle cell (VSMC) function and growth. The aim of this study was to investigate the growth of aortic VSMCs from cirrhotic rats with or without the addition of angiotensin II and to determine whether angiotensin II binding was preserved in cirrhotic VSMCs. METHODS: Cirrhosis was induced by bile duct ligation. Cell growth was studied in cultured aortic VSMCs at passage levels between 4 and 16 by determining cell number and protein synthesis. RESULTS: Proliferation rates of cirrhotic VSMCs were lower than those of control VSMCs. The addition of angiotensin II to control VSMCs caused an increase in cell proliferation and protein synthesis. This increase was not observed in cirrhotic cells. There were more angiotensin II receptors in cirrhotic than in control VSMCs, but no significant changes in affinities were found. Angiotensin II-stimulated protein synthesis was dependent on protein kinase C activity and increased intracellular Ca2+ concentrations. CONCLUSIONS: This study shows abnormalities in growth characteristics and responsiveness to angiotensin II of cultured aortic VSMCs from rats with cirrhosis.


Subject(s)
Angiotensin II/pharmacology , Aorta/drug effects , Liver Cirrhosis, Experimental/physiopathology , Muscle, Smooth, Vascular/drug effects , Animals , Cell Count/drug effects , Dose-Response Relationship, Drug , Male , Rats , Rats, Sprague-Dawley
9.
J Gastroenterol Hepatol ; 12(3): 233-6, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9142641

ABSTRACT

Little is known about the plasma concentrations of cyclic 3',5'-guanosine monophosphate (cGMP) in patients with cirrhosis. However, plasma cGMP concentrations provide information on cellular cGMP production by particulate guanylyl cyclases (which are stimulated by natriuretic peptides, such as atrial natriuretic peptide; ANP). In contrast, because intracellular cGMP elicits vasorelaxant mechanisms, plasma cGMP concentrations may be related to haemodynamic alterations in patients with cirrhosis. The aim of the present study was to measure plasma cGMP concentrations in patients with cirrhosis and controls and to examine the relationship between cGMP levels and plasma ANP concentrations and haemodynamic values. Plasma concentrations of cGMP and ANP and splanchnic and systemic haemodynamics were measured in 23 subjects; 13 subjects had cirrhosis and 10 were controls. All subjects had normal glomerular filtration. Plasma cGMP concentrations were significantly higher in patients (6.5 +/- 0.8 pmol/mL) than in controls (2.7 +/- 0.4 pmol/mL), while plasma ANP concentrations did not significantly differ between the two groups (127 +/- 22 and 123 +/- 27 pg/mL, respectively). In patients with cirrhosis, no significant correlation was found between plasma cGMP concentrations and plasma ANP concentrations, hepatic venous pressure gradient, cardiac output or systemic vascular resistance. In conclusion, in patients with cirrhosis, increased plasma cGMP concentrations may be due to an activation of particulate guanylyl cyclases by natriuretic peptides other than ANP. The present study suggest that plasma cGMP concentrations are not related to cirrhosis-induced haemodynamic alterations.


Subject(s)
Atrial Natriuretic Factor/blood , Cyclic GMP/blood , Hemodynamics , Liver Cirrhosis/blood , Liver Cirrhosis/physiopathology , Adult , Atrial Natriuretic Factor/urine , Cyclic GMP/urine , Female , Humans , Liver Cirrhosis/urine , Male , Middle Aged , Osmolar Concentration , Reference Values
10.
J Hepatol ; 26(3): 678-86, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9075677

ABSTRACT

BACKGROUND/AIMS: Increased nitric oxide production has been implicated in impaired vascular responsiveness to vasoconstrictors in portal hypertension. However, there is no firm evidence concerning the involved nitric oxide synthase isoform. The present study investigated the possible contribution of one nitric oxide synthase isoform, the endothelial constitutive Ca2+-calmodulin dependent, in the overproduction of nitric oxide in portal hypertension. METHODS: Vascular responses to norepinephrine and acetylcholine were evaluated in isolated thoracic aortic rings from normal and portal vein stenosed rats. RESULTS: An impaired concentration-dependent contraction to norepinephrine was observed in intact rings from portal hypertensive rats compared to controls. The hyporeactivity to norepinephrine was reversed after endothelium denudation, the inhibition of nitric oxide synthase with L-NOARG or the inhibition of calmodulin with W-7, but not after pre-incubation with indomethacin. Stimulation of intact rings with norepinephrine after the inhibition of calmodulin with calmidazolium was followed by a decreased vascular response in vessels from normal rats but not in those from portal hypertensive rats. Stimulation of intact rings with norepinephrine in a Ca2+-free medium was followed by a decreased vascular response in vessels from both portal hypertensive and normal rats. No difference in vasoconstrictive responses was observed between the two groups after calmidazolium or in a Ca2+-free medium. Relaxation induced by acetylcholine in norepinephrine-precontracted rings was more marked in rings from portal hypertensive rats than in controls. No differences in the vasodilator responses were observed after relaxations had been inhibited by the removal of the endothelium, pre-incubation with L-NOARG, indomethacin, W-7 or calmidazolium and in a Ca2+-free medium. CONCLUSIONS: This study demonstrates the involvement of the endothelial constitutive Ca2+-calmodulin dependent nitric oxide synthase isoform in the overproduction of nitric oxide in portal hypertension.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Endothelium, Vascular/metabolism , Hypertension, Portal/metabolism , Nitric Oxide Synthase/metabolism , Vasoconstriction/physiology , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Aorta, Thoracic/physiopathology , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Cyclooxygenase Inhibitors/pharmacology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Hypertension, Portal/pathology , Hypertension, Portal/physiopathology , Indomethacin/pharmacology , Male , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/antagonists & inhibitors , Nitroarginine/pharmacology , Norepinephrine/pharmacology , Rats , Rats, Sprague-Dawley , Sulfonamides/pharmacology , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology
11.
J Gastroenterol Hepatol ; 12(2): 167-71, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9083919

ABSTRACT

Although hepatic blood flow (HBF) has been measured in patients with liver disease for many years, the results of these studies have not provided clear information concerning the usefulness of this measurement. Hepatic blood flow was measured in 392 patients with either cirrhosis (n = 356) or hepatic fibrosis (n = 36). The control group included 59 subjects with normal liver architecture. Hepatic clearance of indocyanine green (ICG) was markedly reduced in patients with cirrhosis and hepatic fibrosis compared with controls (182 +/- 5, 276 +/- 22 and 421 +/- 25 mL/min, respectively). In patients with cirrhosis, ICG clearance and extraction were significantly correlated, but were not correlated to HBF. Although HBF did not differ between patients with cirrhosis and controls (1.26 +/- 0.04 vs 1.35 +/- 0.07 L/min, respectively), patients with hepatic fibrosis had lower HBF (1.04 +/- 0.07 L/min; P < 0.05). In patients with cirrhosis, no correlation was observed between HBF and cardiac output, mean arterial pressure, azygos blood flow, the hepatic venous pressure gradient or Pugh's score. However, a significant difference in HBF was observed in patients with and without hepatic encephalopathy (1.00 +/- 0.09 vs 1.28 +/- 0.03 L/min, respectively; P < 0.05). In conclusion, the present study shows that, in patients with cirrhosis, HBF is normal and is not related to other haemodynamic values or liver tests. These results discourage the measurement of HBF in the evaluation of patients with cirrhosis.


Subject(s)
Hemodynamics , Liver Circulation , Liver Cirrhosis/physiopathology , Liver/physiopathology , Aged , Chronic Disease , Coloring Agents , Female , Humans , Indocyanine Green , Liver Function Tests , Male , Middle Aged , Reference Values
12.
Am J Physiol ; 271(6 Pt 2): H2701-9, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8997333

ABSTRACT

Direct measurement of portal venous blood flow is technically difficult, yet crucial for accurate assessment of liver hemodynamic and metabolic functions. The aim of this investigation was to assess the feasibility of implanting transit-time ultra-sound (TTUS) perivascular flow probes on the portal vein of the rat and to validate this technique as a means of directly measuring portal blood flow in conscious rats. A TTUS flow probe was implanted on the portal veins of 10 rats. One week later, portal flow was measured under basal conditions in these rats by TTUS probes and after pharmacological manipulation of portal flow by intravenous injections of Glypressin or infusions of adenosine while the rats were conscious. Portal flow was simultaneously measured in the same rats using radioactive microspheres. Basal systemic hemodynamics, regional blood flows to splanchnic organs, and portal blood pressure were not significantly modified by the presence of the probe on the portal vein compared with a control group of rats not instrumented with flow probes. Basal portal flows measured by the TTUS and microsphere techniques were not different (20.6 +/- 2.6 and 17.6 +/- 1.3 ml/min). After Glypressin, portal flows measured by the TTUS and microsphere techniques were 12.3 +/- 2.9 and 9.3 +/- 1.9 ml/min and, in response to adenosine, increased to 27.2 +/- 3.4 and 31.3 +/- 4.1 ml/min. There was no significant difference between the TTUS and microsphere flows. Both the relationship between absolute flows and the relationship between changes in flows measured by the two techniques were linear with slopes approaching 1.0. Thus TTUS flow probes can be used to directly measure portal flow from the portal vein in conscious rats. This methodology is as effective as the standard technique of radioactive microspheres. More importantly, the TTUS technique allows for continuous direct measurement of portal flow and eliminates the hazards and sources of error associated with the radioactive microsphere technique.


Subject(s)
Portal System/diagnostic imaging , Portal System/physiology , Animals , Evaluation Studies as Topic , Hemodynamics , Male , Microspheres , Radioisotopes , Rats , Rats, Sprague-Dawley , Regional Blood Flow , Rheology/instrumentation , Splanchnic Circulation , Time Factors , Ultrasonography/instrumentation
13.
Eur J Pharmacol ; 312(1): 63-8, 1996 Sep 19.
Article in English | MEDLINE | ID: mdl-8891579

ABSTRACT

In portal hypertension, the role of the vasorelaxant nitric oxide (NO) in long-term splanchnic and systemic vascular tone regulation is unclear. This study examined the effects of long-term administration of a NO synthesis inhibitor on haemodynamics in portal hypertensive rats. Rats were randomly assigned to receive either water (placebo) or 100 mg/kg.day of oral N-nitro-L-arginine methylester (L-NAME) for 28 days. At 14 days, the portal vein was ligated in 10 rats from each group. At 28 days, splanchnic and systemic blood flows were measured in 20 normal and 20 portal vein stenosed rats. Plasma atrial natriuretic peptide (ANP) concentrations as well as plasma and urinary cyclic guanosine monophosphate (cGMP) levels were also measured. Porto-systemic shunts were measured in other portal vein stenosed animals that had or had not received L-NAME. Portal vein stenosed rats that received L-NAME had significantly lower portal tributary blood flow and percentages of portal-systemic shunting (7.3 +/- 0.5 versus 3.7 +/- 0.2 ml/min.100 g and 96 +/- 1 versus 68 +/- 5%, respectively) and higher hepatocollateral vascular resistance (147 +/- 10 versus 295 +/- 30 dyn.s.cm-5.100 g.10(3), respectively) than placebo portal vein stenosed rats. Portal pressure, ANP and cGMP levels did not differ between the groups. Arterial pressure was significantly higher and cardiac index lower after L-NAME than after placebo. Normal rats had similar but less marked L-NAME-induced responses than portal hypertensive rats. The presence of a long-term L-NAME-induced vasoconstriction in collateral vessels and splanchnic and systemic arterioles in portal vein stenosed rats indicates that a NO-mediated vasodilator tone may contribute to the development and the maintenance of collateral circulation as well as splanchnic and systemic vasodilation in portal hypertension. Moreover, the NO-mediated vasodilator tone in portal hypertensive animals seems to be increased.


Subject(s)
Enzyme Inhibitors/pharmacology , Hemodynamics/drug effects , Hypertension, Portal/physiopathology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Atrial Natriuretic Factor/blood , Cyclic GMP/blood , Male , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effects
14.
J Gastroenterol Hepatol ; 11(9): 857-63, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8889966

ABSTRACT

Because renal water retention is a complication of cirrhosis, niravoline (RU 51,599), a novel kappa (kappa) opioid receptor agonist which is known to cause a water diuresis under normal conditions, may be useful in the therapy of chronic liver diseases. Thus, the present study examined the effects of niravoline on renal function in rats with cirrhosis. Urine was collected during the 2 h period following the administration of vehicle (saline) in one groups of animals or niravoline (3 mg/kg, i.v.) in another group. Urinary and plasma osmolality were measured prior to and 2 h after niravoline in a third group of animals. Urine flow and natraemia were significantly higher after niravoline (147 +/- 12 microL/min and 153 +/- 2 mmol/L, respectively) than after vehicle (27 +/- 7 microL/min and 146 +/- 1 mmol/L, respectively). Niravoline significantly decreased urinary osmolality and significantly increased plasma osmolality and free water clearance. This substance did not significantly change urinary sodium excretion. In conclusion, this study shows that niravoline, a kappa opioid receptor agonist, induced a water diuresis in rats with cirrhosis.


Subject(s)
Benzeneacetamides , Diuresis/drug effects , Hemodynamics/drug effects , Kidney/drug effects , Liver Cirrhosis, Experimental/physiopathology , Pyrrolidines/pharmacology , Receptors, Opioid, kappa/agonists , Animals , Kidney Concentrating Ability/drug effects , Male , Natriuresis/drug effects , Rats , Rats, Sprague-Dawley
15.
Dig Dis Sci ; 41(9): 1722-6, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8794785

ABSTRACT

Terlipressin (Glypressin), a vasopressin analog, may be administered to patients with cirrhosis receiving a beta-adrenergic antagonist. Since terlipressin alone and beta-blockers alone both decrease portal pressure, a combination of these substances may have additional portal hypotensive effects. However, the negative side effects of terlipressin may be accentuated by long-term beta-blockade. Thus, the present study examined hemodynamic and metabolic responses to terlipressin in 12 patients receiving nonselective beta-blockers (propranolol or nadolol). Hemodynamics and oxygen (O2) -derived variables were measured prior to and 30 min after the administration (intravenous bolus) of terlipressin (1 to 2 mg, according to body weight). The hepatic venous pressure gradient and azygos blood flow significantly decreased (from 15.3 +/- 1.1 to 12.5 +/- 1.1 mm Hg, and from 0.6 +/- 0.1 to 0.5 +/- 0.1 liters/min, respectively). Arterial and pulmonary wedged pressures significantly increased. Heart rate, cardiac index, and O2 consumption were not significantly affected by terlipressin. In conclusion, in patients with cirrhosis being treated with a nonselective beta-blocker, terlipressin administration decreased portal pressure. Moreover, terlipressin induced only mild systemic hemodynamic effects in these patients. These results suggest that terlipressin can be administered in patients receiving a beta-adrenergic blocker.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Antihypertensive Agents/pharmacology , Hemodynamics/drug effects , Liver Cirrhosis/physiopathology , Lypressin/analogs & derivatives , Oxygen Consumption/drug effects , Adrenergic beta-Antagonists/therapeutic use , Antihypertensive Agents/therapeutic use , Drug Synergism , Female , Humans , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Lypressin/pharmacology , Male , Middle Aged , Portal Pressure/drug effects , Splanchnic Circulation/drug effects , Terlipressin
16.
Liver ; 16(4): 263-6, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8877998

ABSTRACT

Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg.kg-1.min-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356 +/- 50 vs 166 +/- 30 pg/ml, p = 0.04) than in normal rats (186 +/- 23 vs 86 +/- 31 pg/ml, p = 0.06) and rats with portal vein stenosis (103 +/- 37 vs 93 +/- 5 pg/ml, p = 0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg.kg-1.min-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25 +/- 2%) than in normal rats (-11 +/- 1%) and in rats with portal vein stenosis (-13 +/- 2%) (p = 0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.


Subject(s)
Liver Cirrhosis, Experimental/metabolism , Liver Diseases/metabolism , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Disease Models, Animal , Female , Hemodynamics/physiology , Hexamethonium/pharmacology , Norepinephrine/blood , Norepinephrine/metabolism , Portal Vein/abnormalities , Portal Vein/metabolism , Rats , Rats, Sprague-Dawley
17.
Clin Sci (Lond) ; 91(1): 29-33, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8774257

ABSTRACT

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-alpha production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-alpha production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-alpha concentration and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-alpha concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 +/- 13%) and tributary blood flow (33 +/- 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-alpha concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-alpha levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-alpha concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-alpha concentrations. These reductions were not correlated however.


Subject(s)
Hemodynamics/drug effects , Liver Cirrhosis, Experimental/physiopathology , Pentoxifylline/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Vasodilator Agents/pharmacology , Animals , Liver Cirrhosis, Experimental/blood , Male , Portal Pressure/drug effects , Rats , Rats, Sprague-Dawley , Splanchnic Circulation/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/drug effects
18.
J Gastroenterol Hepatol ; 11(3): 230-5, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8742918

ABSTRACT

The haemodynamic effects of nitrovasodilators and their mechanisms of action on portal hypertension remain unclear. The splanchnic and systemic haemodynamic response to the infusion of isosorbide dinitrate (100 micrograms/kg per min), a nitrovasodilator, was investigated in cirrhotic rats. The role of the conscious state in the haemodynamic response to isosorbide dinitrate was examined using rats that were anaesthetized with pentobarbitone. The role of sympathetic tone in the haemodynamic response to isosorbide dinitrate was examined using rats pretreated with the ganglion blocker hexamethonium. Isosorbide dinitrate had no haemodynamic effects in conscious, unblocked normal and cirrhotic rats. Isosorbide dinitrate had no haemodynamic effects in normal and cirrhotic rats treated with hexamethonium. In normal anaesthetized rats, isosorbide dinitrate significantly decreased systemic vascular resistance (414 +/- 25 vs 290 +/- 26 dyn.s/cm-5 per 100 g). In cirrhotic anaesthetized rats, isosorbide dinitrate significantly decreased mean arterial pressure (98 +/- 6 vs 79 +/- 7 mmHg), systemic vascular resistance (318 +/- 30 vs 207 +/- 10 dyn.s/cm-5 per 100 g), portal pressure (14.0 +/- 1.0 vs 11.3 +/- 0.9 mmHg) and portal territory vascular resistance (1362 +/- 163 vs 1031 +/- 182 dyn.s/cm5 per 100 g). In conclusion, this study shows that the portal hypotensive effects of isosorbide dinitrate depend upon the alterations of vascular tone by pentobarbitone.


Subject(s)
Adjuvants, Anesthesia/pharmacology , Anesthesia, General , Hemodynamics/drug effects , Isosorbide Dinitrate/pharmacology , Liver Cirrhosis, Experimental/physiopathology , Pentobarbital/pharmacology , Sympathetic Nervous System/physiopathology , Vasodilator Agents/pharmacology , Animals , Blood Pressure/drug effects , Ganglionic Blockers/pharmacology , Hexamethonium/pharmacology , Male , Portal System/drug effects , Portal System/physiopathology , Rats , Rats, Sprague-Dawley , Splanchnic Circulation/drug effects , Sympathetic Nervous System/drug effects , Vascular Resistance/drug effects
19.
J Gastroenterol Hepatol ; 11(1): 1-6, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8672735

ABSTRACT

The role of nitric oxide (NO) in the hyperkinetic circulation in portal hypertension has not been clearly elucidated. Different doses of NO inhibitors, haemodynamic values and experimental conditions might explain the discrepant results. The aim of the present study was to investigate the acute effects of a specific biosynthesis inhibitor of NO, Nomega-nitro-L-arginine (L-NNA), on the systemic and splanchnic circulation in normal conscious rats and rats with portal hypertension due to either partial portal vein stenosis or secondary biliary cirrhosis. The administration of L-NNA (15 to 960 micrograms.kg-1.min-1) induced a significant dose dependent increase in arterial pressure which was not different among the three groups of rats. Following an acute and maximal vasopressive dose of L-NNA (1 mg.kg-1.min-1) cardiac index decreased more in portal vein stenosed and cirrhotic rats (-45 +/- 3% and -45 +/- 2%, respectively) than in normal rats (-31 +/- 2%), and systemic vascular resistance increased more in the two groups of portal hypertensive rats than in normals (+ 161 +/- 13% and + 154 +/- 10% vs + 85 +/- 6%, respectively). L-NNA caused a greater decrease in portal tributary blood flow in portal vein stenosed and cirrhotic rats (-63 +/- 4% and -55 +/- 4%, respectively) than in normal rats (-45 +/- 6%). Similarly, the increase in portal territory vascular resistance was significantly more marked in portal vein stenosed and cirrhotic rats (+ 337 +/- 62% and + 214 +/- 24%, respectively) than in normal rats (+ 153 +/- 23%). Portal pressure did not change. Following the acute administration of L-NNA, no significant difference in splanchnic and systemic haemodynamics were noted between portal vein stenosed and normal rats, except for portal pressure. In cirrhotic rats, splanchnic and systemic values remained different from normal rats. This study confirms that NO plays a role in the haemodynamic changes in portal hypertension, and shows that NO inhibitors have a dose-dependent effect in conscious portal hypertensive rats.


Subject(s)
Arginine/analogs & derivatives , Enzyme Inhibitors/pharmacology , Hemodynamics/drug effects , Hypertension, Portal/physiopathology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide/physiology , Splanchnic Circulation/drug effects , Animals , Arginine/administration & dosage , Arginine/pharmacology , Consciousness , Constriction , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Hypertension, Portal/etiology , Liver Cirrhosis, Biliary/complications , Male , Nitroarginine , Portal Vein , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effects
20.
J Hepatol ; 22(4): 481-5, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7665867

ABSTRACT

BACKGROUND/AIMS: Since portal tributary blood flow is increased in portal hypertension due to cirrhosis, a reduction in mesenteric arterial blood flow should decrease portal pressure. METHODS: Calibrated stenosis of the superior mesenteric artery was performed in bile duct ligated rats, using a 22-gauge needle. Arterial stenosis was performed 4 weeks after bile duct ligation. Hemodynamic studies were performed in the 5th week following bile duct ligation in conscious rats. RESULTS: At that time, no digestive tract alterations were observed. In rats with mesenteric arterial stenosis, portal pressure was 12.2 +/- 2.0 mmHg; this value was lower than in rats with cirrhosis without arterial stenosis (14.5 +/- 1.1 mmHg) but higher than normal rats (5.8 +/- 0.7 mmHg). In rats with cirrhosis with mesenteric arterial stenosis, portal tributary and mesenteric blood flows were lower than in rats with cirrhosis without arterial stenosis and not significantly different from normal rats. In rats with mesenteric stenosis, cardiac index was significantly lower than in rats with cirrhosis and not significantly different from normal rats. CONCLUSION: This study shows that calibrated superior mesenteric arterial stenosis normalized portal tributary blood flow and reduced but did not normalize the degree of portal hypertension.


Subject(s)
Arterial Occlusive Diseases/physiopathology , Hemodynamics , Liver Cirrhosis, Biliary/physiopathology , Mesenteric Arteries , Splanchnic Circulation , Animals , Bile Ducts , Constriction, Pathologic , Ligation , Male , Rats , Rats, Sprague-Dawley
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