Endothelin and vascular reactivity in cirrhosis.
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Biomedical subjects
Publications and source records attributed to C C Sieber.
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Gastroduodenal ulcers are strongly associated with Helicobacter pylori (HP) infection. Successful eradication drastically diminishes ulcer recurrence. Most of the eradication schemes include metronidazole (Flagyl). The present study was designed to establish the metronidazole resistance rate in Switzerland. Antral biopsies were taken in 153 patients with suspected ulcers (115 men, 38 women, mean age 46 +/- 16 [SD] years) during upper endoscopy for bacteriological testing. Metronidazole resistance (> 8 micrograms/ml) was found in 47/153 (31%) of the isolates. Resistance was found in no case to amoxicillin (Clamoxyl) (0/104 = 0%) and only in 3% (2/66) to clarithromycin (Klazid). Metronidazole resistance of HP in a third of the isolates studied is comparable to numbers found in other European countries. These findings raise the question whether eradication schemes including metronidazole without prior sensitivity testing are justified. Amoxicillin and clarithromycin appear to be valid alternatives.
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Duplex sonography as a non-invasive technique to measure splanchnic and hepatoportal haemodynamics under physiological and pathophysiological conditions has recently attracted much attention. Determination of arterial and venous profiles enables reproducible pre- and postoperative flow estimations. Furthermore, this technique has harvested many interesting results in the complicating haemodynamic changes seen in patients with portal hypertension. The technique can even be considered as gold standard in the evaluation of flow changes in patients after orthotopic liver transplantation. This article reviews the use of duplex scanning in the splanchnic vascular bed.
This study investigated whether nitric oxide (NO) plays a role in the intrahepatic portal circulation in normal rat livers perfused in situ. N omega-nitro-L-arginine (NNA), a specific NO biosynthesis inhibitor, significantly increased baseline portal pressure compared with controls (P < 0.05). Concentration-effect curves to norepinephrine (NE) were performed. Perfusate flow was maintained as constant, and perfusion pressure was continuously measured. NNA markedly enhanced the responsiveness to NE. This effect was abolished by the addition of L-arginine, a specific NO substrate. Presence of indomethacin did not alter the response to NE. The response to NE in the presence of indomethacin and NNA was significantly more than the response to NE in the presence of NNA alone. In vivo, intraportal infusion of NNA significantly enhanced the portal pressure compared with vehicle. This study demonstrates that NO contributes to the basal vascular tone and attenuates the response to NE in intrahepatic portal vascular bed of normal rats. These results support a functional role of NO in the regulation of the intrahepatic portal circulation in normal rats. This study also suggests a synergistic, albeit limited, role of prostacyclin in the intrahepatic circulation.
Pharmacological prophylaxis and the therapy of complications of portal hypertension have recently been attracting more attention. This especially holds true for gastroesophageal variceal bleeding. Vasoconstrictors such as vasopressin, somatostatin, and beta-blockers, as well as vasodilators such as organic nitrates, alpha 2-adrenergic agonists and serotonin-antagonists, are currently used in clinical settings. The aim of this article is to delineate the present pathophysiological concepts accounting for the hemodynamic changes in animal models and patients with portal hypertension, and to summarize the mechanisms of action of the most frequently used pharmacological agents.
BACKGROUND: The locally acting vasodilator nitric oxide has recently been implicated as a possible mediator in the vasodilatation observed in prehepatic portal hypertension. The aim of this study was to assess if nitric oxide could also be implicated in the vasodilation observed in experimental cirrhosis. METHODS: In an in vitro preparation, the vascular responsiveness to potassium chloride of Krebs'-perfused superior mesenteric arterial vascular beds of control (n = 12) and cirrhotic (n = 10) rats with ascites, induced by CCl4, were tested. RESULTS: Increases in perfusion pressures over baseline in response to potassium chloride (125 mmol/L) were significantly lower in vessel preparations of cirrhotic rats (84.7 +/- 12.3 and 134.2 +/- 16.3 mmHg for cirrhotic and control rats, respectively, P < 0.05). This hyporeactivity was overcome by incubating the same vessel preparations with the stereospecific nitric oxide biosynthesis antagonist N omega-nitro-L-arginine (10(-4) mol/L). The corresponding increases in perfusion pressures were 145.1 +/- 18.0 and 173.0 +/- 14.8 mm Hg for cirrhotic and control rats, respectively (P = NS). Nitric oxide formation blockade increased the vascular response to KCl in cirrhotic and control rats, the respective percentage changes being 84.6% +/- 14.8% and 38.5% +/- 12.1% (P < 0.05). CONCLUSIONS: (1) Superior mesenteric arterial vascular beds of cirrhotic rats express a significant contracting hyporeactivity to KCl and (2) nitric oxide at least partly mediates the hyporesponsiveness in this in vitro preparation.
Most studies testing vasoactive agents in portal-hypertensive rats have been performed in young animals. To assess age-related changes in hemodynamic responses to adrenergic stimuli, we examined (a) responsiveness to norepinephrine (0.14 to 12.0 micrograms.kg-1.min-1) in young (3-mo-old) and aged (9-mo-old) sham-operated and portal-hypertensive rats and (b) response to propranolol (2 and 10 mg.kg-1 body wt), nitroglycerin (3.6 mg.kg-1.min-1) or saline solution in aged portal-hypertensive rats. Aged rats exhibited significantly (p < 0.05) smaller responses to norepinephrine with regard to increases in mean arterial pressure and superior mesenteric arterial vascular resistance, irrespective of portal hypertension. Portal hypertension alone potentiated this reduced response in aged animals and was associated with cardiovascular hyporesponsiveness to norepinephrine in young rats. Portal pressure was significantly (p < 0.05) lower in aged sham-operated rats than in young sham-operated rats over a wide range of norepinephrine doses. Portal-hypertensive aged rats showed significantly (p < 0.05) lower heart rates. Furthermore, systemic and splanchnic cardiovascular responses to propranolol and nitroglycerin mediated by the sympathetic nervous system were decreased or negligible in aged rats, compromising the portal-hypotensive effects of these drugs. In summary, aged rats express diminished cardiovascular responsiveness to adrenergic stimuli. Therefore age should be considered an important factor in studies evaluating pharmacological agents for the treatment of portal hypertension.
Increased levels of circulating vasodilators have been claimed to be the causative factor in the hyporesponsiveness to endogenous vasopressors in portal hypertension. To investigate whether this hyporeactivity to vasopressors is also present in an in vitro system perfused with a synthetic medium, the responsiveness to graded concentrations of norepinephrine, arginine-vasopressin, and potassium chloride was tested in perfused superior mesenteric arterial beds of normal rats and rats with portal hypertension induced by partial portal vein ligation (PVL). The same vasopressors were tested after incubation of vessel preparations with the stereo-specific nitric oxide formation inhibitor N omega-nitro-L-arginine (NNA, 10(-4) mol/L). Vessel preparations of PVL compared with normal rats (n = 8 per group and vasopressor) expressed a significant (P less than 0.05) hyporeactivity to norepinephrine, arginine-vasopressin, and potassium chloride over a wide range of concentrations. This hyporesponsiveness was overcome by preincubating vessel preparations with NNA. In summary, portal hypertension is accompanied by a significant in vitro hyporeactivity of splanchnic vessels to norepinephrine, arginine-vasopressin, and potassium chloride, and secretion of nitric oxide in this preparation seems responsible for this blunted response.
Vasoactive effects of natural somatostatin (SRIF-14) and its analogue octreotide were studied in in vitro perfused superior mesenteric arterial beds of normal (Sham) and portal hypertensive (PVL) rats. Tested concentrations covered the whole range used in clinical settings (10(-10) to 10(-5) M for SRIF-14 and 10(-11) to 10(-6) M for octreotide, respectively). Vessel resistances only minimally changed to infusions of SRIF-14 (from 3.5 +/- 0.4 to 3.7 +/- 0.5 mmHg.ml-1.min and 3.8 +/- 0.3 to 3.9 +/- 0.4 mmHg.ml-1.min for PVL and Sham) and octreotide (from 3.3 +/- 0.2 to 3.4 +/- 0.4 mmHg.ml-1.min and 3.8 +/- 0.4 to 4.0 42- 0.4 mmHg.ml-1.min for PVL and Sham). The same was true for bolus injections. In contrast, norepinephrine induced significant increases in vessel resistance (up to 110.6 +/- 20.1 mmHg.ml-1.min). In conclusion, SRIF-14 and octreotide exert no direct effect on vascular smooth muscle tone in splanchnic resistance vessels of Sham and PVL rats. The vasoconstriction reported in vivo seems therefore probably mediated by the ability of these peptides to inhibit the secretion of vasodilatatory substances.
The endothelial cell plays an important role in the local control of vascular smooth muscle tone. Portal hypertension is accompanied by systemic vasodilatation and a decreased response to vasoconstrictors, changes especially evident in the superior mesenteric arterial bed. To evaluate a possible effect of the locally released endothelium-derived relaxing factor nitric oxide (NO), we tested the effect of NO blockade in in vitro perfused superior mesenteric arterial beds of normal (sham) and portal hypertensive (PVL) rats, induced by partial portal vein ligation. A significant (n = 7/group; P = 0.02) hyporeactivity to the vasoconstrictive properties of the alpha-adrenoceptor agonist methoxamine (3 x 10(-6) to 3 x 10(-4) M) was prevented by blocking NO formation in PVL compared with sham rats, using the stereospecific biosynthesis antagonist N omega-nitro-L-arginine (10(-4) M, n = 7/group; NS for all methoxamine concentrations tested). This effect was reversed by the NO precursor L-arginine (10(-3) M, n = 5/group). In conclusion, these in vitro results in mesenteric vessels demonstrate that 1) portal hypertension is accompanied by a hyporeactivity to the vasopressor methoxamine and 2) locally released NO in this preparation is responsible for the decreased vasoconstrictive response.
Malnutrition occurs frequently in the elderly and is correlated with decreased functionality and thereby quality of life, as well as increased morbidity and mortality. This holds true for elderly people living in the community, patients in acute-care hospitals, as well as residents in long-term care facilities. To diagnose malnutrition, it is crucial to have sensitive, easy-to-use and specific tools at hand. The focus of this article is to compare strengths and weaknesses of the most commonly used assessment tools for malnutrition in the elderly, Malnutrition Universal Screening Tool (MUST), Mini Nutrition Assessment (MNA), Subjective Global Assessment (SGA), and Nutrition Risk Screening (NRS 2002). In conclusion, 15 years after its introduction, the Mini Nutritional Assessment (MNA), which was especially developed for elderly people, remains the gold-standard for ambulatory living elderly and those living in long-term care facilities, whereas the NRS 2002 has especially good potential in the acute-care setting, as it was developed specifically for hospitalized patients who need nutritional support.