Jaundiced patients have systemic hypotension and are more susceptible to hemorrhagic shock than nonjaundiced individuals. We have hypothesized that the mechanism whereby these cardiovascular ...complications arise is linked to a disturbance of the vascular neuroeffector process in the cardiovascular system. With the use of 3-day bile duct-manipulated (sham-operated) and bile duct-ligated rats, we have evaluated alpha-adrenoceptor function and amine uptake using in vivo and in vitro techniques. Blunted pressor responsiveness to norepinephrine, electrical stimulation, and the alpha 1-adrenoceptor agonists, methoxamine and phenylephrine, was observed in the bile duct-ligated pithed rats. In contrast, normal responsiveness to BHT-933 and clonidine, the alpha 2-adrenoceptor agonists, was seen in these animals. The uptake 1 blocker, cocaine, caused potentiation of equal magnitudes of the pressor responsiveness to electrical stimulation and norepinephrine in the sham-operated and bile duct-ligated pithed rats. In aortic rings prepared from the bile duct-ligated rats, blunted in vitro vascular reactivity to norepinephrine and the same alpha 1-adrenoceptor agonists was seen. Bile duct ligation had no effect on norepinephrine uptake or its kinetics in stressed and unstressed arterial rings and portal veins. We have thus concluded that bile duct ligation induces a defect in the functional expression of cardiovascular alpha 1-adrenoceptors without any effects on the activity of alpha 2-adrenoceptors or norepinephrine uptake.
Renal dysfunction occurs in patients with biliary obstruction. Plasma accumulation of bile acids and oxidative stress have been proposed as contributory factors. Bile acids can alter the renal ...handling of electrolytes and water by blocking the Na(+)-H+ antiport in the tubule. Oxidative stress, defined as an imbalance between radical generating systems and radical scavenging systems giving rise to free radical induced tissue damage, occurs in patients with liver disease. Bile acids cause oxidative damage to tubular cell membranes by stimulating the generation of oxygen free radicals from mitochondria, as well as promoting their release from neutrophils and macrophages. Oxidative stress can promote the formation of a variety of vasoactive mediators including endothelin-1, cysteinyl leukotrienes, as well as the F2-isoprostanes, endogenous products of lipid peroxidation. These mediators can each affect renal function directly by causing renal vasoconstriction or decreasing the glomerular capillary ultrafiltration coefficient, and thus reduce glomerular filtration rate. Collectively, these factors contribute to the onset of renal failure in patients with biliary obstruction.
1. This study assesses the effects of sodium status on venous responsiveness to noradrenaline and the neurohumoral profile in pre-ascitic cirrhotic patients. Eight cirrhotic patients and ten control ...subjects were studied after both a low (20 mmol/day) and a high (200 mmol/day) sodium diet. Venous responsiveness to increasing doses of noradrenaline in a dorsal hand vein and various plasma hormone levels were measured. Maximal response (Rmax.) and the dose of noradrenaline that yielded 50% of Rmax. (ED50) were then calculated. 2. A significantly smaller dorsal hand vein diameter was observed in the control subjects on a low sodium (2.23 +/- 0.14 mm) compared with a high sodium (2.57 +/- 0.15 mm; P = 0.04) diet, but not in the cirrhotic patients. Rmax. was not significantly different in either group on both diets. With low sodium intake, ED50 was similar in the two groups. However, on high sodium intake, control subjects had a significantly higher ED50 (34.4 +/- 7.4 ng/min) than the cirrhotic patients (5.03 +/- 0.86 ng/min; P < 0.003). Plasma noradrenaline in the control subjects fell significantly with the change from a low (1.29 +/- 0.11 nmol/l) to a high (0.68 +/- 0.09 nmol/l; P < 0.001) sodium diet, but remained elevated in the cirrhotic patients. Cirrhotic patients had significantly higher atrial natriuretic factor levels and lower plasma renin activity than the control subjects on both diets. 3. In conclusion, pre-ascitic cirrhotic patients show no evidence of venodilatation. Their sympathetic nervous activity is not suppressible by volume expansion. Relative hyper-responsiveness of the peripheral venous circulation to adrenergic stimulation with high sodium intake is present.
Background Systemic hypotension may result in postoperative renal failure in jaundiced patients. Attenuated responsiveness to eatecholamines and hypovolaemia has been reported in jaundiced animals ...and may be a mechanism contributing to the increased susceptibility of jaundiced patients to haemorrhagic shock. This suggests that an alternative to vasoactive amines to control perioperative hypotension could be desirable.
Methods This study evaluated the pressor response to vasopressin in normovolaemic 3‐day bile duct‐ligated rats and in 3‐day bile duct‐ligated rats after an acute controlled haemorrhage. It also evaluated the response after volume loading with 0.9 per cent saline, 7.5 per cent saline, colloid and mannitol before controlled haemorrhage. In addition, blood volume was measured using radiolabelled albumin. All the data obtained from bile duct‐ligated rats were compared with data from sham‐operatcd animals.
Results Attenuated pressor responses to vasopressin were not observed in either normotensive bile duct‐ligated rats or in bile duct‐ligated rats subjected to controlled haemorrhage. Volume loading with the four fluids over the dosing range 25–73 μl per g body‐weight in bile duct‐ligated rats reversed the susceptibility to haemorrhagic hypotension.
Conclusion Although no reduction in blood volume was demonstrated, bile duct‐ligated rats may have a reduced effective blood volume manifesting itself as a latent hypovolaemia and/or tendency to hypotension. Preoperative fluid loading could be beneficial because it corrects hypovolaemia and improves cardiovascular function, as well as improving the cardiovascular response to haemorrhage.
The function and role of the heart and the contribution of cardiac beta-adrenoceptors in the pathogenesis of circulatory failure in obstructive jaundice were studied in the 3-day bile duct-ligated ...(BDL) rat using three different techniques to measure cardiac function and beta-adrenoceptor activity, number, and affinity. The techniques were the pithed rat preparation, the isolated working heart preparation, and a competitive radioligand binding assay for beta-adrenoceptors. The results of these experiments were compared with those obtained in 3-day bile duct-manipulated (sham operated; SO) rats. Impaired indexes of basal cardiac contractility were observed in the BDL pithed rats and isolated working hearts. In these two preparations, responsiveness to norepinephrine and the beta-adrenoceptor agonists, isoproterenol and dobutamine, was unaffected by bile duct ligation. The affinity and number of cardiac beta-adrenoceptors in membranes from the hearts of SO and BDL rats were not significantly different from each other. These experiments have established for the first time that the 3-day BDL rat has a cardiac myopathy associated with intact responsiveness to beta-adrenoceptor agonists, a normal unchanged affinity and number of cardiac beta-adrenoceptors.
1. There is currently considerable interest in the role of locally produced vasodilators such as nitric oxide and adenosine in the pathogenesis of the peripheral vasodilatation of cirrhosis. However, ...the signal transduction pathways involving guanylate cyclase and adenylate cyclase have not been clearly delineated in the isolated blood vessel. 2. We therefore aimed to examine the in vitro vasorelaxant effects of the endothelium-dependent dilator bethanechol, the endothelium-independent dilator sodium nitroprusside and adenosine, as drugs that work via activation of guanylate and adenylate cyclases, in isolated aortic and superior mesenteric arterial rings from cirrhotic and control rats. 3. Cirrhosis was induced by chronic bile duct ligation and section of 24-28 days' duration, while controls underwent sham operation. The vessels were precontracted with the alpha 1-adrenoceptor agonist phenylephrine, then relaxed by incremental doses of the three drugs. 4. Marked attenuation of vasoconstriction induced by phenylephrine in isolated aortic and mesenteric arterial rings from cirrhotic rats compared with the control vessels was observed. 5. There were no significant differences in relaxation between the cirrhotic and control vessels to the three drugs. We conclude that in vitro vasodilatory responses mediated through signal transduction pathways involving guanylate cyclase and adenylate cyclase remain unchanged in a rat model of biliary cirrhosis.
The role of bile acids in post-surgical acute renal failure in jaundiced patients is obscure. In this study the effects of 11 bile acids were assessed on freshly isolated rat glomeruli and proximal ...tubular fragments using
de novo protein synthesis and lactate dehydrogenase (LDH) leakage as markers of cytotoxicity. Lithocholic acid inhibited protein synthesis from 5
μ
m, chenodeoxycholic and deoxycholic acid from 50
μ
m (
P<0.05). The concentration of hydrophobic bile acids that inhibited protein synthesis by 50% (IC
50) was 10
μ
m, 75
μ
m and 80
μ
m for lithocholic, chenodeoxycholic and deoxycholic acids, respectively. The glycine and taurine conjugates of these bile acids had no significant effect on
de novo protein synthesis up to 200
μ
m. Lithocholic acid (50
μ
m), chenodeoxycholic (200
μ
m) and deoxycholic acids (200
μ
m) caused a significant increase (
P<0.05) in LDH leakage. Lithocholic acid also directly inhibited LDH activity above 50
μ
m (
P<0.05), whereas chenodeoxycholic acid and deoxycholic acid had no effect on LDH below 500
μ
m, at which concentration they caused a slight increase in activity. The cytotoxic bile acids had no effect on the level of reactive oxygen species in kidney fragments. Hydrophobic bile acids inhibit protein synthesis and increase membrane permeability. Hydrophobic bile acids also directly alter LDH activity. Kidney cells are susceptible to the hydrophobic bile acids at concentration significantly below their critical micellar concentration. These results suggest that both glomeruli and tubules are highly sensitive to hydrophobic bile acids.
In response to increased popularity and greater demand for medicinal plants, a number of conservation groups are recommending that wild medicinal plants be brought into cultivation systems. We ...collected four medicinal herbs Cichorium pumilum, Eryngium creticum, Pistacia palaestina and Teucrium polium used in traditional Arab medicine for greenhouse cultivation to assess the effects of different fertilization regimes on their growth and antioxidant activity. Wild seedlings were collected and fertilized with either 100% Hoagland solution, 50% Hoagland solution, 20% Hoagland solution or irrigated with tap water. Plant height was measured and the number of green leaves and branches counted weekly. Thereafter, the aboveground parts of plants were harvested for preparing a water-soluble powder extracts of which antioxidant activity was measured by their ability to suppress the oxidation of beta-carotene. Of the fertilization regimes, we found either 20 or 50% Hoagland solution produced the most consistent response of the plant growth parameters. All powders prepared from the four wild growing plants inhibited oxidation of beta-carotene. Increasing the amount of fertilizer caused a significant concentration-dependent increase in antioxidant activity of the cultivated T. polium compared with the wild type. In contrast, increasing the amount of fertilizer caused a significant concentration-dependent reduction in the antioxidant activity of powders prepared from the cultivated E. creticum when compared with wild plants. Our results showed that cultivation success should not rely solely on parameters of growth but should incorporate assessment related to indices of therapeutic potential.
The therapeutic benefit of ursodeoxycholic acid (UDCA) in treating cholestatic liver disease is globally recognized. It is generally accepted that the mechanism of action of UDCA can be attributed to ...several diverse processes that appear to be uniformly targeted towards minimizing the deleterious actions of accumulated hydrophobic bile acids in the cholestatic liver. Since hydrophobic bile acids are prooxidants, emerging in vitro evidence suggests that UDCA may have an antioxidant mechanism of action. We hypothesize that UDCA suppresses the extent of lipid peroxidation in the cholestatic liver. This hypothesis was tested by assessing the extent of lipid peroxidation in livers harvested from chronic bile duct ligated (CBDL) rats dosed daily for 24 days with 5, 10, or 15 mg/kg UDCA. The extent of lipid peroxidation was evaluated by determining the hepatic content of conjugated dienes, lipid peroxides, and malondialdehyde. The data were compared with identical data collected from unoperated control and 24-day bile duct manipulated (SO) rats. In the two groups of control rats, UDCA has no effect on the serum indices of liver function. In CBDL rats, UDCA suppressed the increased extent of lipid peroxidation in the liver in a dose-dependent manner in the absence of improvement of laboratory parameters of liver function and hepatic architecture. In conclusion, UDCA suppresses the augmented extent of lipid peroxidation in the diseased liver of CBDL rats.
Background. Surgery on patients with obstructive jaundice is associated with a significant risk of postoperative renal failure. Bile acids are implicated as nephrotoxins because they accumulate in ...the plasma and the kidney becomes their only excretory route in cholestasis. The experimental evidence favoring this proposal is inadequate and unconvincing. Therefore, we designed an animal experiment involving bile duct ligated (BDL) rats in which we could correlate variations in serum and urine bile acids with indices of nephrotoxicity and renal function. Hypothesis. Bile acids are putative nephrotoxins. Materials and Methods. Total serum and urine bile acid concentrations and profiles were determined using liquid chromatography gas chromatography mass spectrometry selected ion monitoring. Nephrotoxicity was assessed by renal histopathology and by determination of the urinary activities of the following enzymes: muramidase, glutamate dehydrogenase, alkaline phosphatase, N-acetyl-β-D-glucosaminidase, and lactate dehydrogenase. Renal function was assessed by measuring urine osmolality, daily osmolar excretion, sodium excretion (UNaV), potassium excretion (UKV), and total protein and albumin excretion. Results. Maximum plasma concentrations and renal clearance of bile acids occurred between the third or fourth postoperative day following BDL. This peak coincided with maximal disruption of proximal convoluted tubule architecture and postoperative changes in renal function-increased urine flow rate and decreases in urine osmolality and sodium excretion. Thereafter, 1) plasma levels of bile acids returned toward normal levels, 2) urinary bile acid clearance declined, 3) normal renal histology was restored, and 4) normal renal function was reestablished. Throughout this period, fluctuations in enzymuria were evident. However, these shifts did not coincide with plasma and urine bile acid concentrations and histological and functional changes. Discussion and Conclusions. Transient functional impairment of renal cation and water transport and nonspecific morphological changes in the proximal convoluted tubule occur 3 to 4 days following bile duct ligation in rats. These functional and morphological changes occurred when plasma total and urinary bile acids were at their peaks. Although it is tempting to equate association with causality, we cannot implicate bile acids as being responsible for the aberrations in renal function and structure following BDL. Accordingly, we have concluded that elevated plasma concentrations of bile acids are renal exacerbates acting in concert with other factors, be they prerenal or renal in origin to precipitate a cascade of events leading to postoperative renal failure in cholestasis.
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