Systemic arterial vasodilatation has been implicated in the pathogenesis of sodium retention in cirrhosis. Hydrophobic bile acids, which have vasodilatory actions, may be involved. Ursodeoxycholic ...acid, a hydrophilic bile acid, could potentially decrease systemic arterial vasodilatation, possibly due to its antioxidant effects, and improve sodium handling in cirrhosis. The effects of ursodeoxycholic acid on systemic, renal and forearm haemodynamics, liver function and renal sodium handling were assessed in vasodilated cirrhotic patients with refractory ascites treated with a transjugular intrahepatic porto-systemic shunt (TIPS). Eight cirrhotic patients with refractory ascites without TIPS placement served as controls for the sodium handling effects of ursodeoxycholic acid. From 1 month post TIPS, seven patients were studied before, after 1 month of treatment with ursodeoxycholic acid (15 mg.day-1.kg-1) and at 1 month follow-up. Lipid peroxidation products were used as indices of its antioxidant effects. Ursodeoxycholic acid caused a significant reduction in sodium excretion in both groups (P<0.05). This, in the post-TIPS patients (urinary sodium excretion: 35+/-8 mmol/day at 1 month versus 93+/-21 mmol/day at baseline, P<0.05), was due to a significant increase in sodium reabsorption proximal to the distal tubule (P<0.05), without any significant changes in systemic, renal or forearm haemodynamics, or in liver function. No significant change in lipid peroxidation products was observed. We conclude that: (i) in cirrhotic patients with refractory ascites, ursodeoxycholic acid causes sodium retention, (ii) the abnormality in sodium handling in the post-TIPS cirrhotic patients appears to be the result of a direct effect on the proximal nephron, suggesting that factors other than systemic vasodilatation also contribute to sodium retention in cirrhosis, (iii) caution should be exercised in administering ursodeoxycholic acid in cirrhotic patients with ascites.
Alpha 1-Adrenoreceptor affinity constants (KD) and receptor numbers (Bmax) were determined in the kidneys of 3-day-old bile-duct-ligated (BDL) jaundiced rats using 3H-prazosin. The results were ...compared to 3-day-old pair-fed and nonpair-fed sham-operated rats as well as nonoperated rats as controls. Abdominal surgery (sham and BDL) resulted in a tendency towards a decrease in KD in all three groups of rats compared to nonoperated controls. The Bmax was also increased in the sham-operated groups compared to the nonoperated controls. In contrast, the tendency for a rise in the Bmax in the BDL group was significantly smaller than the rise seen in the two sham-operated groups. In summary, obstructive jaundice suppresses the normal renal alpha 1-adrenoreceptor response to abdominal surgery in the rat.
Total serum bile acid concentrations are elevated in individuals with liver disease. Ursodeoxycholic acid (UDCA) therapy in such patients results in a further significant rise in plasma levels to the ...extent that it becomes the major circulating bile acid. In laboratory animals, bile acids, such as taurocholic acid, have also been shown to possess a diuretic-like action, as they can promote diuresis, natriuresis, and kaliuresis by inhibiting tubular sodium reabsorption. The aim of the present study was to assess the effect of 1 month's UDCA therapy on cardiovascular function in cirrhotic patients.
Two groups of patients with cirrhosis were studied, six with primary biliary cirrhosis (PBC) and six with postnecrotic liver cirrhosis (PNC). Cardiovascular function was assessed by determination of blood pressure, heart rate, and by two-dimensional and pulsed Doppler echocardiography.
In PBC patients, 1 month's treatment with UDCA significantly reduced diastolic volume without changing systolic, diastolic, and mean blood pressures, heart rate, systolic and stroke volumes, ejection fraction, cardiac output, and systemic vascular resistance. In PNC patients, UDCA significantly reduced cardiac output, with a tendency to reduce left ventricular volumes, without any changes in systolic, diastolic, and mean blood pressures.
UDCA caused reductions in diastolic volume in the PBC patients and cardiac output in the PNC patients. Such reductions are not unlike that seen in individuals treated with diuretics. This diuretic-like action deserves further study, particularly in cirrhotic patients who are also being treated with diuretics or show evidence of cardiac myopathy.
To evaluate if L-arginine-nitric oxide-pathways are involved in the neural relaxation of the sphincter of Oddi, we studied the effect of nitric oxide synthase inhibition on electrical field ...stimulation-induced relaxation of the sphincter of Oddi in the guinea pig in vitro. After incubation with atropine (1 microM), phentolamine (1 microM) and propranolol (1 microM), histamine (50 microM) and cholecystokinin-octapeptide (25 nM) produced similar increases in sphincter tone. Subsequent field stimulation induced sphincteric relaxation, that was significantly greater when the initial tone had been raised by cholecystokinin (5 Hz, 59 +/- 9%; 10 Hz, 79 +/- 9%) compared to histamine (5 Hz, 27 +/- 3%; 10 Hz, 40 +/- 7%). N-omega-Nitro-L-arginine methyl ester (L-NAME, 100 microM), which competitively inhibits nitric oxide synthase, markedly suppressed this relaxation. The subsequent addition of L-arginine (1 mM), but not D-arginine (1 mM), restored the relaxation. Hexamethonium (100 microM) did not affect the relaxation, but tetrodotoxin (1 microM) completely abolished it. Sodium nitroprusside caused a dose-dependent relaxation of the sphincter (ED50 13 nM), which was unaffected by L-NAME. In conclusion, endogenous nitric oxide synthase products represent a major transmitter of non-adrenergic non-cholinergic relaxation of the sphincter of Oddi in the guinea pig. This relaxation is partially facilitated by cholecystokinin.
Pulmonary emphysema would be expected to reduce angiotensin converting enzyme (ACE) activity due to diminished capillary bed. However, transpulmonary angiotensin conversion has been found to be ...unaffected or marginally reduced in emphysema. In the present study we examined the activity of ACE in an experimental model of emphysema. Vmax and Km of ACE were determined in lung homogenates of six hamsters with elastase-induced emphysema and seven control hamsters. In the emphysematous lungs, ACE activity was significantly elevated due to marked increase in Vmax (19.2 +/- 1.7 vs. 4.9 +/- 1.6 nmol/min/mg protein for emphysematous and control lungs, P < 0.01). The Km of ACE was unaffected by emphysema. We suggest that the increase in ACE activity may be an adaptive change to enable adequate metabolic activity in the face of progressive reduction in pulmonary capillary surface area in emphysema.
Investigators studying the pathophysiological sequelae of bile duct ligation use different species of laboratory animals at varying postoperative times. There is also considerable variation in the ...type of control animal used for these experiments. In this study, we have attempted to validate our choice of the 3-day bile-duct-manipulated rat as the most appropriate control to study peripheral vascular neuroeffector mechanisms in bile-duct-ligated rats. We have compared the in vitro contractile response to norepinephrine in the absence and presence of cocaine, and the accumulation of the amine using
3H-norepinephrine of arterial rings and portal veins prepared from three different types of control rats—unoperated control, the 3-day bile-duct-manipulated and the 3-day pair-fed, bile-duct-manipulated rats. In vitro arterial reactivity to norepinephrine in the sham-operated rats was significantly attenuated and was associated with a cocaine-sensitive increase in norepinephrine uptake. Portal veins from the same animals showed no changes in in vitro reactivity to norepinephrine, although bile-duct manipulation and pair-feeding enhanced amine uptake. This study has demonstrated that bile-duct manipulation and pair-feeding attenuate in vitro vascular reactivity and enhance norepinephrine uptake. These in vitro changes are more pronounced in arterial tissue than venous tissue. In conclusion, these data indicate that bile-duct manipulation is the control of choice when measuring in vitro vascular neuroeffector mechanisms in 3-day bile-duct-ligated rats. Furthermore, these data emphasize the need to validate the control when experiments involving bile-duct ligation are undertaken.
Heart energy efficiency, which is affected by catecholamines, has previously been shown to decline in rats with prolonged normobaric O2 exposure.
Oxygen exposure affects dose response of the heart to ...catecholamines.
Epinephrine dose-response (10(-10) - 5 x 10(-6) mol.L-1) was measured in the isolated working heart excised from control rats breathing air, and rats exposed to normobaric 100% oxygen for either 24 h or 49 h. The variables measured were input (oxygen consumption (VO2) and output power, cardiac contractility (Emax and maximal dP/dT), coronary resistance, heart frequency (fH) and left ventricular pressure. Variable (Y*) dose response to epinephrine concentration (C) was fitted to the equation: Y* = Ymax/(1 + (C/C50)n), Ymax--maximal Y*, C50--C for half Ymax and n--an empirical power.
Oxygen exposure of the intact rat had little influence on baseline cardiac variables, but did affect sensitivity to catecholamines. A general effect of the O2 exposure was a left shift of the dose-response curve for example, C50 was reduced by 72, 41 and 43 x 10-8 mol.L-1 for VO2, fH and Emax, respectively, after the 24 h exposure.
There was a pronounced change in the dose-response in hearts from 24 h O2-exposed rats, a change partially reversed in hearts from 49 h O2-exposed rats. The high dose, which had a stimulatory effect on hearts from control rats, failed to stimulate hearts from hyperoxic rats.
