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Continuous recording of mean cerebral blood flow velocity (MCBFV) by Doppler ultrasound allows detection of low-frequency (LF) oscillations, which reflect sympathetic activity in the cerebral circulation. To establish whether the sympathetic drive to the cerebral circulation is altered in patients with compensated cirrhosis, and, if so, where alterations take place, LF oscillations of MCBFV, heart rate (RR interval) and systolic arterial pressure (SAP) were analysed in 10 patients with cirrhosis and 10 control subjects during supine rest and on stimulation of carotid baroreceptors using a neck chamber applying sinusoidal suction. Bivariate analysis was used to study the relationship between pairs of oscillations. In the case of a significant association, the delay in the appearance of the oscillation in MCBFV, SAP and RR was calculated. Baroreceptor stimulation induced significant increases in SAP LF and RR LF power in both groups, while MCBFV LF power increased only in controls. During baroreceptor stimulation, the lag phase between SAP LF and MCBFV LF power was significantly lower in cirrhotic patients than in control subjects (0.96 compared with 1.59 rad; P<0.01), indicating altered sympathetic regulation of the cerebral circulation. The baroreflex arc was intact, as indicated by the similar pattern of RR-SAP interval in patients and controls. Plasma noradrenaline levels increased significantly in both groups in response to head-up tilt. These results indicate that patients with cirrhosis have an altered sympathetic regulation of the cerebral circulation that is characterized by an inadequate response of resistance microvessels, despite adequate baroreceptor function.

The effect of the NSAIDs indomethacin, indoprofen, diclofenac and acetylsalicylic acid on the increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) induced by nitric oxide‐donor agents was tested in human whole platelets and in platelet crude homogenate.In whole platelets, indomethacin reduced the increase in cyclic GMP induced by the nitric oxide‐donors (NO‐donors) sodium nitroprusside (NaNP) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in a dose‐dependent way, its IC50being 13.7 μmand 15.8 μm, respectively.Of the other cyclooxygenase inhibitors tested, only indoprofen reduced the increase in cyclic GMP induced by both NO‐donors in a dose‐dependent way (IC50=32.7 μm, NaNP and 25.0 μm, SNAP), while acetylsalicylic acid (up to 1000 μm) and diclofenac (up to 100 μm) were ineffective.However, in platelet crude homogenate neither indomethacin nor indoprofen reduced the cyclic GMP production.Indomethacin (10 μm), indoprofen (30 μm), diclofenac (100 μm) and acetylsalicylic acid (1000 μm) showed a comparable efficacy in inhibiting platelet thromboxane B2(TXB2) production, suggesting that the inhibitory effect of indomethacin and indoprofen on the increase in cyclic GMP induced by both NO‐donors was not mediated by inhibition of cyclooxygenase.In vitro, the NSAIDs analysed did not interfere with nitrite production of SNAP.The unhomogeneous behaviour of NSAIDs on the increase in cyclic GMP induced by NO‐donors in whole platelets may contribute to the different pharmacological and toxicological characteristics of the drugs, providing new knowledge on the effect of indomethacin and indoprofen.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2excretion received the thromboxane-receptor antagonist ONO-3708 (3 μg · kg−1· min−1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2receptors; bleeding time showed a twofold increase (432 ± 65 vs. 131 ± 17 seconds; P< 0.005), and platelet aggregation to U-46619 (an agonist of TXA2receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 ± 0.70 vs. 1.72 ± 0.57 mL/min; P< 0.001) and diuresis (4.74 ± 0.79 vs. 3.94 ± 0.66 mL/min; P< 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2excretion. These results suggest a role for renal TXA2as a modulator of water handling in cirrhotic patients with ascites.