Cerebrovascular reactivity and cerebral perfusion of rats with acute liver failure: role of L‐glutamine and asymmetric dimethylarginine in L‐arginine‐induced response

Abstract

Cerebral blood flow (CBF) is impaired in acute liver failure (ALF), however, the complexity of the underlying mechanisms has often led to inconclusive interpretations. Regulation of CBF depends at least partially on variations in the local brain L-arginine concentration and/or its metabolic rate. In ALF, other factors, like an increased concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and elevated level of L-glutamine, may contribute to CBF alteration. This study demonstrated strong differences in the reactivity of the middle cerebral arteries and their response to extravascular L-arginine application between vessels isolated from rats with thioacetamide (TAA)-induced ALF and control animals. Our results also showed the decrease in the cerebral perfusion in TAA rats measured by arterial spin labeling perfusion magnetic resonance. Subsequently, we aimed to investigate the importance of balance between the concentration of ADMA and L-arginine in the CBF regulation. In vivo, intraperitoneal L-arginine administration in TAA rats corrected: (i) decrease in cerebral perfusion, (ii) decrease in brain extracellular L-arginine/ADMA ratio and (iii) increase in brain L-glutamine concentration. Our study implicates that impaired vascular tone of cerebral arteries is most likely associated with exposure to high ADMA and L-glutamine levels resulting in limited availability of L-arginine and might be responsible for reduced cerebral perfusion observed in ALF.

Decreased Expression and Uncoupling of Endothelial Nitric Oxide Synthase in the Cerebral Cortex of Rats with Thioacetamide-Induced Acute Liver Failure

“…eNOS is critically involved in the maintenance of adequate cerebral blood flow (CBF) [76]. Therefore, deactivation of eNOS is a likely cause of the CBF impairment in the prefrontal cortex of TAA rats which was consistently observed in the present and in a previous study [77], as well as in studies in which different CBF recording procedures have been used [78]. Importantly in this context, several reports have implicated the participation of nNOS in CBF control (Santizo et al, 2000, Chi et al, 2003.…”

“…Isolated prefrontal cortex tissue was homogenized (1/5; w/v) in Locke buffer (154 mM NaCl, 5.6 mM KCl, 1.0 mM MgCl2, 2.3 mM CaCl2, 8.6 mM HEPES, 5.6 mM glucose, 0.1 mM glycine, pH 7.4) and diluted 10 times. Homogenate samples were incubated with NOS substrate L-arginine (100 µM) and/or L-NAME (100 µM), EDTA (1 mM), BH4 (100 nM) for 10 min, at 22-25 • C. The dose of L-arginine was chosen based on the literature and our previous study [77]. Subsequently, 10 µM carboxy-H2 DCFDA was added to each reaction mixture.…”

Mitochondrial Changes in Rat Brain Endothelial Cells Associated with Hepatic Encephalopathy: Relation to the Blood–Brain Barrier Dysfunction

“…The importance of this mechanism comes to light when confronted with the previous observation that l -glutamine infusion in the absence of hyperammonemia impairs cerebrovascular CO 2 reactivity, most likely by reducing l -arginine availability and NO synthesis [ 90 ]. A recent study from our laboratory demonstrated strong differences in the reactivity of the middle cerebral arteries and in their response to extravascular l -arginine application between vessels isolated from rats with TAA-induced HE and control animals, implicating that impaired vascular tone of cerebral arteries, which may involve, among other factors, their persistent exposure to high l -glutamine [ 91 ].…”