Treatment of hypotension in septic shock.
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Angiotensin II↗
Biomedical subjects
C M Pastor
Publications and source records attributed to C M Pastor.
Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats.
Systemic vascular hyporeactivity to vasoconstrictors has been described in rats following endotoxin administration. Inducible nitric oxide synthase (iNOS) expression is known to occur in the liver in endotoxemia, but consequences of iNOS induction on hepatic hemodynamics are unknown. The reactivity of the hepatic circulation to phenylephrine was tested in perfused livers from normal rats and rats previously injected with endotoxin (20 mg/kg ip). In control rats (n = 5), phenylephrine-induced portal pressure increases were similar in livers perfused with Krebs-Henseleit-bicarbonate (KHB) buffer, KHB plus the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mM), or KHB plus the substrate for NO synthesis, L-arginine (1 mM). In contrast, livers from endotoxin-treated rats (n = 5) exhibited a marked reduction in the vasoconstrictive response to phenylephrine (14.6 vs. 55.1% in livers from control rats, P < 0.05). Perfusion with L-NMMA restored the phenylephrine response, and the L-NMMA effect was reversible with L-arginine. Perfusate NO2-/NO3- and guanosine 3',5'-cyclic monophosphate (cGMP) levels were increased in endotoxin-treated rats and significantly reduced by L-NMMA perfusion. In control livers, the NO donor S-nitroso-N-acetyl-DL-penicillamine blocked the portal pressure increase after phenylephrine administration. These results suggest that rat hepatic circulation takes part in the systemic vascular hyporeactivity to vasoconstrictors observed in endotoxemia and that NO is involved in this hyporeactivity to phenylephrine.
Animals↗
Sources of arginine for induced nitric oxide synthesis in the isolated perfused liver.
Hepatocytes can be stimulated to express high levels of inducible nitric oxide synthase (iNOS), which utilizes arginine for nitric oxide (NO) synthesis. Hepatocytes also synthesize and catabolize arginine, an intermediate in the urea cycle, raising the possibility that the urea pathway may provide substrate for hepatic NO synthesis. To identify the sources of arginine for iNOS, we measured the release of NO-2 + NO-3 and urea in isolated rat livers perfused in a recirculation model with a Krebs-Henseleit-bicarbonate buffer containing either no added amino acid, arginine, or precursors for urea synthesis. To induce iNOS expression, rats were injected with killed Corynebacterium parvum (C. parvum) or with endotoxin. In livers from C. parvum- and endotoxin-treated rats, we found that 1) an intracellular source of arginine exists that provides substrate to iNOS; 2) additional exogenous arginine increase NO synthesis, demonstrating that endogenous arginine is insufficient for maximal NO synthesis; and 3) an increase in the rate of endogenous arginine synthesis within the urea cycle is inefficient in increasing NO synthesis, demonstrating the independence of the two pathways in the liver.
Animals↗
Regulation and functions of nitric oxide in the liver in sepsis and inflammation.
The liver plays important roles in metabolic and immune responses during sepsis. It is the major site of acute-phase protein synthesis and is responsible for the clearance of circulating pathogens. In addition to mediators such as cytokines and eicosanoids, numerous studies have emphasized the role of nitric oxide (NO.) in influencing hepatic function during sepsis. The induction and the distribution of inducible nitric oxide synthase in the liver, the regulation of the enzyme, and the functions of NO. in the liver are the subject of this review.
Amino Acid Oxidoreductases↗
Nitric oxide donor prevents hepatic and systemic perfusion decrease induced by endotoxin in anesthetized rabbits.
Controversial studies have been published concerning the role of nitric oxide (NO) release (beneficial or deleterious) during sepsis. Severe hypotension has been treated by NO inhibitors in humans, but animal studies described an increased mortality rate with this treatment. We hypothesized that an NO donor might be beneficial in maintaining liver flow during endotoxemia. To answer that question, mean arterial pressure (MAP), aortic, hepatic artery, and portal vein blood flow velocities (AoV, HAV, and PVV) (Doppler technique) were measured after endotoxin injection (Escherichia coli, Salmonella minnesota, and Salmonella enteritidis, 400 micrograms each, intravenously) in anesthetized and mechanically ventilated rabbits. Fifteen animals were treated with saline solution (10 mL/hr) or linsidomine perfusion (2 mg over 3 hours, 10 mL/hr). Saline-treated animals experienced a hypodynamic shock with a decrease in MAP, AoV, and PVV. In contrast, HAV increased without fully compensating the PVV decrease. In linsidomine-perfused rabbits, AoV and PVV remained at control level, and HAV increased without any further effect on MAP. Serum lactate levels increased in the saline-treated group and did not change in linsidomine-treated animals. These findings show that at the early phase of an endotoxin shock, and in the absence of intense fluid resuscitation, linsidomine perfusion is beneficial in maintaining systemic and hepatic perfusion while preventing lactic acidosis. These data suggest that, in the early phase of endotoxemia, NO is insufficiently released to allow adequate liver perfusion.
Animals↗
Effect of modifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model.
The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.
Animals↗