Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and l-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased (∼35%) but aortic blood flow increased during endotoxin infusion ( P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio ( P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance (∼3- to 4-fold), whereas AVP or LC attenuated this drop ( P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability ( P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE (∼2-fold increase) but not AVP infusion ( P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P (∼2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.
Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase.