Echocardiographic and survival studies in mice undergoing endotoxic shock:Effects of genetic ablation of inducible nitric oxide synthase and pharmacologic antagonism of platelet-activating factor

Evidence implicating inducible nitric oxide synthase (iNOS) in the alterati ons of cardiac function characteristic of septic shock has come mostly from studies on anesthetized animals, isolated hearts, cultured myocytes, or ho sts treated with pharmacologic inhibitors that lack complete specificity fo r iNOS. Platelet-activating factor (PAF) can participate in the induction o f iNOS and has also been implicated in cardiac dysfunction in sepsis. The p resent studies assessed cardiac function in a model of sepsis in awake mice in which the gene for iNOS was either normal or selectively disrupted. Mic e of each genotype were treated with parenteral fluids or with a highly spe cific antagonist of PAF. Endotoxic shock was induced by challenge with bact erial lipopolysaccharide (LPS) after priming with heat-killed Propionobacte rium acnes. Wild-type mice increased stroke volume and cardiac output in re sponse to LPS. These changes were absent in iNOS-deficient mice. When treat ed with parenteral fluids, LPS-challenged wild-type and iNOS-deficient mice both had a marked reduction in cardiac output. Antagonism of PAF had no ef fect on echocardiographic indices in wild-type mice, but selectively overca me the bradycardia and reduced cardiac output elicited by fluid administrat ion in LPS-shocked, iNOS-deficient mice. Thus, there are major cardiovascul ar effects of PAF that are shared by rather than mediated by iNOS. Neither complete iNOS deficiency nor antagonism of PAF improved survival, whether t ested as single or combined intervention. On the contrary, complete deficie ncy of iNOS was detrimental to survival. Finally, we tested the hypothesis that iNOS deficiency might improve survival if the deficiency were specific but partial. For this, we used mice with one normal and one disrupted gene for iNOS. No survival advantage was evident for these iNOS heterozygotes. Thus, partial or complete inhibition of iNOS, with or without antagonism of PAF, afforded no evident benefit beyond the previously demonstrated reduct ion in hypotension. Finally, these studies demonstrate that echocardiograph y preceded by acclimatization is feasible in unanesthetized mice, a finding which should expand the value of genetically manipulated animals expand th e value of genetically for analysis of cardiac function. (C) 1999 Academic Press.