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SllmmaryInhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N~~ (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N~-amino-t-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVKI and PVKI, p ~< 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p -0.046) compared with controls (n = 6). Moreover, N'~ increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of t-arginine did not improve survival or alter the cardiopulmonary effects of N~~ -arginine, which suggests that inhibition of NOS may not have been competitive, In normal animals, N~176 alone (n = 3) increased SVtLI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N~'-amino-L-arginine, or both.

Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P < 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P < 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P < 0.025). E. coli produced significant endotoxemia (P < 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P < 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.

Ten antiprotozoal drugs were tested in vitro against four axenic strains of the intestinal parasite Blastocystis hominis. Inhibitory drugs in order of effectiveness were emetine, metronidazole, furazolidone, trimethoprim sulfamethoxazole, 5-chloro-8-hydroxy-7-iodo-quinoline (Entero-Vioform), and pentamidine. Moderately inhibitory were two quinolines other than iodochlorhydroxquin. These were chloroquine and 5,7-diiodo-8-hydroxy-quinoline (Floraquin). Diloxanide furoate was not inhibitory. Paromomycin and other antibiotics were not inhibitory. Entero-Vioform and metronidazole have been effective in human and higher primate diarrhea caused by B. hominis.