Activated Protein C Prevents Endotoxin-Induced Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide

Abstract

Background — Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-α (TNF-α) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-α production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock. Methods and Results — Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO 2 − /NO 3 − . The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-α and expression of TNF-α mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor DIP-APC, an active site-blocked APC, showed any effect on these ET-induced changes. Both inhibition of TNF-α production by leukocytopenia and treatment with anti-rat TNF-α antibody produced effects similar to those induced by APC. Aminoguanidine, a selective inhibitor of iNOS, inhibited both the hypotension and the increases in plasma levels of NO 2 − /NO 3 − in this animal model. Conclusions — These observations strongly suggest that APC inhibits iNOS induction by decreasing TNF-α production, leading to the prevention of ET-induced hypotension. Furthermore, such effects of APC were not dependent on its anticoagulant effects but rather on its serine protease activity.

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

“…Hence, a more severe septic shock state in PC ϩ/Ϫ mice supports previous evidence that PC contributes to the regulation of BP. 30,57 Importantly, although previous studies described the effect of aPC administration on reduction of hypotension independent of its anticoagulant properties, 30 the present study shows an aggravated hypotensive state in mice expressing ϳ50% of normal PC levels. The convergence of the results of these different approaches strongly suggests a mechanistic role of aPC in the prevention of hypotension.…”

“…In a rat model of endotoxemia, aPC prevented LPS-induced hypotension, an effect that was dependent on its serine protease activity. 30 Although administration of aPC appears to be beneficial to a subset of patients with severe septicemia, there is little available evidence to suggest that deficiencies in PC would lead to a more severe host response to the septic state, 31 ie, although therapeutically somewhat effective, there is no proof that aPC is on the mechanistic pathway to septic responses. Thus, a new experimental model of PC-deficient mice becomes a valuable tool to study gene associations in this disease, particularly with regard to those genes that might have a reciprocal relationship with the PC pathway.…”

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

“…Animal models using blocking antibodies to EPCR showed an important regulatory role of the protein C system with inflammation and coagulation related to Escherichia coli infection [13]. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis Study (PROWESS), patients diagnosed with sepsis and acute organ dysfunction were treated with recombinant human APC, which resulted in a mortality reduction of 19.4% [14][15][16][17][18]. It was initially believed that APC increased patient survival through its anticoagulant properties, reducing microvasculature thrombi formation and promoting blood flow.…”

Proteína C ativada no tratamento de recém-nascido com sepse, choque e disfunção de múltiplos órgãos e sistemas: relato de caso e revisão de literatura

“…Entre os pacientes tratados com a medicação, a taxa de mortalidade foi significativamente menor (24,7%), quando comparado à taxa de mortalidade do grupo placebo (30,8%) (p = 0,005), determinando a interrupção precoce do estudo. Vincent e col. observaram que, entre os pacientes tratados com PCA, o desenvolvimento de falência orgânica ocorreu mais tardiamente e a recuperação dos quadros de choque e falência respiratória, mais rapidamente, confirmando os resultados obtidos em modelos experimentais 34,35 . A incidência de sangramento grave foi de 3,5% nos pacientes que receberam a PCA e 2% no grupo placebo (p = 0,06).…”