Contractions to histamine in pulmonary and mesenteric arteries from endotoxemic rabbits: modulation by vascular expressions of inducible nitric-oxide synthase and histamine H1-receptors.

Abstract

The inducible isoform of nitric-oxide synthase (iNOS) is highly expressed after induction of endotoxemia and contributes to vascular hypocontractility in endotoxemia. Circulating levels of histamine are elevated in animal models of sepsis and in patients with septic shock. This study assessed whether the vascular effects of histamine play a significant role in the pathophysiology of endotoxemic shock despite the hyporesponsiveness to vasoconstrictors associated with iNOS up-regulation. Rabbits were rendered endotoxemic by lipopolysaccharide (LPS; 100 microg/kg, i.v.). In mesenteric arteries taken from animals at 6 h of LPS administration, the contractile response to histamine was significantly impaired but histamine-evoked contractions in pulmonary arteries were unchanged. Western blot revealed a drastic increase in iNOS expression in mesenteric vessels after LPS, but endotoxin-induced iNOS increase was not so marked in pulmonary vessels. On the other hand, expression of endothelial nitric-oxide synthase was suppressed under LPS challenge in both types of vessels. In the presence of NG-nitro-l-arginine or (S)-ethylisothiourea used for iNOS inhibition, histamine-evoked contractions of endotoxemic pulmonary and mesenteric vessels were significantly enhanced. This was possibly associated with a dramatic increase in H1-receptor expression at the gene and protein levels, as determined by Northern blot and immunoblot analyses. Furthermore, we found that LPS-induced endotoxemia caused prominent increases in production of histamine through induction of histidine decarboxylase in tissues, including blood vessels. From these results, we propose that histamine may contribute to the development of endotoxin-induced pulmonary hypertension.