Format

Send to

Choose Destination
Mol Med. 2007 Sep-Oct;13(9-10):488-94.

Adrenomedullin and adrenomedullin binding protein-1 protect endothelium-dependent vascular relaxation in sepsis.

Author information

1
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, and The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.

Abstract

Downregulation of vascular endothelial constitutive nitric oxide synthase (ecNOS) contributes to the vascular hyporesponsiveness in sepsis. Although coadministration of the potent vasodilatory peptide adrenomedulin (AM) and the newly discovered AM binding protein (AMBP-1) maintains cardiovascular stability and reduces mortality in sepsis, it remains unknown whether AM/AMBP-1 prevents endothelial cell dysfunction. To investigate this possibility, we subjected adult male rats to sepsis by cecal ligation and puncture (CLP), with or without subsequent intravenous administration of the combination of AM (12 microg/kg) and AMBP-1 (40 microg/kg). Thoracic aortae were harvested 20 h after CLP (i.e., the late stage of sepsis) and endothelium-dependent vascular relaxation was determined by the addition of acetylcholine (ACh) in an organ bath system. In addition, ecNOS gene and protein expression was assessed by RT-PCR and immunohistochemistry, respectively. The results indicate that ACh-induced (i.e., endothelium-dependent) vascular relaxation was significantly reduced 20 h after CLP. Administration of AM/AMBP-1 prevented the reduction of vascular relaxation. In addition, ecNOS gene expression in aortic and pulmonary tissues was downregulated 20 h after CLP and AM/AMBP-1 attenuated such a reduction. Moreover, the decreased ecNOS staining in thoracic aortae of septic animals was prevented by the treatment with AM/AMBP-1. These results, taken together, indicate that AM/AMBP-1 preserves ecNOS and prevents reduced endothelium-dependent vascular relaxation (i.e., endothelial cell dysfunction) in sepsis. In light of our recent finding that AM/AMBP-1 improves organ function and reduces mortality in sepsis, it is most likely that the protective effect of these compounds on ecNOS is a mechanism responsible for the salutary effect of AM/AMBP-1 in sepsis.

PMID:
17932560
PMCID:
PMC2014730
DOI:
10.2119/2007-00113.Zhou
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Feinstein Institute Icon for PubMed Central
Loading ...
Support Center