Adrenomedullin and Adrenomedullin Binding Protein-1 Protect Endothelium-Dependent Vascular Relaxation in Sepsis

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 µg/kg) and AMBP-1 (40 µg/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.

Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock

“…This finding fits with Gupta et al reporting that the salutary effect of activated protein C in rats was not associated with complete reversal of the LPS-induced increase in blood NO and ADM levels [ 15 ]. It is tempting to speculate that HAM1101 attenuated excess NO and ADM formation rather than completely blocking it while maintaining the constitutive production necessary for organ homoeostasis [ 9 , 12 ]. Clearly, the attenuated iNOS activation is not mirrored by reduced NO 2 − + NO 3 − levels.…”

“…Adrenomedullin (ADM) has been referred to as a double-edged sword in sepsis [ 1 ]: during cecal ligation and puncture (CLP)- [ 2 – 4 ], endotoxin- [ 5 ], or Staphylococcus aureus α-toxin-induced sepsis [ 6 ], ADM administration restored organ perfusion during the hypodynamic shock phase. This effect coincided with attenuated systemic inflammation [ 7 ], decreased activation of the inducible nitric oxide synthase (iNOS) and peroxynitrite formation [ 8 ], and reduced organ dysfunction [ 9 ], apoptosis [ 10 ], and mortality [ 6 ]. ADM release is therefore referred to as a protective adaption to systemic inflammation [ 11 ] and circulatory shock [ 12 ].…”

Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models

“…With respect to endothelium-dependent vascular relaxation, AM is known to induce vasodilation which is mediated partially by endothelium-derived nitric oxide [ 92 - 96 ]. Also, in a rat model of sepsis induced by cecal ligation and puncture, administration of AM and AM-binding protein (AMBP-1 also known as complement factor H) were shown to prevent against endothelial cell dysfunction and decreased endothelium-dependent vascular relaxation in thoracic aorta [ 97 ]. These studies implicate AM as having a protective role in cardiovascular disease and endothelial dysfunction, but further research needs to be performed to investigate how AM directly impacts cardiac endothelial cells to regulate their function.…”

Resuscitation of Uncontrolled Traumatic Hemorrhage Induced by Severe Liver Injury: The Use of Human Adrenomedullin and Adrenomedullin Binding Protein-1

“…In addition, studies have shown that downregulation of vascular endothelial constitutive nitric oxide synthase (ecNOS) contributes to vascular hyporesponsiveness in sepsis 28 . In this regard, we have previously shown that acetylcholine induced vascular relaxation was significantly reduced in late sepsis, i.e., 20 h in a rat model of cecal ligation and puncture (CLP) 29 . Gene and protein expression of ecNOS in aortic and pulmonary tissues were downregulated in late sepsis.…”