Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis: role of adrenomedullin and adrenomedullin binding protein-1

Abstract

Objective: To determine whether the combined administration of adrenomedullin and adrenomedullin binding protein-1 (AM/AMBP-1) has any modulatory effects on the cardiovascular response during the progression of sepsis.

Summary background data: Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Recent studies have shown that AM, a newly reported potent vasodilator peptide, plays a major role in initiating the hyperdynamic response. Moreover, the reduced vascular responsiveness to AM appears to be responsible for the transition from the hyperdynamic phase to the hypodynamic phase of sepsis. Although the novel AMBP-1 augments AM-mediated action in vitro, it remains unknown whether AM/AMBP-1 maintains vascular responsiveness to AM at the late stage of sepsis.

Methods: Sepsis was induced by cecal ligation and puncture (CLP) in adult male rats. Human AMBP-1 (40 microg/kg body weight) was infused intravenously at the beginning of sepsis for 20 minutes and synthetic AM (12 microg/kg body weight) was continuously administrated for the entire study period using an Alzert micro-osmotic pump, beginning 3 hours before the induction of sepsis. At 20 hours after the onset of sepsis (i.e., the late stage), cardiac output, systemic oxygen delivery, stroke volume, total peripheral resistance, and organ blood flow in the liver, gut, kidneys, and heart were determined using radioactive microspheres. Plasma levels of transaminases (ALT, AST) and lactate were also measured. Additional studies were conducted to determine whether administration of AM alone or AMBP-1 alone alters the cardiovascular response at 20 hours after CLP. In additional rats, the necrotic cecum was excised at 20 hours after CLP following AM/AMBP-1 treatment, the peritoneal cavity irrigated with saline, and the midline incision closed in layers. Survival was then examined for a period of 10 days thereafter.

Results: Administration of AM/AMBP-1 prevented the decrease in the measured systemic and regional hemodynamic parameters at 20 hours after the onset of sepsis. Moreover, AM/AMBP-1 significantly attenuated hepatic damage and the elevation of plasma lactate, and prevented hemoconcentration. Treatment with AM/AMBP-1 reduced the overall 10-day mortality rate from 57% to 7%. Neither AM nor AMBP-1 alone was sufficient to maintain cardiovascular stability at 20 hours after CLP.

Conclusions: Since AM/AMBP-1 delays or even prevents the transition from the hyperdynamic phase to the hypodynamic phase of sepsis, attenuates tissue injury, and decreases sepsis-induced morality, these agents should provide a novel approach for maintaining cardiovascular stability and preventing cell and organ damage during the progression of polymicrobial sepsis.

Figure 1. Alterations in cardiac output (CO, A), systemic oxygen delivery (DO₂, B), and total peripheral resistance (TPR, C) in sham-operated animals and septic animals treated with vehicle (normal saline) or AM/AMBP-1 at 20 hours after the surgery. There were six animals in each group. Data are expressed as means ± SE and compared by one-way ANOVA and the Tukey test. *P < .05 versus sham-operated animals; #P < .05 versus CLP animals treated with vehicle.

Figure 2. Alterations in portal blood flow (A), hepatic arterial blood flow (B), and total hepatic blood flow (C) in sham-operated animals and septic animals treated with vehicle (normal saline) or AM/AMBP-1 at 20 hours after the surgery. There were six animals in each group. Data are expressed as means ± SE and compared by one-way ANOVA and the Tukey test. *P < .05 versus sham-operated animals; #P < .05 versus CLP animals treated with vehicle.

Figure 3. Alterations in small intestinal blood flow (A), renal blood flow (B), and cardiac blood flow (C) in sham-operated animals and septic animals treated with vehicle (normal saline) or AM/AMBP-1 at 20 hours after the surgery. There were six animals in each group. Data are expressed as means ± SE and compared by one-way ANOVA and the Tukey test: *P < .05 versus sham animals; #P < .05 versus CLP animals treated with vehicle.

Figure 4. Alterations in plasma levels of alanine aminotransferase (ALT, A) and aspartate aminotransferase (AST, B) and plasma levels of lactate (C) in sham-operated animals and septic animals treated with vehicle (normal saline) or AM/AMBP-1 at 20 hours after the surgery. There were six animals in each group. Data are expressed as means ± SE and compared by one-way ANOVA and the Tukey test. *P < .05 versus sham-operated animals; #P < .05 versus CLP animals treated with vehicle.

Figure 5. Effects of AM/AMBP-1 on the survival rate at 10 days after CLPE with vehicle treatment and CLPE with AM/AMBP-1 treatment. There were 14 animals in each group. Data were analyzed by the Kaplan-Meier method and compared by the log-rank test. *P < .05 versus CLPE plus vehicle.