The Pivotal Role of Adrenomedullin in Producing Hyperdynamic Circulation During the Early Stage of Sepsis

Abstract

Background: Initial cardiovascular responses during sepsis are characterized by hyperdynamic circulation. Although studies have shown that a novel potent vasodilatory peptide, adrenomedullin (ADM), is up-regulated under such conditions, it remains unknown whether ADM is responsible for initiating the hyperdynamic response. Objective: To determine whether increased ADM release during early sepsis plays any major role in producing hyperdynamic circulation. Design, Intervention, and Main Outcome Measure: Synthetic rat ADM (8.5 µg/kg of body weight) was infused intravenously in normal rats for 15 minutes at a constant rate.Cardiacoutput,strokevolume,andmicrovascularblood flow in various organs were determined immediately as well as 30 minutes after ADM infusion. At 30 minutes after infusion, plasma ADM level was also measured. In additional groups, rats were subjected to sepsis by cecal ligation and puncture. At 1.5 hours after cecal ligation and puncture, specific anti-rat ADM antibodies were infused, which completely neutralized the circulating ADM. Various hemodynamic variables were measured 5 hours after cecal ligation and puncture (ie, the early stage of sepsis). Results: Cardiac output, stroke volume, and microvascular blood flow in the liver, small intestine, kidney, and spleen increased, and total peripheral resistance decreased 0 and 30 minutes after ADM infusion. In addition, plasma levels of ADM increased from the preinfusion level of 92.7 ± 5.3 to 691.1 ± 28.2 pg/mL 30 minutes after ADM infusion, which was similar to ADM levels observed during early sepsis. Moreover, 5 hours after the onset of sepsis, cardiac output, stroke volume, and microvascular blood flow in various organs increased and total peripheral resistance decreased. Administration of anti-ADM antibodies, however, prevented the occurrence of the hyperdynamic response. Conclusions: The results suggest that increased ADM production and/or release plays a major role in producing hyperdynamic responses during early sepsis. Since our previous studies have shown that vascular responsiveness to ADM decreases in late sepsis, maintenance of ADM vascular responsiveness by pharmacological agents during the course of sepsis may prevent transition from the hyperdynamic to the hypodynamic state.

Midregional Proadrenomedullin Predicts Mortality and Major Adverse Cardiac Events in Patients Presenting With Chest Pain: Results From the CHOPIN Trial

“…ADM is elevated in response to a variety of stimuli, including sepsis and ventricular pressure/volume overload. [17][18][19][20][21] A double-monoclonal antibody sandwich immunoassay for the measurement of the more stable midregional (MR) fragment of the precursor (pro-ADM) has been identified. 22 Baseline and the change in MR-proADM concentrations after ACS have been shown to be associated with risk of major clinical events, including death.…”

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

“…Vascular smooth muscle cells consequently react by relaxation, which is both endothelial cell-dependent through the AM-induced release of NO (6) and endothelial cell-independent through a protein kinase A-dependent regulation of calcium dependent K ϩ channels (7). Recent studies have shown that up-regulation of AM plays a major role in initiating the hyperdynamic response during the early stage of sepsis and that a reduced vascular sensitivity to AM appears to be responsible for the transition from the hyperdynamic to the hypodynamic phase of shock during the progression of experimental polymicrobial sepsis that usually precedes death (8).…”

Adrenomedullin binding protein-1 is downregulated during polymicrobial sepsis in the rat

“…However, we found that the small intestine is a major source of AM production in sepsis and LPS may increase AM production (8,24). Elevated levels of AM play a major role in producing the early hyperdynamic phase of sepsis (25,26). On the other hand, in the late phase of sepsis, there is a decreased vascular response to AM, which is probably caused by the reduction of AMBP-1 (6).…”