MR-proADM Mechanism of Action

Mechanism of action

Adrenomedullin, a 52 amino acid peptide, is a member of the calcitonin peptide family and is widely expressed in many tissues and organs.1 It can be upregulated by lipopolysaccharide (LPS) or pro-inflammatory cytokines during the course of bacterial, viral or fungal infections. Adrenomedullin has been shown to play a significant role in many physiological processes, including cellular growth, development, chemotaxis and migration.2-7 It also has potent anti-microbial activity, eliciting its response through membrane channel formation and lysis, as well as anti-apoptotic actions.8-11 However, two main actions are of significant interest in many disease conditions.

Microcirculation and vascular endothelial barrier function properties

Growing evidence indicates that Adrenomedullin plays a key role in reducing vascular permeability and enhancing the stability of the endothelial system.

 

In summary, Adrenomedullin can accurately reflect the pathophysiological changes occurring in the microcirculation during disease conditions, which may lead to organ dysfunction. Consequently, monitoring Adrenomedullin levels can be valuable in evaluating disease progression or assessing the efficacy of therapeutic interventions on the host response.

Adrenomedullin: A key role in organ protection

  • Predicts organ dysfunction and outcome early12
  • Protects against endothelial permeability and organ damage13-15
  • Provides protective effects to organs in response to bacterial induced shock16-17
  • Stabilizes microcirculation during inflammation18
  • Restores endothelial stability in infected organs19 

Vasodilatory properties

Adrenomedullin is well-known for its vasodilatory properties. Increased circulating concentrations result in potent and sustained hypotension, primarily due to the generation of nitric oxide in the vasculature. Transient concentration surges contribute to the dramatic hypotension and vascular collapse observed in patients experiencing acute episodes of systemic capillary leak syndrome.20 Both acute and chronic increases in Adrenomedullin can lead to a significant decrease in total peripheral resistance, a drop in blood pressure, and an increase in heart rate, cardiac output, and stroke volume.

 

Therefore, fluctuations in Adrenomedullin levels can significantly impact blood supply to organs in certain disease settings.

Adrenomedullin: Vasodilation is key

  • Acts as key mediator of vascular tone regulation resulting in an intense, prolonged vasorelaxation and hypotension1,21-25
  • Helps maintain blood supply to individual organs through its widespread production1,22,26
  • Supports localized cellular production to meet specific perfusion requirements of individual organs27,28
  • Plays a significant role in hemorrhagic and endotoxic shock29,30,31 pulmonary hypertension32, hypertrophy33-34, hypoxia35-40, oxidative stress41, ischaemic myocardial injury42-45 and ischaemic injury and organ failure

 

Difference between Adrenomedullin and MR-proADM

Reliable and accurate measurement of Adrenomedullin is challenging/limited due to several factors, including its short half-life, fast metabolism, low concentrations, rapid degradation by proteases, and binding to compliment factor H. Consequently, Adrenomedullin levels are often underestimated. The measurement of Mid-Regional proAdrenomedullin (MR-proADM) provides a solution to these issues.

 

Biosynthesis of MR-proADM

MR-proADM is a fragment of 48 amino acids that splits from the proAdrenomedullin (proADM) molecule in a 1:1 ratio with Adrenomedullin, and therefore proportionally represents the levels and activity of Adrenomedullin. Its biological inactivity means that it does not bind to vessel walls and surfaces as found with Adrenomedullin. This biological inactivity, along with the longer half-life of MR-proADM results in a more accurate estimation of plasma concentration levels compared to Adrenomedullin.2-3

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  2. Kohno M, Yokokawa K, Kano H, Yasunari K, Minami M, Hanehira T, et al. Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells. Hypertension (Dallas, Tex : 1979). 1997;29(6):1309-13.
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