CGRP Degradation
Neutral endopeptidase (NEP) is the primary enzyme responsible for degrading CGRP in human tissues, while angiotensin-converting enzyme (ACE) appears to have an inhibitory rather than degradative role in CGRP metabolism. 1
Primary Degradation Pathway
- NEP serves as the most important enzyme for CGRP degradation in human skin and peripheral tissues. 1
- When NEP is blocked with phosphoramidon, CGRP levels increase significantly and can be directly measured in tissue samples, demonstrating NEP's critical role in CGRP catabolism. 1
- Inhibition of NEP with phosphoramidon increases both the intensity and size of CGRP-mediated neurogenic flare responses, providing functional evidence of reduced CGRP degradation. 1
Role of ACE in CGRP Metabolism
- ACE does not contribute to CGRP degradation; instead, it appears to have an inhibitory role in CGRP metabolism. 2
- When ACE is blocked with captopril alongside NEP inhibition, CGRP levels actually decrease compared to NEP inhibition alone, suggesting ACE blockade augments CGRP catabolism rather than preventing it. 2
- Combined inhibition of NEP and ACE does not produce additive effects on CGRP accumulation, further supporting that these enzymes do not work synergistically in CGRP degradation. 2
Clinical Implications
- Brush border peptidases in the intestinal epithelium also degrade peptides including CGRP-related molecules, representing an additional site of peptide metabolism. 3
- The specificity of NEP for CGRP degradation has therapeutic relevance for conditions involving neurogenic inflammation, including migraine and complex regional pain syndrome. 1
- Monoclonal antibodies targeting CGRP can effectively block both exogenous and endogenous CGRP activity, demonstrating CGRP's neurotransmitter role and providing an alternative therapeutic approach to enzyme inhibition. 4
Functional Consequences of Reduced Degradation
- NEP inhibition increases CGRP-mediated vasodilation and flare responses, confirming that endogenous NEP activity normally limits CGRP bioavailability. 5
- Blocking CGRP degradation with phosphoramidon paradoxically suppresses sweating while increasing the area of axon reflex flare, likely due to elevated CGRP and substance P levels. 5