Endothelins in Pediatric Medicine
Endothelins
Key Points
- Most potent vasoconstrictor known in human physiology
- Critical role in pulmonary vascular resistance
- Major therapeutic target in pediatric pulmonary hypertension
- Significant involvement in developmental biology
Introduction
Endothelins are a family of potent vasoactive peptides that play crucial roles in vascular homeostasis, tissue development, and various pathological conditions in pediatric patients. Their understanding is essential for managing several pediatric conditions, particularly pulmonary hypertension and cardiovascular disorders.
Types and Structure
Isoforms
- Endothelin-1 (ET-1)
- 21 amino acid peptide
- Primary isoform in human vasculature
- Most relevant in clinical medicine
- Endothelin-2 (ET-2)
- Differs by 2 amino acids from ET-1
- Important in ovarian physiology
- Endothelin-3 (ET-3)
- Differs by 6 amino acids from ET-1
- Critical in neural crest development
- Role in melanocyte development
Biosynthesis
- PreproET-1 → BigET-1 → ET-1
- Endothelin Converting Enzyme (ECE) role
- Regulation of synthesis and secretion
Mechanism and Physiology
Receptor Types
- ETA Receptor
- Primary location: Vascular smooth muscle
- Main effect: Vasoconstriction
- Target for therapeutic intervention
- ETB Receptor
- Location: Endothelial cells and smooth muscle
- Effects: Vasodilation via NO release
- Role in ET-1 clearance
Physiological Actions
- Cardiovascular System
- Potent vasoconstriction
- Positive inotropic effect
- Cardiac remodeling
- Developmental Roles
- Neural crest migration
- Craniofacial development
- Enteric nervous system formation
Clinical Significance
Pathological Conditions
- Pulmonary Arterial Hypertension
- Elevated ET-1 levels
- Vascular remodeling
- Treatment targets
- Congenital Heart Disease
- Role in pulmonary overcirculation
- Postoperative management
- Developmental Disorders
- Hirschsprung's disease
- Craniofacial abnormalities
Diagnostic Applications
- Biomarker in pulmonary hypertension
- Prognostic indicator
- Treatment response monitoring
Therapeutic Applications
Endothelin Receptor Antagonists (ERAs)
- Bosentan
- Dual ETA/ETB receptor antagonist
- Pediatric dosing: 2-4 mg/kg/dose BID
- Liver function monitoring required
- Ambrisentan
- Selective ETA receptor antagonist
- Pediatric dosing: 0.25-0.5 mg/kg/day
- Better liver safety profile
- Macitentan
- Next-generation ERA
- Enhanced tissue penetration
- Emerging pediatric data
Clinical Management
- Monitoring Requirements
- Monthly liver function tests
- Hemoglobin/hematocrit
- Pregnancy testing in females of childbearing age
- Drug Interactions
- CYP3A4 inhibitors/inducers
- Phosphodiesterase inhibitors
- Contraceptive considerations
