Mechanisms and drug therapy of pulmonary hypertension at high altitude.

Abstract

Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension.

• Authors: Urs Scherrer, Yves Allemann, Emrush Rexhaj, Stefano F Rimoldi, Claudio Sartori
• Journal: High altitude medicine & biology (High Alt Med Biol) Vol. 14 Issue 2 Pg. 126-33 (Jun 2013) ISSN: 1557-8682 [Electronic] United States
• PMID: 23795732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Anti-Inflammatory Agents
• Antihypertensive Agents
• Biomarkers
• Endothelin-1
• Vasodilator Agents
• Nitric Oxide

Topics

• Acute Disease
• Adaptation, Physiological
• Altitude Sickness (drug therapy, etiology, physiopathology)
• Anti-Inflammatory Agents (therapeutic use)
• Antihypertensive Agents (therapeutic use)
• Biomarkers (metabolism)
• Chronic Disease
• Endothelin-1 (metabolism)
• Female
• Fetal Development
• Foramen Ovale, Patent (physiopathology)
• Humans
• Hypertension, Pulmonary (drug therapy, etiology, physiopathology)
• Nitric Oxide (metabolism)
• Oxidative Stress
• Pre-Eclampsia (physiopathology)
• Pregnancy
• Pulmonary Edema (drug therapy, etiology, physiopathology)
• Risk Factors
• Sympathetic Nervous System (physiopathology)
• Vasodilator Agents (therapeutic use)