Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension.

Abstract

STUDY OBJECTIVES:

Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance.

DESIGN AND SETTING:

Case series from a single institutional PH center.

PATIENTS:

Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied.

MEASUREMENTS AND RESULTS:

Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products.

CONCLUSIONS:

Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.

• Authors: David Langleben, Jocelyn Dupuis, Isaac Langleben, Andrew M Hirsch, Murray Baron, Jean-Luc Senécal, Michele Giovinazzo
• Journal: Chest (Chest) Vol. 129 Issue 3 Pg. 689-95 (Mar 2006) ISSN: 0012-3692 [Print] United States
• PMID: 16537869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexanones
• Endothelin-1
• Glucosides
• precarthamin

Topics

• Cyclohexanones
• Endothelin-1 (metabolism)
• Endothelium, Vascular (physiopathology)
• Female
• Glucosides
• Humans
• Hypertension, Pulmonary (etiology, metabolism)
• Indicator Dilution Techniques
• Male
• Microcirculation (physiology)
• Pulmonary Diffusing Capacity
• Thermodilution