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


METHODS
Case series from a single institutional PH center.


METHODS
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.


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.
Langleben
David
D
Center for Pulmonary Vascular Disease, Division of Cardiology, Room E-258, Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, QC, Canada H3T 1E2. david.langleben@mcgill.ca
Dupuis
Jocelyn
J
Langleben
Isaac
I
Hirsch
Andrew M
AM
Baron
Murray
M
Senécal
Jean-Luc
JL
Giovinazzo
Michele
M
D003512:Cyclohexanones; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D005960:Glucosides; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D007201:Indicator Dilution Techniques; D008297:Male; D008833:Microcirculation / Q000502:physiology; D011653:Pulmonary Diffusing Capacity; D013815:Thermodilution
D003512:Cyclohexanones; D019332:Endothelin-1; D005960:Glucosides; C415324:precarthamin