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.
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
David
D
Langleben
Jocelyn
J
Dupuis
Isaac
I
Langleben
Andrew M
AM
Hirsch
Murray
M
Baron
Jean-Luc
JL
Senécal
Michele
M
Giovinazzo
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