Vasoconstrictive effects of endothelin-1, endothelin-3, and urotensin II in isolated perfused human lungs and isolated human pulmonary arteries.
BACKGROUND
Urotensin II (UII) has been identified as a ligand for the orphan receptor GPR14 through which it elicits potent vasoconstriction in humans and non-human primates. The pulmonary vasculature is particularly sensitive; human UII (hUII) exhibits a potency 28 times that of endothelin (ET)-1 in isolated pulmonary arteries obtained from cynomolgus monkeys. However, hUII induced vasoconstriction in isolated human intralobar pulmonary arteries is variable, possibly as a result of location dependent differences in receptor density or because it is only uncovered by disease dependent endothelial dysfunction.


METHODS
The vasoactivity of both hUII and gobi UII (gUII) in comparison with ET-1 and ET-3 was studied in isolated perfused lung preparations (n = 14) and isolated intralobar pulmonary arteries (n = 40, mean diameter 548 (27) microm) obtained from 17 men of mean (SE) age 67 (2) years and eight women of mean (SE) age 65 (3) years with a variety of vascular diseases.


RESULTS
ET-1 (10 pM-100 nM) and ET-3 (10 pM-30 nM) elicited vasoconstriction in the lung preparations, inducing comparable increases in pulmonary arterial pressure of 24.8 (4.5) mm Hg and 14.5 (4.9) mm Hg, respectively, at 30 nM (p = 0.13). Similarly, ET-1 (10 pM-300 nM) and ET-3 (10 pM-100 nM) caused marked vasoconstriction in isolated pulmonary arteries, inducing maximal changes in tension of 4.36 (0.26) mN/mm and 1.54 (0.44) mN/mm, respectively, generating -logEC(50) values of 7.67 (0.04) M and 8.08 (0.07) M, respectively (both p<0.05). However, neither hUII nor gUII (both 10 pM-1 micro M) had any vasoactive effect in either preparation.


CONCLUSIONS
UII does not induce vasoconstriction in isolated human pulmonary arterial or lung preparations and is therefore unlikely to be involved in the control of pulmonary vascular tone.
Bennett
R T
RT
Department of Cardiothoracic Surgery, Castle Hill Hospital, Hull & East Yorkshire Hospitals NHS Trust, Cottingham, UK.
Jones
R D
RD
Morice
A H
AH
Smith
C F C
CF
Cowen
M E
ME
D000368:Aged; D000704:Analysis of Variance; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008168:Lung / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000187:drug effects*; D014579:Urotensins / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D019334:Endothelin-3; D014579:Urotensins; D014662:Vasoconstrictor Agents; C029677:urotensin II