Endothelin 1 causes pulmonary vasodilation in rats.
Endothelin 1 (ET-1), a peptide produced by endothelial cells, causes transient dilation of some systemic vascular beds. To test whether low concentrations of ET-1 could also dilate the pulmonary vascular bed, we examined its effects in isolated blood- and salt solution-perfused rat lungs and in conscious catheterized rats. In blood-perfused lungs undergoing hypoxic (3% O2) vasoconstriction, repeated additions of 0.5 nM ET-1 to the perfusate elicited transient partial vasodilations. The higher concentration of 5 nM caused a larger transient vasodilation followed by vasoconstriction. In nine conscious rats exposed to 8% O2, intravenous ET-1 (0.2 nmol/kg) reversed the hypoxic pressor response by 63 +/- 8% without affecting cardiac output. In eight salt solution-perfused lungs vasoconstricted with 25 mM KCl, 0.5 nM ET-1 caused a maximum vasodilation of 35 +/- 3% with a half-life of 10.7 +/- 1.1 min. The vasodilation was not inhibited by blockers of cyclooxygenase (3.1 microM meclofenamate), platelet-activating factor receptors (10 microM Web 2086), histamine H1 receptors (50 microM chlorpheniramine), or endothelium-derived relaxing factor activity (10 microM hemoglobin and 50 microM methylene blue). However, it was reduced by approximately 50% with the K+ channel blockers, tetraethylammonium chloride (10 mM) and glybenclamide (10 microM), and the inhibitor of Na(+)-K+ pumping, ouabain (0.1 mM). These results indicate that ET-1 is a potent dilator of the pulmonary vascular bed of the rat and that the mechanism of dilation may involve activation of ATP-sensitive K+ channels and membrane hyperpolarization.
Hasunuma
K
K
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Rodman
D M
DM
O'Brien
R F
RF
McMurtry
I F
IF
D000818:Animals; D016232:Endothelins; D011464:Epoprostenol / Q000378:metabolism / Q000502:physiology; D006632:Histamine / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects*
D016232:Endothelins; D010455:Peptides; D010972:Platelet Activating Factor; D015221:Potassium Channels; D009569:Nitric Oxide; D011189:Potassium Chloride; D006632:Histamine; D011464:Epoprostenol