Lack of iNOS impairs endothelial function in endothelin-1 transgenic mice.
BACKGROUND
Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation.


METHODS
We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS-/-) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788.


RESULTS
Systolic blood pressure was similar in ET+/+, iNOS-/- and wild-type mice, but was significantly elevated in ET+/+ iNOS-/- crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 +/- 5 vs. 78 +/- 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS-/- animals (75 +/- 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 +/- 4%), iNOS-/- mice (38 +/- 5%) and ET+/+ iNOS-/- mice (44 +/- 4%) to a similar extent as compared with wild-type littermates (66 +/- 4%; p < 0.05).


CONCLUSIONS
Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS-/- animals.
Quaschning
Thomas
T
Department of Nephrology, University Hospital of Freiburg, Freiburg, Germany.
Voss
Florian
F
Herzfeld
Sophia
S
Relle
Katharina
K
Kalk
Philipp
P
Godes
Michael
M
Pfab
Thiemo
T
Kraemer-Guth
Annette
A
Bonz
Andreas W
AW
Theuring
Franz
F
Galle
Jan
J
Hocher
Berthold
B
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*
D019332:Endothelin-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse