Increase in nitric oxide bioavailability improves endothelial function in endothelin-1 transgenic mice.
BACKGROUND
Endothelin-1 (ET-1) has been described as a very potent vasoconstrictor. Nevertheless, transgenic mice overexpressing ET-1 have been shown to exhibit normal blood pressure. We thus hypothesized that vascular ET-1 effects may be antagonized by increased activity of other regulatory systems, such as the increase in bioavailability of the endothelial counterpart of ET-1, nitric oxide (NO).


METHODS
Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine (10(-10)-10(-4) mol/l), sodium nitroprusside (10(-10)-10(-4) mol/l), ET-1 (10(-10)-10(-7) mol/l) and big ET-1 (10(-10)-10(-7) mol/l), respectively, in ET-1 transgenic mice and corresponding controls. To unmask the impact of the NO system, we furthermore analysed vessel rings incubated in vitro with the NO-synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) mol/l).


RESULTS
Maximum endothelium-dependent relaxation was enhanced in ET-1 transgenic mice (93+/-3% vs 84+/-4% for wild-type littermates; P<0.05) and was inhibited by preincubation with L-NAME in both ET-transgenic mice and wild-type littermates (11+/-5% vs 9+/-4% maximum relaxation, respectively). Endothelium-independent relaxation was similar among all groups. Maximum vascular contraction to ET-1 and big ET-1 was reduced in ET-1 transgenic mice (P<0.05 vs wild-type littermates). Preincubation with L-NAME reduced this difference, indicating the involvement of augmented NO availability. Correspondingly, urinary nitrate/nitrite excretion was significantly elevated in ET-1 transgenic mice.


CONCLUSIONS
These data suggest that in transgenic mice overexpressing ET-1, increased NO bioavailability counteracts the contractile potency of elevated ET-1 levels and leads to an improvement of endothelium-dependent relaxation. Thus, in the presence of an activated ET system, up-regulation of NO production may be capable of maintaining vascular tone in a normal range and therefore may prevent the development of hypertension.
Quaschning
Thomas
T
Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany.
Koçak
Serkan
S
Bauer
Christian
C
Neumayer
Hans-Hellmut
HH
Galle
Jan
J
Hocher
Berthold
B
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology* / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D009599:Nitroprusside / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D000109:Acetylcholine