In-vivo interaction of nitric oxide and endothelin.
OBJECTIVE
Endothelin-1 (ET-1) was initially characterized as a potent vasoconstrictor. However, the expected role of ET-1 as a major blood pressure controlling peptide could not be clearly established. Moreover, ET-1 transgenic mice are not hypertensive. We assume that counter-regulating mechanisms such as the nitric oxide (NO) system or an altered expression of endothelin receptors might cause this finding.


RESULTS
An intravenous (i.v.) bolus injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) resulted in a significantly higher blood pressure increase in ET-1 transgenic mice, as compared to non-transgenic littermates. On the other hand, blood pressure increased similarly after an i.v. injection of ET-1 in ET-1 transgenic mice and non-transgenic littermates. Pretreatment with dexamethasone abolished the higher blood pressure increase after L-NAME in ET-1 transgenic mice. Urinary excretion of NO metabolites was elevated in ET-1 transgenic mice and decreased significantly after dexamethasone treatment. Immunohistochemistry revealed that the inducible NO synthase (iNOS) was highly expressed in intrarenal arteries in these mice. Dexamethasone pretreatment abolished vascular iNOS expression. No vascular iNOS expression was detectable in non-transgenic littermates. Furthermore, immunohistochemistry revealed that ET-1 transgenic mice are characterized by an increased tissue density of CD4-positive lymphocytes and macrophages. Analysis of endothelin receptor expression and function revealed that the endothelin subtype A (ETA) receptor was not differently expressed in ET-1 transgenic mice as compared to age-matched littermates. The blood pressure response to an ETA receptor antagonist was likewise similar in ET-1 transgenic mice and age-matched littermates. The endothelin subtype B (ETB) receptor density was decreased in ET-1 transgenic mice. Treatment with an ETB receptor antagonist led to a non-significant slightly higher blood pressure increase in ET-1 transgenic mice as compared to controls.


CONCLUSIONS
The endothelin receptor expression pattern and the blood pressure responses to ETA and ETB receptor antagonists could not explain the lack of hypertension in ET-1 transgenic mice. Overexpression of the human ET-1 gene causes chronic kidney inflammation with an induction of vascular iNOS expression. The induction of iNOS expression might cause a new local balance between vascular ET-1 and nitric oxide, resulting in no alterations of blood pressure.
Hocher
Berthold
B
Department of Nephrology, Charité, Humboldt University of Berlin, Germany. berthold.hocher@charite.de
Schwarz
Anja
A
Slowinski
Torsten
T
Bachmann
Sebastian
S
Pfeilschifter
Josef
J
Neumayer
Hans H
HH
Bauer
Christian
C
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000008:administration & dosage / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D008955:Models, Cardiovascular; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000378:metabolism
D000959:Antihypertensive Agents; D015415:Biomarkers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009569:Nitric Oxide; C086539:BQ 788; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D019331:NG-Nitroarginine Methyl Ester