Endothelin ETA receptor-subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans.
BACKGROUND
Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade.


METHODS
The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects.


METHODS
Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow.


RESULTS
Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions.


CONCLUSIONS
Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.
Bayerle-Eder
M
M
Department of Clinical Pharmacology, Vienna University, Vienna, Austria.
Langenberger
H
H
Pleiner
J
J
Polska
E
E
Mensik
C
C
Eichler
H-G
HG
Wolzt
M
M
Schmetterer
L
L
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007444:Inulin; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D012079:Renal Circulation / Q000187:drug effects; D017595:Renal Plasma Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D010130:p-Aminohippuric Acid
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D000804:Angiotensin II; D007444:Inulin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D010130:p-Aminohippuric Acid