Reduced endogenous endothelin-1-mediated vascular tone in chronic renal failure.
BACKGROUND
Endothelin-1 generated by the vascular endothelium contributes to basal vascular tone and blood pressure in healthy humans. Plasma concentrations of endothelin-1, which are elevated in chronic renal failure (CRF), may contribute to increased vascular tone.


METHODS
We investigated the contribution of endogenous and exogenous endothelin-1 to the maintenance of vascular tone in patients with CRF (creatinine > or = 200 mumol/liter) and in age- and sex-matched healthy subjects. In a series of experiments, we measured forearm vascular responses to intra-arterial norepinephrine (30 to 240 pmol/min), endothelin-1 (5 pmol/min), the selective endothelin A (ETA) receptor antagonist BQ-123 (3 mg/hr), the mixed endothelin-converting enzyme and neutral endopeptidase inhibitor phosphoramidon (30 nmol/min), and the selective neutral endopeptidase inhibitor thiorphan (30 nmol/min).


RESULTS
The maximum reduction in forearm blood flow (FBF) to norepinephrine in CRF (33 +/- 7%) was similar to that in controls (43 +/- 7%, P = 0.53). Endothelin-1 also produced a similar reduction in FBF in CRF (35 +/- 6%) and controls (36 +/- 5%, P = 0.81). BQ-123 increased FBF in CRF (11 +/- 4%) but significantly less than in controls (44 +/- 10%, P = 0.02). Phosphoramidon increased FBF in CRF (68 +/- 20%), again significantly less than in controls (181 +/- 41%, P = 0.001). Thiorphan reduced FBF similarly in CRF (22 +/- 6%) and controls (14 +/- 6%, P = 0.39). Responses to phosphoramidon were substantially greater than to BQ-123.


CONCLUSIONS
These studies show that endogenous generation of endothelin-1 contributes to the maintenance of resting vascular tone in patients with CRF, as well as in healthy subjects. Although the contribution of endogenous endothelin-1 to resting vascular tone appears to be reduced in CRF, ETA receptor antagonism, and particularly endothelin-converting enzyme inhibition, should be explored as means by which to reduce vascular tone and blood pressure in patients with CRF.
Hand
M F
MF
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, United Kingdom.
Haynes
W G
WG
Webb
D J
DJ
D000328:Adult; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D007269:Injections, Intra-Arterial; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D044022:Receptor, Endothelin A; D012039:Regional Blood Flow / Q000187:drug effects; D015244:Thiorphan / Q000494:pharmacology; D014666:Vasomotor System / Q000503:physiopathology*