Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X.
OBJECTIVE
This study sought to assess the contribution and action of nitric oxide and endothelin-1 in peripheral resistance vessels of patients with syndrome X.


BACKGROUND
Patients with syndrome X may have a generalized disorder of vascular and endothelial function, promoting vasospasm.


METHODS
Changes in blood flow responses to intrabrachial infusion of the endothelium-dependent vasodilators substance P and acetylcholine, the endothelium-independent nitric oxide donor sodium nitroprusside and the endothelin type A (ET(A)) receptor antagonist BQ-123 were assessed using venous occlusion plethysmography in 10 patients with syndrome X and 10 matched control subjects. Vasoconstrictor responses to the nitric oxide synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA) and endothelin-1 were also determined.


RESULTS
There were no significant differences in the responses to acetylcholine, substance P, sodium nitroprusside or BQ-123 between patients and control subjects. However, despite similar degrees of vasoconstriction in response to L-NMMA in both groups, endothelin-1 caused a reduction in forearm blood flow of only 20 +/- 2% in patients with syndrome X compared with 35 +/- 3% in matched control subjects at 90 min (p < 0.001). Although plasma endothelin-1 concentrations were not significantly higher in patients with syndrome X (4.8 vs. 4.0 pg/ml, p = 0.17), the vasoconstriction caused by endothelin-1 infusion correlated inversely with plasma endothelin-1 concentrations (r = -0.51, p = 0.04).


CONCLUSIONS
Patients with syndrome X had normal basal and stimulated nitric oxide activity and basal endogenous ET(A) receptor-mediated vascular tone. However, despite otherwise normal vascular function, there was reduced responsiveness to exogenous endothelin-1, possibly reflecting overactivity of this system and ET(A) receptor downregulation.
Newby
D E
DE
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Scotland, United Kingdom. D.E.Newby@ed.ac.uk
Flint
L L
LL
Fox
K A
KA
Boon
N A
NA
Webb
D J
DJ
D000704:Analysis of Variance; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D017566:Microvascular Angina / Q000503:physiopathology*; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012044:Regression Analysis; D014655:Vascular Resistance; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)