The effect of cerivastatin therapy on vascular responses to endothelin antagonists in humans.
Endothelin blocking drugs have vasodilator effects mediated at least in part via the nitric oxide system. Hypercholesterolaemia is associated with vascular dysfunction manifest as impaired nitric oxide-mediated vasodilatation and arterial stiffness. Treatment with HMG CoA reductase inhibitors (statins) has proven mortality benefits in a range of patient populations. Subjects (n = 5) received either placebo or 800 mug cerivastatin for an 8-week period in a double-blind, placebo-controlled, cross-over study. Cerivastatin reduced the total plasma cholesterol compared with baseline by 27% (5.4 +/- 0.4 mmol/L versus 7.3 +/- 0.4 mmol/L, P = 0.04). Selective endothelin-A receptor blockade caused an increase in forearm blood flow (FBF) (18.0 +/- 7.2%, P = 0.04). Compared with placebo, cerivastatin therapy caused a trend towards a further increase in FBF (18.0 +/- 7.2% versus 52.0 +/- 19.0%, P = 0.06). Selective endothelin-B receptor blockade reduced FBF (-11.0 +/- 3.9%, P = 0.02) with no difference between placebo and cerivastatin therapy (-11.0 +/- 3.9% versus -13.0 +/- 3.6%, P = 0.9). Combined endothelin-A/endothelin-B receptor blockade increased FBF (39.8 +/- 13.4%, P < 0.01) with no difference between placebo and cerivastatin therapy (39.8 +/- 13.4% versus 42.4 +/- 19.0%, P = 0.7). There was a trend towards a reduction in the augmentation index between cerivastatin and placebo (6.2 +/- 2.7 versus 9.1 +/- 2.4, n = 5, P = 0.4) compared with baseline (7.2 +/- 1.0). In conclusion, statin therapy may decrease large artery stiffness and increase the vasodilating effects of endothelin-A receptor blockade.
Leslie
Stephen J
SJ
Centre for Cardiovascular Science, The University of Edinburgh, Western General Hospital, Edinburgh, UK. s.j.leslie@ed.ac.uk
Spratt
James C
JC
Grieg
Lynn
L
Attina
Teresa
T
Denvir
Martin A
MA
Webb
David J
DJ
D008078:Cholesterol, LDL / Q000097:blood; D003187:Compliance; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009842:Oligopeptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D008078:Cholesterol, LDL; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; C086539:BQ 788; C086276:cerivastatin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)