Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Comparison of acetylcholine and substance P.
BACKGROUND
Whether the abnormal responses of the human coronary circulation to acetylcholine in patients with hypertension and hypercholesterolemia extend to other, nonmuscarinic stimulators of the endothelium and whether this signifies a specific abnormality of NO is not known.


RESULTS
We studied 26 patients with angiographically normal coronary arteries, 10 without risk factors, and 16 with either hypertension (n = 9) and/or hypercholesterolemia (n = 10). Dose-response curves were performed with acetylcholine, substance P, and sodium nitroprusside before and after NG-monomethyl-L-arginine (L-NMMA). Substance P produced predominantly epicardial coronary dilation, whereas the dilating effect of acetylcholine was mainly microvascular. There was no correlation between the responses to the two drugs. L-NMMA did not affect the response to sodium nitroprusside, but it suppressed dilation in response to both substance P and acetylcholine, suggesting that the latter promote bioavailability of NO from the coronary vascular endothelium. Compared with patients without risks, those with hypercholesterolemia and hypertension had significantly reduced vasodilation with substance P: 21% versus 12.6% (P = .004) increase in epicardial coronary diameter and 35% versus 19% (P < .05) decrease in vascular resistance. Similar differences were noted with acetylcholine but not with sodium nitroprusside or adenosine. Epicardial and microvascular dilations with substance P or acetylcholine after L-NMMA were similar in patients with and without risk factors, indicating that the reduced effect of endothelium-dependent vasodilators in those with hypertension and hypercholesterolemia is due to diminished NO activity.


CONCLUSIONS
(1) Substance P- and acetylcholine-induced coronary vasodilation, like that to acetylcholine, is at least partly due to stimulation of NO activity, indicating that the dysfunction of the coronary vascular endothelial cell layer is not restricted to muscarinic receptors. (2) Hypertension and hypercholesterolemia are associated with depression of both basal and pharmacologically stimulated bioavailability of NO.
Quyyumi
A A
AA
National Institutes of Health, Cardiology Branch, NHLBI, Bethesda, MD 20892-1650, USA.
Mulcahy
D
D
Andrews
N P
NP
Husain
S
S
Panza
J A
JA
Cannon
R O
RO
D000109:Acetylcholine / Q000494:pharmacology*; D000328:Adult; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D012016:Reference Values; D013373:Substance P / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013373:Substance P; D000109:Acetylcholine