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Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Comparison of acetylcholine and
A A Quyyumi1, D Mulcahy, N P Andrews
1National Institutes of Health, Cardiology Branch, NHLBI, Bethesda, MD 20892-1650, USA.
Insights
Hypertension and hypercholesterolemia impair nitric oxide (NO) bioavailability in coronary circulation. This dysfunction affects endothelium-dependent vasodilation, not just muscarinic pathways, impacting NO activity.
Area of Science:
- Cardiovascular Physiology
- Endothelial Function
- Nitric Oxide Biology
Background:
- Coronary circulation abnormalities in hypertension and hypercholesterolemia are not fully understood.
- Investigating responses to non-muscarinic endothelium stimulators is crucial.
- The role of nitric oxide (NO) in these responses requires clarification.
Purpose of the Study:
- To determine if coronary vasodilation to non-muscarinic endothelium-dependent agents is impaired in hypertension and hypercholesterolemia.
- To assess the contribution of nitric oxide (NO) to these vasodilation responses.
- To investigate whether endothelial dysfunction in these conditions is specific to muscarinic receptors.
Main Methods:
- Studied 26 patients: 10 healthy controls and 16 with hypertension and/or hypercholesterolemia.
- Administered acetylcholine, substance P, and sodium nitroprusside to assess coronary vasodilation.
- Utilized NG-monomethyl-L-arginine (L-NMMA) to inhibit NO synthesis and evaluate NO-dependent responses.
Main Results:
- Substance P primarily caused epicardial dilation; acetylcholine mainly affected microvascular tone.
- L-NMMA inhibited vasodilation by substance P and acetylcholine, confirming NO involvement.
- Patients with hypertension/hypercholesterolemia showed significantly reduced vasodilation to substance P and acetylcholine compared to controls.
Conclusions:
- Coronary vasodilation induced by substance P and acetylcholine relies partly on NO stimulation.
- Endothelial cell dysfunction in hypertension and hypercholesterolemia extends beyond muscarinic receptors.
- These conditions are linked to reduced basal and stimulated NO bioavailability in the coronary vasculature.
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.
Methods And 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.