Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries.
BACKGROUND: In a variety of disease states, endothelium-dependent vasodilation is abnormal. Reduced nitric oxide (NO) production, increased destruction of NO by superoxide, diminished cellular levels of L-arginine or tetrahydrobiopterin, and alterations in membrane signaling have been implicated. We examined these potential mechanisms in human vessels. METHODS AND RESULTS: Relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin, as well as superoxide production and NO synthase expression, were examined in vascular segments from patients with identified cardiovascular risk factors. Endothelium-dependent relaxations were also studied after incubation with L-arginine, L-sepiapterin, and liposome-entrapped superoxide dismutase (SOD) and after organoid culture with cis-vaccenic acid. Relaxations to acetylcholine and to a lesser extent the calcium ionophore A23187 were highly variable and correlated with the number of risk factors present among the subjects studied. Treatment of vessels with L-arginine, L-sepiapterin, liposome-entrapped SOD, or cis-vaccenic acid did not augment endothelium-dependent relaxations. Hypercholesterolemia was the only risk factor associated with high levels of superoxide; however, there was no correlation between superoxide production and the response to either endothelium-dependent vasodilator used. CONCLUSIONS: In human internal mammary arteries, depressed endothelium-dependent relaxations could not be attributed to increases in vascular superoxide production, deficiencies in either L-arginine or tetrahydrobiopterin, or reduced membrane fluidity. Variability in signaling mechanisms may contribute to the differences in responses to acetylcholine and the calcium ionophore A23187.
Huraux, C; Makita, T; Kurz, S; Yamaguchi, K; Szlam, F; Tarpey, MM; Wilcox, JN; Harrison, DG; Levy, JH
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