Superoxide production, risk factors, and endothelium-dependent relaxationsin human internal mammary arteries

Background-In a variety of disease states, endothelium-dependent vasodilati on is abnormal. Reduced nitric oxide (NO) production, increased destruction of NO by superoxide, diminished cellular levels of L-arginine or tetrahydr obiopterin, 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 A23 187, and nitroglycerin, as well as superoxide production and NO synthase ex pression, were examined in vascular segments from patients with identified cardiovascular risk factors. Endothelium-dependent relaxations were also st udied after incubation with L-arginine, L-sepiapterin, and liposome-entrapp ed superoxide dismutase (SOD) and after organoid culture with cis-vaccenic acid. Relaxations to acetylcholine and to a lesser extent the calcium ionop hore A23187 were highly variable and correlated with the number of risk fac tors present among the subjects studied. Treatment of vessels with L-argini ne, L-sepiapterin, liposome-entrapped SOD, or cis-vaccenic acid did not aug ment endothelium-dependent relaxations. Hypercholesterolemia was the only r isk factor associated with high levels of superoxide; however, there was no correlation between superoxide production and the response to either endot helium-dependent vasodilator used. Conclusions-In human internal mammary arteries, depressed endothelium-depen dent relaxations could not be attributed to increases in vascular superoxid e production, deficiencies in either L-arginine or tetrahydrobiopterin, or reduced membrane fluidity. Variability in signaling mechanisms may contribu te to the differences in responses to acetylcholine and the calcium ionopho re A23187.