Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium.

Abstract

Hypercholesterolemia, before atherosclerosis, is known to reduce agonist-(e.g., acetylcholine) mediated nitric oxide (NO) production within 2 weeks of a cholesterol-enriched diet. However, no data exist on the effect of hypercholesterolemia on the basal release of NO from blood vessels. We studied the basal release of NO in rabbit coronary arteries by addition of the NO synthase blocker yV G -nltro-L-arginine-methyl ester (L-NAME). Basal release of NO was markedly attenuated 2 weeks after introduction of a 0.5% cholesterol addition to the diet One week later, the adherence of neutrophils to the coronary endothelium was significantly enhanced (i.e., threefold; p<0.01 different from control). The increased adhesiveness could be attributed to enhanced endothelial adhesion rather than to changes in the properties of the leukocytes. Both phenomena could be reversed by addition of L-arginine to isolated coronary arteries. Administration of 10 mg/day lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, markedly attenuated both the reduced basal NO production and the increased adhesiveness of the endothelium. These results support the concept that NO is an important protective agent produced by the endothelium to preserve the integrity of the endothelium and may protect it against atherogenesis. (Arteriosclerosis and Thrombosis 1993;13:771-776) KEY WORDS • endothelium-derived relaxing factor • nitric oxide • lovastatin • leukocyte adherence A therosclerosis is thought to be induced by injury / \ or pathophysiological changes to the vascular J. \ . endothelium.1 One of the earliest alterations to the endothelium after exposure to high cholesterol levels is the loss of endothelium-derived relaxing factor (EDRF), now identified as nitric oxide (NO).W EDRF has been shown to exert a variety of physiological actions in addition to its well-known relaxation of vascular smooth muscle, 4 including inhibition of platelet aggregation, 5 attenuation of leukocyte adherence to the endothelium, 6 -7 and the quenching of superoxide radicals. -9Many investigators have shown a reduction in agonistmediated EDRF production or release in atherosclerotic vessels. 1011 Recently, however, a significant endothelial dysfunction characterized by reduced EDRF release was shown within 2 weeks after initiation of a 0.5% cholesterol supplement to the diet, before any coronary artery plaque occurred.12 This is consistent with other reports of endothelial dysfunction in rabbit coronary arteries without plaque that are adjacent to Supported by research grant GM-45434 from the National Institutes of Health.Address for correspondence: Dr. Allan M. Lefer, Department of Physiology, Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107-6799. Received October 29, 1992 revision accepted February 16, 1993. plaque-lined coronary arteries. 13 However, no data are available on leukocyte adherence to the coronary endothelium over the course of the hypercholesterolemic preplaque period. Moreover, the relation of adherence t...

Inhibition of NO Synthesis Induces Inflammatory Changes and Monocyte Chemoattractant Protein-1 Expression in Rat Hearts and Vessels

“…Therefore, our present results suggest that early inflammatory and proliferative changes play a key role in the development of subsequent structural changes observed during late phases in this model. Although a short-term reduction in NO synthesis has been shown to increase neutrophil rolling and adherence to the endothelium, 32,33 no such polymorphonuclear cells was observed in the lesions.…”

Interaction of Diabetes and Hypertension on Determinants of Endothelial Adhesiveness

“…In addition, it is likely that this endothelial dysfunction will result in increased adherence of other blood cell elements, such as neutrophils and platelets. 25,26 Furthermore, these risk factors may also have important direct effects on circulating cells to enhance their activity. Indeed, we have previously observed that mononuclear cells isolated from patients with non-insulin-dependent diabetes mellitus bind more avidly to cultured ECs than do mononuclear cells derived from control subjects.…”

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

“…Inhaled nitric oxide gas reverses pulmonary hypertension (27), reverses pulmonary vasoconstriction (28), improves lung function in affected patients and increases ventilation-perfusion ratios (29). In addition, nitric oxide inhibits platelet aggregation (13 -15), platelet (30,31) and leukocyte (16)(17)(18) adhesion on endothelial cells and vascular albumin leakage (19,20). Thus, nitric oxide seems to contribute greatly to maintaining physiological functions in the lung.…”

“…The endothelium releases numerous biologically important materials, one of which is endothelium-derived relaxing factor (EDRF): nitric oxide (8) or nitrosothiol (9)(10)(11). EDRF released from vascular endothelial cells plays an important role in cardiovascular and pulmonary systems, being involved in vasodilation (12), inhibition of platelet aggregation (13 -15), leukocyte adhesion (16)(17)(18) and vascular albumin leakage (19,20). Although DEP is thought to be a causative factor responsible for the recent increase in patients with pulmonary diseases, neither the cause-and-result relationship nor the pathogenic mechanism has been demonstrated.…”