Enhanced contractile mechanisms in vasospasm: is endothelial dysfunction the whole story?

Abstract

The importance of the endothelium in regulating vascular tone and reactivity is well recognized. The endothelium produces a variety of substances including nitric oxide (NO), prostaglandins, endothelin-1, and an unidentified hyperpolarization factor that control vascular tone, thrombus formation, platelet and leukocyte adhesion and aggregation, and cellular proliferation. Alterations in the synthesis or activity of these substances appear to play a major role in the pathogenesis of a variety of diseases. Emphasis has been placed on alterations in the generation and function of NO as an underlying mechanism for abnormal vascular reactivity in atherosclerosis and other vascular diseases. Studies in both animal models and humans demonstrate that NO-mediated responses are decreased in atherosclerosis, diabetes, and a wide variety of vascular diseases. But measurements of NO in atherosclerosis have produced variable results with decreases1 and increases2 in the levels of NO reported. Inactivation of NO by reactive oxygen species may account for the decrease in NO-mediated responses.3 See p 1545 Although the absence of vasodilator mechanisms may impair the ability of the coronary circulation to respond to increases in myocardial oxygen consumption or vasoactive substances, for vasospasm to occur, an increase in contractile mechanisms must also occur. Previous studies from the laboratory of Akira Takeshita and coworkers in animal models of coronary vasospasm have suggested that increased vascular contractions are primarily related to smooth muscle hyperreactivity.4 Takeshita and coworkers compared the relative contributions of abnormal endothelium-dependent responses versus smooth muscle function to enhanced vascular muscle contractions in a model of vasospasm to determine whether vasospasm is due to altered NO-mediated responses, enhanced vasoconstrictor responses, or both.4 Endothelium-dependent responses were examined in two ways: measurements of serotonin-induced constriction and substance P–induced …