Incubation of aortic strips with ethacrynic acid, at pH 7.4, markedly decreases tissue sulfhydryl (SH) groups and decreases aorta sensitivity to all tested vasodilators. This desensitization to vasodilators could be achieved under conditions which did not alter norepinephrine- or KCl-induced contraction of rabbit aortic strips. There appears to be two distinct vasodilation responses, one activated by direct interaction with a specific receptor site and not necessarily requiring SH oxidation as a primary event, and a second group of nonspecific vasodilators in which vasodilation is correlated with ability to react with SH groups. Besides " specific receptors," a hypothetical model is presented which contends that all vasodilators act through a common intermediate reaction involving critical SH groups witimin the tissue.