COX-2 inhibition potentiates vasoconstriction in the absence of NO. Healthy large vessels maintain tone predominantly using NO. If NO is depleted, COX-2–derived prostanoids (eg, PGI) compensate. Then, inhibition of COX-2 leads to constriction because PGI synthesis is blocked and may predispose to cardiovascular side effects. Repletion with NO prevents the increase in tone mediated by COX-2 blockade.