SUMMARY In vitro studies were performed to investigate the direct effects of the cyclooxygenase inhibitors (COI), meclofenamate, imidazol, acetylsalicylic acid (ASA), indomethacin, and acetominophen on the plasma kailikrein system and on urinary kailikrein excretion. Biological (guinea pig ileum) and colorimetric (synthetic substrate) methods were used. Results showed that all COIs except ASA affected both the activation of pre-kallikrein in plasma and the direct activity of plasma kailikrein, but none of the COIs tested was able to alter the urinary kailikrein excretion. Additionally, in Wistar rats we studied the effects of chronic administration of ASA, meclofenamate, and indomethacin on the plasma kailikrein system and urinary kailikrein excretion. In contrast to the in vitro studies, administration of these COIs reduced the amount of total 24-hour urinary kailikrein excretion. Moreover, the pre-plasma kailikrein and total plasma kailikrein levels were diminished in all experimental groups. However, only ASA and meclofenamate increased the free-plasma kailikrein levels despite the fact the three COIs used reduced the high molecular weight kininogen. Thus, in vitro data suggest an important and direct effect of meclofenamate, imidazol, indomethacin, and acetominophen on the plasma kailikrein system, without any effect on urinary secretion. ASA was the only COI that showed no direct effect in these experiments. Chronic COI administration in Wistar rats suggests that ASA, meclofenamate, and indomethacin affect both the plasma kallikrein-kinin system and kailikrein excretion. When these drugs are used to evaluate the interactions between prostaglandins and the kallikrein-kinin system, their possible effects through both mechanisms, directly or via prostaglandin inhibition, should be considered. the circulation to the kidney was sustained by a major prostaglandin component; withdrawal of this component resulted in significant hemodynamic effects, particularly reduction in blood flow.45 Prostaglandins (PGs) modulate the effects of vasoactive hormones by attenuating the renal actions of the renin-angiotensin system 6 and contributing to or mediating their effects on the kallikrein-kinin system (KKS).7 Moreover, renal KKS is able to stimulate the renal prostaglandin system. 7 Evidence that the renal KKS and PGs are interrelated comes from the relationships between the urinary excretion rates of kailikrein and PGs, 8 the effect of alterations in KKS activity on renal PGs production, 9 ' I0 and the effect of PGs" or cyclooxygenase inhibitors (COIs) on the renal KKS.12 Therefore, we decided to evaluate if COIs, per se, can affect the KKS directly, since many studies analyzed the interaction between both systems by employing prostaglandin inhibition only.