The purpose of this study was to investigate the mechanisms involved in the angiotensin II-induced increase in the contractile response of the hypertensive wall after prolonged incubation in the organ-bath buffer. In 5-h incubated rings, the contractile response to angiotensin II in aortic rings with endothelium from spontaneously hypertensive rats (SHRs) was markedly exaggerated in comparison to 2-h incubated rings. No such potentiation was observed in SHR rings after removal of the endothelium or in intact and denuded Wistar-Kyoto (WKY) rat rings. Aspirin and SQ29548 inhibited and cycloheximide and actinomycin D reduced the time-dependent enhanced response to angiotensin II in rings with endothelium from SHRs. In SHR rings with endothelium incubated for 2 h, the contractions caused by angiotensin II were potently inhibited by piroxicam but were unaffected by NS-398. Conversely, in rings incubated for 5 h, the hyperresponsiveness to angiotensin II was inhibited to a greater extent by NS-398 than by piroxicam. Piroxicam but not NS-398 had a further inhibitory effect on the residual angiotensin II-induced contraction in actinomycin D-treated rings incubated for 5 h. In conclusion, our study shows that long-term incubation leads to hyperresponsiveness to angiotensin II in SHR aorta with endothelium. The enhanced response is associated with the induced release of vasoconstrictor prostanoids sensitive to the inhibitory effect of NS-398, a preferential inhibitor of COX-2.