Antihypertensive properties of a nitric oxide-releasing naproxen derivative in two-kidney, one-clip rats

Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hyper tension. In this study, we tested the hypothesis that a nitric oxide-releas ing derivative of naproxen would ameliorate hypertension in the rat. Hypert ension was induced by partially occluding one renal artery (the "2K, 1C" mo del), and 2 wk later the rats started receiving naproxen, the nitric oxide- releasing derivative HCT-3012, or vehicle each day for 2 wk. Naproxen signi ficantly exacerbated the hypertension. HCT-3012 significantly reduced blood pressure relative to both the naproxen- and vehicle-treated groups. Both n aproxen and HCT-3012 markedly suppressed whole blood thromboxane B-2 synthe sis. In studies of anesthetized rats, naproxen significantly enhanced the l ate hypertensive response to endothelin-1 and significantly blunted the ear ly hypotensive response. In contrast, HCT-3102 did not affect either respon se to endothelin-1. In vitro, HCT-3012 significantly reduced the responsive ness of aortic rings to the contractile effects of phenylephrine. These stu dies suggest that HCT-3012 reduces blood pressure in hypertensive rats, not simply through the vasodilatory actions of the nitric oxide it releases, b ut through alterations in the responsiveness of the vasculature to endogeno us pressor agents.