Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat.
NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.
Muscará
M N
MN
Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada.
McKnight
W
W
Del Soldato
P
P
Wallace
J L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009288:Naproxen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; C111751:naproxen-n-butyl nitrate; D009569:Nitric Oxide; D013929:Thromboxane B2; D009288:Naproxen; D019331:NG-Nitroarginine Methyl Ester