Cyclooxygenase-2 products compensate for inhibition of nitric oxide regulation of renal perfusion.
Cyclooxygenase (COX)-2 is in the macula densa, cosegregating with neuronal nitric oxide synthase (nNOS). It is hypothesized that in response to acute inhibition of NOS, the influence of COX-2-derived prostanoids is exaggerated, compensating for renal vasoconstriction. Blood pressure (BP) and renal blood flow (RBF) were measured after selective COX-2 inhibition with NS-398 followed by NOS inhibition with L-nitro arginine methyl ester (L-NAME) or after L-NAME followed by NS-398. BP was 106 +/- 4 mmHg and was unaffected by NS-398. L-NAME after NS-398 increased BP by 27 +/- 2 mmHg, decreased RBF by one-half, and doubled renal vascular resistance (RVR; P < 0.001). Initial L-NAME increased BP by 26 +/- 3 mmHg (P < 0.001) and decreased RBF by 44% (P < 0.001), doubling RVR. After L-NAME, NS-398 induced a further 7 +/- 3-mmHg rise in BP (P < 0.05), decreased RBF by 20% (P < 0.025), and increased RVR by 23% (P < 0.01). The constrictor response to COX-2 inhibition after L-NAME could not be duplicated by either selective nNOS inhibition or NOS-independent renal vasoconstriction. Acute NOS inhibition unmasked renal vasoconstriction with COX-2 inhibition, suggesting that the influence of COX-2-derived vasodilator eicosanoids is exaggerated to maintain renal perfusion, compensating for the acute loss of NO.
Beierwaltes
William H
WH
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA. wbeierw1@hfhs.org
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007191:Indazoles; D007527:Isoenzymes; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester