Cyclooxygenase 2 inhibition suppresses tubuloglomerular feedback: roles of thromboxane receptors and nitric oxide.
Thromboxane (TxA(2)) and nitric oxide (NO) are potent vasoactive autocoids that modulate tubuloglomerular feedback (TGF). Each is produced in the macula densa (MD) by cyclooxygenase-2 (COX-2) and neuronal nitric oxide synthase (nNOS), respectively. Both enzymes are similarly regulated in the MD and their interaction may be an important factor in the regulation of TGF and glomerular filtration rate. We tested the hypothesis that TGF is modified by the balance between MD nNOS-dependent NO and MD COX-2-dependent TxA(2). We measured maximal TGF during perfusion of the loop of Henle (LH) by continuous recording of the proximal tubule stopped flow pressure response to LH perfusion of artificial tubular fluid (ATF) at 0 and 40 nl/min. The response to inhibitors of COX-1 (SC-560), COX-2 [parecoxib (Pxb)], and nNOS (l-NPA) added to the ATF solution was measured in separate nephrons. COX-2 inhibition with Pxb reduced TGF by 46% (ATF + vehicle vs. ATF + Pxb), whereas COX-1 inhibition with SC-560 reduced TGF by only 23%. Pretreatment with intravenous infusion of SQ-29,548, a selective thromboxone/PGH(2) receptor (TPR) antagonist, blocked all of the SC-560 effect on TGF, suggesting that this effect was due to activation of TPR. However, SQ-29,548 only partially diminished the effect of Pxb (-66%). Specific inhibition of nNOS with l-NPA increased TGF, as expected. However, the ability of Pxb to reduce TGF was significantly impaired with comicroperfusion of l-NPA. These data suggest that COX-2 modulates TGF by two proconstrictive actions: generation of TxA(2) acting on TPR and by simultaneous reduction of NO.
Araujo
Magali
M
Dept. of Medicine, Georgetown Univ., 4000 Reservoir Rd., Bldg. D-395, Washington, DC 20057, USA.
Welch
William J
WJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D025461:Feedback, Physiological; D006834:Hydrazines / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007555:Isoxazoles; D008565:Membrane Proteins; C109599:N(omega)-propylarginine; D011720:Pyrazoles; D017482:Receptors, Thromboxane; C115461:SC 560; D009569:Nitric Oxide; D013928:Thromboxane A2; C045749:SQ 29548; D001120:Arginine; C409945:parecoxib; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat