title: Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine.
abstract: The objective of this study was to examine the role of cylcooxygenase (COX)-2-derived prostaglandins (PG) in modulating the renal hemodynamic effects of norepinephrine (NE) during low or normal sodium intake. The relative contribution of each COX isoform in producing the PG that attenuate the renal NE effects during normal sodium intake was also evaluated. The renal response to three doses of NE (50, 100, and 250 ng. kg(-1). min(-1)) was evaluated in anesthetized dogs pretreated with vehicle, a selective COX-2 inhibitor (nimesulide), or a nonselective COX inhibitor (meclofenamate). Intrarenal infusion of the two lower doses of NE in vehicle-pretreated dogs with normal sodium intake (n = 8) elicited an increase in renal vascular resistance (RVR; 21 and 34%) without inducing changes in glomerular filtration rate (GFR). The highest dose of NE in this group induced a further increment in RVR (113%) and a decrease in GFR (33%). Pretreatment with nimesulide in dogs with normal sodium intake (n = 7) did not modify the NE-induced increments in RVR but enhanced the decreases in GFR induced by the three NE doses (12, 26, and 64%). The renal hemodynamic response to NE in meclofenamate-pretreated dogs with normal sodium intake (n = 7) was similar to that found in dogs pretreated with nimesulide. Infusion of the lowest dose of NE to vehicle-pretreated dogs with low sodium intake (n = 6) did not modify GFR and elicited an increase in RVR (42%). Infusion of the second and third doses of NE led to a decrease in GFR (35 and 91%) and a rise in RVR (82 and 587%). Infusion of the first two doses of NE in nimesulide-pretreated dogs with low sodium intake (n = 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater (P < 0.05) than those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PGE(2) and 6-keto-PGF(1alpha) elicited by NE was prevented in the nimesulide-pretreated dogs. Our results show that COX-2 inhibition potentiates the renal hemodynamic effects of NE and propose that the PG involved in modulating them are mainly derived from COX-2 activity.
authors.affiliation: Department of Physiology, School of Medicine, University of Murcia, 30100 Murcia, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Llinás
authors.forename: R
authors.initials: R
authors.lastname: López
authors.forename: F
authors.initials: F
authors.lastname: Rodríguez
authors.forename: F
authors.initials: F
authors.lastname: Roig
authors.forename: F J
authors.initials: FJ
authors.lastname: Salazar
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000652:urine; D004285:Dogs; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology*; D012982:Sodium, Dietary / Q000008:administration & dosage; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011453:Prostaglandins; D012982:Sodium, Dietary; D008469:Meclofenamic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C049235:11-dehydro-thromboxane B2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D009638:Norepinephrine