Selective Cyclooxygenase-2 Inhibitor Nimesulide Research Articles

Role of nitric oxide and cyclooxygenase-2 in regulating the renal hemodynamic response to norepinephrine.

We have reported that the renal hemodynamic effects of norepinephrine (NE) are modulated by cyclooxygenase-2 (COX-2)-derived metabolites. Our main objective was to examine whether there is an interaction between nitric oxide (NO) and COX-2 in modulating the renal hemodynamic effects of NE. NE was infused at three doses to anesthetized dogs pretreated with vehicle (n = 8), a selective COX-2 inhibitor (nimesulide) (n = 6), an NO synthesis inhibitor [NG-nitro-l-arginine methyl ester; l-NAME] (n = 8), or with nimesulide and l-NAME (n = 5). During NE infusion, PGE2 excretion increased (125%) in the control group and did not change in the l-NAME-treated dogs. The simultaneous inhibition of NO and COX-2 potentiated to a greater extent the NE-induced renal vasoconstriction than inhibition of either NO or COX-2. The NE-induced renal vasoconstriction during NO and COX-2 inhibition was reduced (P < 0.05) by infusing an AT1 receptor antagonist (n = 6). These results suggest that there is an interaction between NO and COX-2 in protecting the renal vasculature from the NE effects and that angiotensin II partly mediates the NE-induced renal vasoconstriction when NO synthesis and COX-2 activity are reduced.

The effect of α-melanocyte stimulating hormone on endotoxin-induced intestinal injury

We investigated the effect of α-melanocyte stimulating hormone (α-MSH) on endotoxin-induced intestinal inflammation and the role of nitric oxide and prostaglandins in this response. α-MSH treatment (25 μg/rat, intraperitoneally (i.p.); twice daily) reduced the severity of the lesions macroscopically and microscopically. This protective effect was found to be confined mainly to the distal ileum. These lesions were reversed by pretreatment with the non-selective COX inhibitor indomethacin (10 mg/kg, subcutaneously (s.c.)) but not by the selective COX-2 inhibitor nimesulide (3 mg/kg, s.c.), the NO donor sodium nitroprusside (4 mg/kg, i.v.) or the iNOS inhibitor dexamethasone (3 mg./kg, i.p.) at macroscopic level and reversed by Indo or Dex at microscopic level. Increased peroxidase activity -index of tissue neutrophil infiltration- in the distal ileum of LPS-treated rats was decreased by α-MSH and this effect was reversed by pretreatment with Indo. In conclusion, the neuropeptide α-MSH has a beneficial effect on endotoxin-induced distal intestinal lesions by a mechanism which probably involves nitric oxide and COX-1 derived prostaglandins.

Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase-2.

We report that overexpression of human (h) cyclooxygenase-2 h(COX-2) in the brain of a transgenic mouse line leads to selective induction of endogenous complement component C1qB expression in neurons. No detectable induction of the C3 and C4 complement components in the brain was found. Chronic treatment of mice with the selective COX-2 inhibitor nimesulide reduced the hCOX-2-mediated induction of hippocampal C1qB mRNA expression. The data suggest that neuronal COX-2 expression may influence inflammatory responses in the brain, in part through modulation of complement gene expression. Because there is extensive evidence that C1q and other complement components are involved in Alzheimer's disease (AD) neurodegeneration, this study advances our understanding of the apparent benefits of COX-2 inhibition in AD.

Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine.

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.

The Basis of Prostaglandin Synthesis in Coral: MOLECULAR CLONING AND EXPRESSION OF A CYCLOOXYGENASE FROM THE ARCTIC SOFT CORAL GERSEMIA FRUTICOSA

In vertebrates, the synthesis of prostaglandin hormones is catalyzed by cyclooxygenase (COX)-1, a constitutively expressed enzyme with physiological functions, and COX-2, induced in inflammation and cancer. Prostaglandins have been detected in high concentrations in certain corals, and previous evidence suggested their biosynthesis through a lipoxygenase-allene oxide pathway. Here we describe the discovery of an ancestor of cyclooxygenases that is responsible for prostaglandin biosynthesis in coral. Using a homology-based polymerase chain reaction cloning strategy, the cDNA encoding a polypeptide with approximately 50% amino acid identity to both mammalian COX-1 and COX-2 was cloned and sequenced from the Arctic soft coral Gersemia fruticosa. Nearly all the amino acids essential for substrate binding and catalysis as determined in the mammalian enzymes are represented in coral COX: the arachidonate-binding Arg(120) and Tyr(355) are present, as are the heme-coordinating His(207) and His(388); the catalytic Tyr(385); and the target of aspirin attack, Ser(530). A key amino acid that determines the sensitivity to selective COX-2 inhibitors (Ile(523) in COX-1 and Val(523) in COX-2) is present in coral COX as isoleucine. The conserved Glu(524), implicated in the binding of certain COX inhibitors, is represented as alanine. Expression of the G. fruticosa cDNA afforded a functional cyclooxygenase that converted exogenous arachidonic acid to prostaglandins. The biosynthesis was inhibited by indomethacin, whereas the selective COX-2 inhibitor nimesulide was ineffective. We conclude that the cyclooxygenase occurs widely in the animal kingdom and that vertebrate COX-1 and COX-2 are evolutionary derivatives of the invertebrate precursor.

Role of cyclooxygenase-2-derived metabolites and nitric oxide in regulating renal function.

The aim of this study was to examine the relative contribution of both cyclooxygenase (COX) isoforms in producing the prostaglandins (PG) involved in the regulation of renal function, when nitric oxide (NO) synthesis is reduced. In anesthetized dogs with reduction of NO synthesis, the renal effects of a nonisozyme-specific COX inhibitor (meclofenamate) were compared with those elicited by a selective COX-2 inhibitor (nimesulide) before and during an extracellular volume expansion (ECVE). Intrarenal N(G)- nitro-L-arginine methyl ester (L-NAME) infusion (1 microg x kg(-1) x min(-1); n = 6) did not elicit renal hemodynamic changes and reduced (P < 0.01) the renal excretory response to ECVE. Intravenous nimesulide (5 microg x kg(-1) x min(-1); n = 6) did not modify renal hemodynamic and reduced (P < 0. 05) sodium excretion before ECVE. Simultaneous L-NAME and nimesulide infusion (n = 7) elicited an increment (37%) in renal vascular resistance (RVR; P < 0.05) before ECVE and no hemodynamic changes during ECVE. The reduced excretory response elicited by L-NAME and nimesulide was similar to that found during L-NAME infusion. Finally, simultaneous L-NAME and meclofenamate infusion (10 microg x kg(-1) x min(-1); n = 7) induced an increase in RVR (91%, P < 0.05), a decrease in glomerular filtration rate (35%, P < 0.05), and a reduction of the renal excretory response to ECVE that was greater (P < 0.05) than that elicited by L-NAME alone. The results obtained support the notion that PG involved in regulating renal hemodynamic and excretory function when NO synthesis is reduced are mainly dependent on COX-1 activity.

Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2).

Molecular models of the complex between the selective COX-2 inhibitor nimesulide and the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 have been built using a combination of homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and interaction energy decomposition. It is found that nimesulide exploits the extra space made available by the replacement at position 523 of an isoleucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 numbering). Two alternate binding modes are proposed which are compatible with the pharmacological profile of this agent as a COX-2 selective inhibitor.

Effect of the selective cyclooxygenase-2 inhibitor nimesulide on kainate-induced seizures in the rat brain

Effect of the selective cyclooxygenase-2 inhibitor nimesulide on kainate-induced seizures in the rat brain

Effects of the selective cyclooxygenase-2 inhibitor nimesulide on vascular contractions in endothelium-denuded rat aorta

We have examined the effects of the selective cyclooxygenase-2 inhibitor nimesulide and the non-selective cyclooxygenase inhibitor indomethacin on vascular responsiveness of endothelium-denuded rat aorta. Isometric contractions were obtained to the α-adrenoceptor agonists phenylephrine (full agonist) and clonidine (partial agonist relative to phenylephrine) and to endothelin-1 and KCl. Maximum contractile responses to the partial agonist clonidine were significantly reduced by nimesulide (10 μM) and by indomethacin (10 μM) to 60.8±8.5% ( n=8) and 69.0±9.6% ( n=12) of control, respectively, as compared with the effects of vehicle (99.0±5.8%; n=17). The inhibitors had lesser effects against contractions to phenylephrine: nimesulide had no significant effect, whereas indomethacin caused a small but significant reduction in the maximum contraction to phenylephrine to 90.3±5.0% ( n=12) of control (vehicle: 108.0±5.2%, n=15 nimesulide: 111.8±5.9%, n=5). Neither nimesulide nor indomethacin had any effect on contractions to endothelin-1 or KCl. These actions differed from the effects of the Ca 2+ entry blocker nifedipine, which significantly reduced contractions to clonidine and KCl to a similar extent. The maximum contraction to clonidine was also significantly reduced by the thromboxane receptor antagonist SQ 29548 (1 μM) to 83.4±6.4% of control ( n=7) (vehicle 115.5±7.5%, n=7). It is concluded that the cyclooxygenase inhibitors nimesulide or indomethacin reduce vascular responsiveness to α-adrenoceptor agonists in endothelium-denuded rat aorta, presumably by preventing the formation of vasoconstrictor prostaglandins in aortic smooth muscle by cyclooxygenase-2. This reduced vascular responsiveness was most clearly seen with the partial agonist clonidine.