ep-092 and dazmegrel

Orthograde and retrograde microperfusion experiments were conducted in Sprague-Dawley rats to evaluate the participation of vasoconstrictive eicosanoids as mediators of tubuloglomerular feedback (TGF) signals. Retrograde perfusion with 160 microM arachidonic acid (AA) added to a hypotonic solution enhanced the stop-flow pressure (SFP) feedback responses compared with those obtained with the control hypotonic solution (delta SFP, 1.6 +/- 0.4 vs. 10.1 +/- 0.7 mmHg with AA). Blockade of thromboxane A2 (TxA2) with the receptor blocker EP 092 or the synthesis inhibitor UK 38485 did not alter the magnitude of the SFP feedback responses obtained with an isotonic solution. Similarly, nordihydroguaiaretic acid, a lipoxygenase inhibitor, did not alter maximal SFP feedback responses. Although indomethacin (5 mM) did induce attenuated SFP feedback responses (delta SFP, 9.5 +/- 0.7 vs. 0.5 +/- 0.4 mmHg with indomethacin), normal feedback responses were restored within 15-90 s after cessation of indomethacin perfusion. Additionally, SFP feedback responses were not inhibited with 5 mM piroxicam, a different cyclooxygenase inhibitor. These data fail to support a role for either TxA2 or lipoxygenase end products as mediators of TGF signals. The rapid restoration of feedback responses after indomethacin exposure and the lack of blockade with piroxicam suggest that transmission of feedback signals is not dependent on cyclooxygenase products.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Homeostasis; Imidazoles; Kidney Glomerulus; Kidney Tubules; Male; Masoprocol; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains

The ontogeny of the renal response to continuous systemic infusion of atrial natriuretic peptide (ANP) was studied in chronically instrumented fetal, newborn, and adult nonpregnant sheep. Plasma immunoreactive ANP (ANPir) concentrations during low (0.025 microgram.kg-1.min-1) and high rate (0.1 microgram.kg-1.min-1) ANP infusion were similar between each group of animals. Decrease in renal blood flow velocity (RBFV) and rise in renal vascular resistance (RVR) were observed in fetal and newborn lambs during ANP infusion. The percent changes in RBFV and RVR were of significantly (P less than 0.05) greater magnitude during high ANP infusion rate in fetuses (-28.5 +/- 8.5 and 93 +/- 6.4%) than in adult sheep (-6.6 +/- 3.2 and -4.4 +/- 4.9%). ANP produced no changes in urine flow (V) in fetuses but increased V significantly in newborn lambs and adult sheep. Glomerular filtration rate increased significantly during ANP infusion in adult sheep but not in fetal and newborn lambs. Percentage changes in urinary excretion rate of Na (UNaV) during high ANP infusion rate were significantly higher in adult sheep (3,520 +/- 2,414%) than in newborn (157 +/- 106%) and fetal lambs (198 +/- 84%). These results suggest that the cardiovascular, renal hemodynamic, and possibly renal function responses to continuous ANP infusion increase during maturation, the overall response being larger in adult animals.

Topics: Animals; Homeostasis; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Male; Masoprocol; Piroxicam; Prostaglandins; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Thromboxane A2

We examined the effect of glomerular immune complex (IC) deposition on glomerular eicosanoid synthesis and the role of the eicosanoids in glomerular pathophysiology. Rats received daily 10 mg i.v. injections of native bovine gamma-globulin (NBGG) or cationic bovine gamma-globulin (CBGG) for 21 days; age-matched controls were maintained. Immunofluorescence and electron microscopy showed mesangial deposits of IC in the NBGG group and capillary wall deposits in the CBGG group, without light or electron microscopic evidence of leukocyte infiltration. One week after the last antigen dose, GFR was similar in all three groups, but RPF increased in the rats given CBGG; (8.37 +/- 0.90 vs. control 5.54 +/- 0.56 ml/min, P less than 0.05). Glomerular synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) was normal in animals that received NBGG. Rats given CBGG had increased glomerular production of PGE2, (2.23 +/- 0.37 vs. control 1.03 +/- 0.16 ng/mg glomerular dry wt, P less than 0.05) and TxB2 (3.12 +/- 0.50 vs. control 0.48 +/- 0.07 ng/mg glomerular dry wt, P less than 0.001). Proteinuria only developed in the rats given CBGG, 86.6 +/- 18 mg/24 hr, which correlated with glomerular TxA2 synthesis, r = 0.82, P = 0.01. Acute administration of the TxA2 synthesis inhibitor, UK-38,485, and a TxA2 receptor antagonist, EP-092, to rats given CBGG did not affect GFR or RPF. The cyclo-oxygenase inhibitor, indomethacin, reduced both GFR and RPF by up to 40% in CBGG-immunized rats. Oral administration of UK-38,485 for six days to nephrotic rats did not result in a statistically significant reduction of proteinuria despite 85% inhibition of glomerular TxB2. We conclude that cationic antigen induces a glomerular disease pathologically similar to membranous nephropathy. The increment of RPF is most probably due to increased glomerular PGE2. The increased TxA2 has no effect on glomerular hemodynamics and probably is not a component in the pathogenesis of proteinuria.

Topics: Animals; Antigen-Antibody Complex; Cations; Dinoprostone; gamma-Globulins; Glomerular Filtration Rate; Glomerulonephritis; Imidazoles; Immunization; Immunoglobulin G; In Vitro Techniques; Indomethacin; Kidney Glomerulus; Microscopy, Electron; Prostaglandins E; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane B2