terutroban and Kidney-Diseases

Topics: Animals; Atrasentan; Cardiovascular Diseases; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Kidney Diseases; Male; Methyldopa; Naphthalenes; NG-Nitroarginine Methyl Ester; Pre-Eclampsia; Pregnancy; Prenatal Care; Propionates; Rats; Receptors, Thromboxane A2, Prostaglandin H2; Sex Factors; Sympatholytics

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.

Topics: Animals; Atrasentan; Endothelin A Receptor Antagonists; Female; Gene Expression Regulation; Heart Diseases; Hemodynamics; Kidney; Kidney Diseases; Myocardium; Naphthalenes; Pre-Eclampsia; Pregnancy; Propionates; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Thromboxane A2, Prostaglandin H2

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress.

Topics: Animals; Apolipoproteins E; Arachidonate 12-Lipoxygenase; Aspirin; Diabetes Mellitus, Experimental; Female; Gene Deletion; Kidney Diseases; Mice; NADPH Oxidases; Naphthalenes; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphoproteins; Propionates; Proteinuria; Receptors, Thromboxane