dinoprost and ramatroban

Recent studies show that 8-iso-prostaglandin F(2alpha), a member of F(2)-isoprostane family, acts as a vasoconstrictor via TP receptor activation; and its local release may contribute to an abnormal vasomotor tone associated with hypercholesterolemia. The purpose of this study was to examine whether ramatroban, a TP receptor antagonist, improves abnormal vascular reactivity in vivo in hypercholesterolemic rabbits. The plasma 8-iso-prostaglandin F(2alpha) levels in hypercholesterolemic groups were significantly higher than those in normal groups. The treatment by ramatroban reversed the attenuation of the vascular response to acetylcholine in hypercholesterolemic groups. However, L-N(G)-nitroarginine methyl ester, a nitric oxide synthase inhibitor, did not inhibit the protective effects of ramatroban. Attenuation of the vascular response to acetylcholine in hypercholesterolemic rabbits was significantly enhanced by 8-iso-prostaglandin F(2alpha). Attenuation of the vascular response to acetylcholine by a cholesterol-rich diet and 8-iso-prostaglandin F(2alpha) was canceled by ramatroban. These findings suggest that ramatroban improves the vascular response in vivo to acetylcholine in hypercholesterolemic rabbits by blocking the action of 8-iso-prostaglandin F(2alpha).

Topics: Acetylcholine; Animals; Carbazoles; Dinoprost; F2-Isoprostanes; Hypercholesterolemia; Male; Nitroprusside; Rabbits; Receptors, Thromboxane; Sulfonamides; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function.. The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined.. BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA.. NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Antioxidants; Carbazoles; Cholestasis; Dinoprost; Glutathione; Ligands; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sodium; Sulfonamides; Thioctic Acid; Thromboxane B2

8-Epi-prostaglandin F2alpha (8-epi-PGF2alpha) is an F2-isoprostane formed mainly via noncyclooxygenase pathways in vivo. We investigated whether 8-epi-PGF2alpha has any effect on airflow obstruction and plasma exudation in vivo. Airflow obstruction was quantified by measuring lung resistance (RL) in anesthetized and ventilated guinea pigs, and plasma exudation was quantified by the Evans Blue dye method (20 mg/kg intravenously). Intratracheal instillation of 8-epi-PGF2alpha (1 nmol or 10 nmol) caused dose-related increases in RL. Furthermore, the higher dose of 8-epi-PGF2alpha produced Evans Blue dye extravasation in main bronchi and intrapulmonary airways. A prostanoid TP-receptor antagonist, BAY u3405 (1 mg/kg intravenously), abolished the airway effects of 8-epi-PGF2alpha (10 nmol). A thromboxane A2 (TxA2) synthase inhibitor, OKY-406 (30 mg/kg intravenously), significantly attenuated these effects of 8-epi-PGF2alpha (10 nmol). The level of TxB2, a stable TxA2 metabolite, increased in bronchoalveolar lavage fluid (BALF) after 8-epi-PGF2alpha instillation. We conclude that 8-epi-PGF2alpha causes airflow obstruction and plasma exudation in vivo. This effect may be mediated primarily via prostanoid TP-receptors, and a secondary generation of TxA2 may be involved in part of the airway responses in 8-epi-PGF2alpha in the guinea pig.

Topics: Airway Obstruction; Animals; Bronchoalveolar Lavage Fluid; Carbazoles; Dinoprost; Guinea Pigs; Histamine Antagonists; Male; Methacrylates; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2; Thromboxane B2; Vasoconstrictor Agents

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carbazoles; Dinoprost; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Sulfonamides; Thromboxanes; Trachea