dinoprost and phenidone

The mechanisms responsible for diabetes mellitus-induced enhancement of prostaglandin (PG) F2 alpha response were investigated in vascular smooth muscles isolated from diabetic mice and rats. Streptozocin (150 mg/kg, i.v. bolus, 6 week-elapsed)-ddY mice and (60 mg/kg, i.v. bolus)-Wistar rats and genetically diabetic GK-rats were used. The responses to PGF2 alpha were enhanced in small blood vessels such as mesenteric arteries (diabetic rats) and veins (diabetic mice) and they were reduced in large blood vessels such as the aorta and vena cava (diabetic rats). The enhanced response to PGF2 alpha in diabetic blood vessels was significantly inhibited by nordihydroguaiaretic acid (NDGA) (0.03 mM) and phenidone (0.05 mM), lipoxygenase inhibitors, cycloheximide (1 mg/kg, i.v.), a protein synthesis inhibitor and actinomycin D (2.8 mg/kg, i.v.), a RNA polymerase inhibitor, but neither inhibited by cyclooxygenase inhibitors, a thromboxane antagonist, nor Ca2+ antagonists. The PGF2 alpha response was also enhanced with aging alone, whereas the extent of enhancement was less than that with diabetes mellitus, and not significantly blocked by NDGA. These results demonstrate that diabetes mellitus-induced imbalance in the regulation of the eicosanoid metabolic pathways (suppressed cyclooxygenase and accelerated lipoxygenase) may cause the enhancement of PGF2 alpha-induced responses in small blood vessels.

Topics: Aging; Animals; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Dinoprost; Drug Interactions; In Vitro Techniques; Lipoxygenase Inhibitors; Male; Masoprocol; Mesenteric Arteries; Mesenteric Veins; Mice; Mice, Inbred Strains; Muscle Contraction; Muscle, Smooth, Vascular; Protein Biosynthesis; Pyrazoles; Rats; Rats, Wistar

1. The effects of phenidone (P, 10(-4)-10(-3) M), sodium diclofenac (D, 10(-5)-10(-4) M) and ethacrynic acid (E, 10(-5)-10(-4) M), proposed as inhibitors of eicosanoid synthesis, on the contractions of rat uterus induced by several agonists have been studied. 2. P, D and E inhibit the motility induced by oxytocin (4 mU/ml) (IC50: 4.62 x 10(-4), 2.55 x 10(-4) and 2.98 x 10(-5) M, respectively). 3. P (10(-3) M), D (10(-4) M) and E (10(-4) M) also inhibit the contraction induced by methacholine (10(-5) M), prostaglandin F2a (10(-6) M) and CaCl2 (6 mM), and relaxed, in a dose-dependent way, the tonic component of contraction to KCl (60 mM) (IC50: 5.81 x 10(-4), 6.67 x 10(-5) and 7.55 x 10(-5) M, respectively). 4. The CaCl2 (0.1-10 mM) reverted the relaxation of KCl contraction produced by P, but not by D or E. None of the inhibitions on CaCl2 (6 mM) are reverted by Bay K 8644. 5. D and E also relaxed the tonic contraction to vanadate (10(-4) M) in uterus incubated in calcium free solution P, enhances the vanadate-induced contractions.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium; Calcium Chloride; Diclofenac; Dinoprost; Edetic Acid; Ethacrynic Acid; Female; In Vitro Techniques; Lipoxygenase Inhibitors; Methacholine Compounds; Oxytocin; Potassium Chloride; Pyrazoles; Rats; Rats, Inbred Strains; Uterine Contraction; Vanadates

Topics: Animals; Biotechnology; Cell Differentiation; Cell Division; Cell Fusion; Cells, Cultured; Dinoprost; Dinoprostone; Eicosanoids; Indomethacin; Lipoxygenase; Lipoxygenase Inhibitors; Mice; Muscles; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles

Experiments were designed to determine the role of the endothelium in the facilitation by anoxia of contractile responses of isolated coronary arteries. Rings and strips of canine coronary arteries, with or without endothelium, were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution. To determine the release of a vasoactive substance(s) from the endothelial cells, strips without endothelium were layered with strips containing endothelium. In rings and in layered preparations with endothelium, anoxia (95% N2-5% CO2) augmented contractile responses to prostaglandin F2 alpha. Hypoxia (10 or 5% O2) caused contractions in the presence of indomethacin. Removal of the endothelium abolished the anoxic facilitation, and the hypoxic contractions. Inhibitors of cyclo-oxygenase, lipoxygenase or phospholipase A2 or of adrenergic, serotonergic and histaminergic receptors did not prevent the response to anoxia. Likewise, inhibitors of the endothelium-derived factor(s) (quinacrine, phenidone and methylene blue) did not affect the anoxic facilitation. Hypoxia and anoxia caused contraction of coronary arteries without endothelium when layered with femoral arteries and veins with endothelium. Anoxic facilitation was observed in femoral arteries, but not in femoral veins, with endothelium. These experiments indicate that hypoxia and anoxia cause the release of a diffusible vasoconstrictor substance(s) from endothelial cells. The sensitivity of smooth muscle of different anatomical origin to the facilitatory mediator(s) varies.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Coronary Vessels; Dinoprost; Dogs; Endothelium; Female; In Vitro Techniques; Indomethacin; Isometric Contraction; Male; Methylene Blue; Muscle, Smooth, Vascular; Oxygen; Prostaglandins F; Pyrazoles; Quinacrine; Vasoconstriction