2-3-dinor-6-ketoprostaglandin-f1alpha and Disease-Models--Animal

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Abdominal; Aortic Diseases; Atherosclerosis; Cholesterol; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Induction; Epoprostenol; Hypercholesterolemia; Indomethacin; Male; Norepinephrine; Rabbits; Thiophenes; Vasoconstriction; Vasoconstrictor Agents

The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I(2) (PGI(2)). Mice that overexpress PGI(2) synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI(2) receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI(2) is a potential therapeutic target in the treatment of RSV.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Viral; Cytochrome P-450 Enzyme System; Disease Models, Animal; Epoprostenol; Female; Gene Deletion; Interferon-alpha; Interferon-beta; Interferon-gamma; Intramolecular Oxidoreductases; Lung; Male; Mice; Mice, Transgenic; Pulmonary Edema; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Receptors, Epoprostenol; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Signal Transduction; Weight Loss

Little is known about the pathophysiological processes leading to superimposed preeclampsia. We present an animal model where the uteroplacental blood flow in spontaneously hypertensive rats (SHR) was reduced by a silver clip. Thus, a superimposed preeclampsia-like syndrome could be studied under defined conditions. Urinary excretion of 2,3-dinor-6-keto PGF1 alpha and 11-dehydro-TxB2 were measured by enzyme immunoassays at day 16 and 20 of pregnancy. In gravid, sham-operated animals excretion of 2,3-dinor-6-keto-PGF1 alpha was largely elevated compared to non gravid control animals (day 16: 1259 vs. 258 ng/kg 24h; day 20: 471 vs. 269 ng/kg.24h). However, in the gravid rats with reduced uteroplacental blood flow urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased to non gravid levels (day 16: 335 ng/kg.24h; day 20: 238 ng/kg.24h). By antihypertensive therapy with dihydralazin this effect was largely abolished. Only minor alterations were found in the excretion of 11-dehydro-TxB2. Our findings suggest, that a reduction of uteroplacental blood flow in the spontaneously hypertensive rat decreases the systemic prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Dihydralazine; Disease Models, Animal; Female; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred SHR; Thromboxane B2