Exacerbation of intracranial aneurysm and aortic dissection in hypertensive rat treated with the prostaglandin F-receptor antagonist AS604872.

Intracranial aneurysm (IA) and aortic dissection are both complications of hypertension and characterized by degeneration of the media. Given the involvement of prostaglandin F2α and its receptor, FP, in extracellular matrix remodeling in a mouse model of pulmonary fibrosis, here we induced hypertension and IA in rats by salt loading and hemi-lateral ligation of renal and carotid arteries and examined effects of a selective FP antagonist, AS604872, on these vascular events. AS604872 significantly accelerated degeneration of the media in both cerebral artery and aorta as evidenced by thinning of the media and disruption of the elastic lamina and promoted IA and aortic dissection. Notably, AS604872 induced expression of pro-inflammatory genes such as E-selectin in lesions and significantly enhanced macrophage infiltration. Suppression of surface expression of E-selectin with cimetidine prevented macrophage infiltration and aortic dissection. Thus, AS604872 exacerbates vascular inflammation in hypertensive rats and facilitates IA and aortic dissection. These results demonstrate that both IA and aortic dissection are caused by chronic inflammation of the arterial wall, which is worsened by AS604872, cautioning that other FP antagonists may share such deleterious actions in vascular homeostasis and suggesting that AS604872 can be used to make models of these vascular diseases with extensive degeneration.

Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers.

Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. Indomethacin became the first-choice drug to produce an experimental ulcer model as a result of having a higher ulcerogenic potential than other non-steroidal anti-inflammatory drugs (NSAIDs). There have been several conflicting reports about the ulcerogenic mechanism of indomethacin; the mechanism is still unclear. It has been suggested that indomethacin induces gastric damage via inhibiting the release of protective factors like cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2), bicarbonate, and mucus; increasing aggressive factors like acid; and increasing oxidant parameters while decreasing antioxidant parameters. Classic antiulcer drugs are known to produce antiulcer effects by activating against indomethacin (increasing PGE2, mucus, and bicarbonate production; inhibiting acid secretion; decreasing oxidant parameters; and increasing antioxidants). However, some antiulcer drugs have been shown to inhibit indomethacin-induced ulcers without affecting acid and mucus secretion or oxidant parameters, as well as to inhibit the production of protective factors like COX-1, PGE2, and bicarbonate, and to reduce antioxidant parameters. In order to resolve the contradictions in the abovementioned data, this review hypothesized a relationship between indomethacin-induced ulcers and alpha 2 adrenergic receptors. It is suggested that blockage of alpha 2 adrenergic receptors may be responsible for the increase in the aggressive factors induced by indomethacin, and stimulation of alpha 2 adrenergic receptors may be responsible for the increase of protective factors induced by antiulcer drugs.

Acute and repeated vapor exposure toxicology of 3-(methylthio)propionaldehyde.

Because of its vapor pressure (0.6 torr at 20 C) there is a potential for vapor exposure to 3-(methylthio)propionaldehyde (3-MTP) vapor. Liquid 3-MTP may contain trace amounts of acrolein (up to 0.1%), and therefore acrolein vapor may also be present. Acute exposure (24 min to 4 h) of rats to substantially saturated atmospheres of 3-MTP generated statically (measured concentrations of 261-951 ppm) resulted in marked ocular and respiratory irritancy followed by death. Deaths occurred either during exposure or a few days postexposure, depending on exposure time. Measured acrolein vapor concentrations in these static studies were 16.7-216 ppm. In contrast, when substantially saturated vapor atmospheres were generated dynamically (277-320 ppm 3-MTP) only minor transient signs of irritancy were present, and only 1/40 exposed animals died. Acrolein vapor concentrations ranged 0-6.8 ppm. These findings indicate that the toxicity associated with acute static exposures to 3-MTP vapor was due to accumulated acrolein vapor, and that 3-MTP per se has a low order of acute vapor inhalation toxicity. In a first 9-d repeated vapor exposure study (6 h/d) rats were exposed to 0, 23.6, 96.8 or 246.2 ppm 3-MTP vapor; the mean acrolein concentration was 1.34 ppm (range 1.08-1.72 ppm). There were no mortalities, but exposure concentration-related indications of toxicity were present. These included reduced body weights, hematology (increased lymphocytes), serum chemistry (reduced total protein and globulin), and respiratory tract histopathology. The latter consisted mainly of squamous metaplasia in the anterior nasal passages at all concentrations, being minimal at 23.6 ppm. At the high concentration there was also olfactory atrophy and squamous metaplasia in the larynx, trachea, and larger bronchi; 23.6 ppm was a threshold effect level. The respiratory tract histopathology was compatible with exposure to acrolein vapor. In a second 9-d study, rats were exposed to 0, 0.47, 4.99 or 50.5 ppm (6 h/d); no acrolein could be detected in the chamber air samples. There were no differences between the controls (air alone) and 3-MTP exposed animals with respect to signs, body weights, food consumption, hematology, serum chemistry, urinalysis, and gross and microscopic pathology. Without detectable acrolein vapor, 50.5 ppm 3-MTP was a no observable effects level.

6-Isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a human EP2 receptor antagonist.

On studying the interaction of various ligands with the pharmacologically defined, recombinant human EP2 receptor (Regan et al., Mol Pharmacol 46: 213-220, 1994), we discovered that the putative EP1 receptor antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809) also has affinity for the human EP2 receptor. Moreover, AH 6809 behaved as an EP2 receptor antagonist and inhibited prostaglandin E2 (PGE2)-stimulated increases in cyclic AMP. These findings have significant implications for studies that employ AH 6809 to determine the pharmacological basis of PGE2-induced responses in human cells and tissues.

3-substituted piperazinomethyl benzoxazolinones. Analgesic and anti-inflammatory compounds inhibiting prostaglandin E2.

Fourty-three new benzoxazolinone derivatives having a piperazinomethyl group at the third position of the ring were synthesized by using appropriate benzoxazolinones and 4-substituted piperazines via a Mannich reaction. The structures of the compounds were elucidated by spectral data and microanalyses. Analgesic activities were evaluated by a modified Koster test. All compounds, except 7, 14, 21, 32, and 41, showed analgesic activity higher than that of acetylsalicylic acid. The compounds were also screened for their anti-inflammatory activity using a carrageenan paw edema test, and those exhibiting high anti-inflammatory activity were investigated for their ability to inhibit prostaglandin E2 induced paw edema. The results of anti-inflammatory testing indicated that most of the compounds were more active than indometacin. Ulcerogenic activities of the compounds were also studied and no gastrointestinal bleeding was observed at the 100 mg/kg dose level.

Ulcerogenicity and effect on inhibition of prostaglandin generation of indometacin farnesil, a prodrug of indomethacin, in rat gastric mucosa: comparison with indomethacin or loxoprofen.

Indometacin farnesil was compared with indomethacin and loxoprofen in rats to ascertain whether it caused less gastric mucosal damage than the two older drugs. Damage was evaluated in terms of the size of ulcers that formed after oral administration and the changes in concentrations of prostaglandins E2 and I2 in the mucosa. Indometacin farnesil caused less damage than indomethacin and tended to cause less damage than loxoprofen. Indometacin farnesil was less potent than indomethacin in inhibiting prostaglandin generation by gastric mucosa. This property of indometacin farnesil may contribute to the low ulcerogenicity of this compound.

Aspirin-induced changes in gastric function: role of endogenous prostaglandins and mucosal damage.

The relative roles of prostaglandins and mucosal injury in aspirin-induced changes in gastric function were evaluated. Conscious rhesus monkeys received a subcutaneous injection of sodium bicarbonate or aspirin (25, 50, 100, or 150 mg/kg) and sodium bicarbonate or 150 mg/kg aspirin subcutaneously plus oral sucralfate (25 mg/kg twice a day). Gastric emptying and fluid and H+ outputs were determined during a fasting period and after an 80-ml water load using a 99mTc-diethylenetriaminepentaacetic acid dilution technique. At the end of each study, the monkeys were gastroscoped to assess mucosal damage, which was ranked blindly on a scale of 0 to 5. Biopsy samples were taken from antrum and fundus for determination of prostaglandins and histological evaluation. All doses of aspirin significantly suppressed prostaglandins in both the antrum and fundus. In contrast, the aspirin-induced increase in gastric mucosal injury was dose dependent. Aspirin also produced a dose-dependent decrease in gastric emptying that was significantly correlated with erosions scores. When aspirin-induced lesions were prevented by sucralfate, the inhibition of gastric emptying was blocked during the fasting period and was attenuated following the water load. Acid secretion was also decreased significantly by aspirin. This action was not modified by sucralfate protection, suggesting that aspirin has a direct inhibitory effect on parietal cell secretion. These data show that mucosal damage contributes significantly to the aspirin-induced changes in gastric function. Moreover, prostaglandins may play a role in the control of gastric emptying, especially during early phase of the response to a water load.

Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interrelated, mechanisms. They vary in ulcerogenic activity in different regions of the GI tract. These differences in ulcerogenicity of NSAIDs are due to (a) differing kinetics of absorption in various regions of the GI tract, intracellular distribution within the mucosal cells, and systemic availability, and (b) quantitative and qualitative differences in the biochemical or physiologic systems affected by the drugs. In the stomach, where acid/pepsin influence the ulcerogenic effects of most NSAIDs, prostaglandin (PG)-dependent and PG-independent factors are responsible for the ulcerogenicity of NSAIDs. PG-dependent factors can include the influences of PGs on mucus-bicarbonate secretion, regulation of acid secretion, and blood flow. Recent evidence suggests that CO inhibition may, by diversion of arachidonate, cause enhanced production of vasoconstrictor peptidoleukotrienes and oxyradicals produced by the lipoxygenase pathway, and this may contribute to the genesis of vascular and other mucosal changes induced by NSAIDs. Non-PG-dependent effects of NSAIDs include (a) physical effects of the acidic molecules on surface mucosal cell membranes and mucus, (b) oxyradical production, (c) cytotoxic effects on parietal cells, and (d) inhibitory effects on mucus synthesis, mitochondrial ATP production, cyclic nucleotide production, and a range of other cellular metabolic effects influencing mucosal metabolism and cellular regeneration. In the intestinal tract, two major factors influence the ulcerogenicity of NSAIDs: their capacity to undergo enterophepatic recirculation and the presence of bacteria, which may in part contribute to a immunoinflammatory changes.

Electron microscopic observations comparing the gastric mucosal damage induced in rats and pigs by benoxaprofen and aspirin, reflecting their differing actions as prostaglandin-synthesis-inhibitors.

The ultrastructural changes in the gastric mucosa induced by oral administration of aspirin (2 x 125 mg/kg/day) were compared with the effects of benoxaprofen (20 mg/kg/day) in pigs and normal and arthritic rats after 10 or 14 days' treatment respectively. The object was to compare the effects of drugs having different effects on prostaglandin-synthesizing systems on the development of gastric mucosal damage. Benoxaprofen caused less gastric damage than aspirin. There were fewer lesions in benoxaprofen-treated animals and those which were seen were much less extensive. There were qualitative similarities between the effects of the drug treatments. There were also differences in the mucosal changes produced by both drugs in pigs and rats. This included (1) extravasation of erythrocytes which was seen in rats but not pigs, and (2) interstitial changes also seen in rats but not pigs. These interspecies variations may be due to differences in the resistance of the capillaries to drug effects. There were no differences in the mucosal-cell damage seen in normal compared with arthritic rats.