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The efficacy of N,N'-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P less than 0.05) inhibited basal and LPS-stimulated synthesis of TxA2 measured by its stable immunoreactive (i) metabolite TxB2 in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF1 alpha, the stable metabolite of PGI2, and produced significant shunting to i6-keto-PGF1 alpha. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P less than 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA2 synthesis.

Intracerebroventricular (icv) injection of pentagastrin showed a powerful, dose dependent antidipsogenic effect in the rat. Drinking behavior stimulated by 48 h water deprivation was inhibited by 2000 ng of pentagastrin which also blocked, at lower doses, water intake induced by icv injection of angiotensin II (100 ng) and carbachol (150 ng). Pentagastrin was less effective on food intake stimulated by 24 h starvation. The antidipsogenic effect was not a consequence of behavioral alteration. It is suggested that gastrin-like peptides in the brain may play a role in the regulation drinking, acting as thirst inhibitors.

Administration of E. coli LPS prior to 3.5 mg/Kg dose of thiourea has been reported to protect rats against pulmonary edema and pleural effusion. However, LPS of Shigella sonnei (either in phase I or II) did not show any protective effect. These data might suggest a different mechanism of endotoxins on membranes.

The synthesis of alkyl and aryl ureas (II) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2.]nonane (I), as well as hydrazides (V), (VI) and (VII) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2]-nonan-3-amine (IV), is described. A number of theses compounds showed strong hypotensive and bradycardic activities in rats, as well as weak infiltration anesthesia and antiarrhythmic activity in mice. Antiacetylcholine activity in vitro is also reported.

Intravenous injection of Escherichia coli endotoxin (LPS; 640 micrograms/kg) produced an antidipsogenic effect in 48-h water-deprived rats, which was antagonized by acetylsalicylic acid (ASA; 0.45, 0.9 microM) injected directly into cerebral preoptic area (POA). ASA (0.9 microM) when injected into POA did not elicit, by itself, any effect on drinking. Endotoxin (0.5, 1, and 2 micrograms), when injected directly into POA, produced a dose-dependent inhibition of drinking stimulated by water deprivation. This effect was antagonized by ASA (0.45 microM) injected into POA 15 min before LPS. Injection of LPS (2 micrograms) into brain areas not involved in drinking regulation (superior colliculus or nucleus caudatus) was without effect on 48-h water deprivation-induced thirst. PGI2 (5, 50, and 500 ng) injected ino POA showed a dose-dependent antidipsogenic effect on drinking stimulated by water deprivation. The data suggest that prostaglandins, within the preoptic area, might be involved in the antidipsogenic effect of E coli LPS, given either intravenously or directly into POA.

Escherichia coli LPS (640-1280 mcg/Kg, intravenously) showed a powerful, dose-dependent and long-lasting inhibitory effect on drinking behavior stimulated by 48 h water deprivation, subcutaneous injection of isoprenaline (33.3 mcg/Kg) and intracerebroventricular injection of hypertonic NaCl (2.9%) solution, carbachol (250 ng) and angiotensin II (100 ng). The antidipsogenic effect was neither a consequence of behavioral alterations, nor due to endotoxin peripheral vasodilating activity. Naloxone (60-120-240 mcg/Kg, subcutaneously) did not influence endotoxin inhibition of water intake, thus ruling out an endorphin-mediated effect. When prostaglandin synthesis was inhibited, the effect of endotoxin was reduced. Since prostaglandins do not seem to be involved in the regulation of thirst, the mechanism of the antidipsogenic effect elicited by endotoxin needs further study.

The effects of a highly selective 5-lipoxygenase inhibitor, CGS8515 [methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl) amino]benzoate], on endotoxic shock sequelae and eicosanoid synthesis by peritoneal macrophages were evaluated in the rat. Pretreatment of peritoneal macrophages in vitro with CGS8515 significantly inhibited the synthesis (P less than .01) of immunoreactive leukotriene C4/leukotriene D4 stimulated by the calcium ionophore (A23187). Inhibition of 5-lipoxygenase produced significant shunting to immunoreactive thromboxane B2 formation (P less than .05). In rats sedated with ketamine.HCl (82.5 mg/kg) and xylazine. HCl (27.5 mg/kg), i.v. injection of Salmonella enteritidis endotoxin (25 mg/kg i.v.) produced significant decreases at 30 min in mean arterial pressure (from 89 +/- 4 to 44 +/- 8 mm Hg, N = 5, P less than .001); in white blood cell count (from 10.8 +/- 0.6 to 6.5 +/- 0.8 x 10(3)/mm3, N = 5, P less than .01); in platelet count (from 687 +/- 66 to 392 +/- 65 x 10(3)/mm3, N = 5, P less than .01); and produced an increase of hematocrit (from 46 +/- 1.2 to 57.4 +/- 1.8%, N = 5, P less than .03). CGS8515 (5 mg/kg i.v. 30 min before endotoxin injection, N = 6) blunted the endotoxin-induced hypotension by 35% (P less than .001), the leukopenia by 24% (P less than .03), the thrombocytopenia by 45% (P less than .006) and the hemoconcentration by 16% (P less than .03), compared to the shocked control rats 30 min after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)