Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. coli endotoxemia in anesthetized sheep.

Abstract

We investigated the effects of a new pyridoquinazoline thromboxane synthetase inhibitor infused before administering Escherichia Coli endotoxin into 18 anesthetized sheep with lung lymph fistulas. In normal sheep increasing plasma Ro 23-3423 concentrations were associated with increased plasma levels of 6-keto-PGF1 alpha, a reduced systemic vascular resistance (SVR, r = -0.80) and systemic arterial pressure (SAP, r = -0.92), the mean SAP falling from 80 to 50 mm Hg at the 20 and 30 mg/kg doses. Endotoxin infused into normal sheep caused transient pulmonary vasoconstriction associated with increased TxB2 and 6-keto-PGF1 alpha levels while vasoconstriction and TxB2 increase were significantly inhibited by pretreatment with Ro 23-3423 in a dose-dependent manner. When compared to controls, plasma and lymph levels of 6-keto-PGF1 alpha, PGF2 alpha and PGE2 after endotoxin infusion were increased several-fold by administering Ro 23-3423 up to plasma levels of 10 micrograms/ml. Doses over 30 mg/kg with blood levels above 10 micrograms/ml reduced plasma and lymph levels of 6-keto-PGF1 alpha, PGF2 alpha and PGE2, suggesting cyclooxygenase blockade at this dose. The peak 6-keto-PGF1 alpha levels at 60 min after endotoxin infusion in sheep with Ro-23-3423 levels below 10 micrograms/ml were associated with the greatest systemic hypotension due to a reduced SVR (r = -0.86). After endotoxin infusion the leukotrienes B4, C4, D4 and E4 in lung lymph were assayed by radioimmunoassay and high pressure liquid chromatography and remained at baseline values.

• Authors: D R Morel, P C Huttemeier, M J Skoskiewicz, T Nguyenduy, C Melvin, D R Robinson, W M Zapol
• Journal: Prostaglandins (Prostaglandins) Vol. 33 Issue 6 Pg. 879-902 (Jun 1987) ISSN: 0090-6980 [Print] United States
• PMID: 3118413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Arachidonic Acids
• Endotoxins
• Prostaglandins E
• Prostaglandins F
• Quinazolines
• Ro 23-3423
• Arachidonic Acid
• Thromboxane B2
• 6-Ketoprostaglandin F1 alpha
• Thromboxane-A Synthase
• Dinoprostone
• prostaglandin F1

Topics

• 6-Ketoprostaglandin F1 alpha (metabolism)
• Animals
• Arachidonic Acid
• Arachidonic Acids (metabolism)
• Blood Pressure (drug effects)
• Dinoprostone
• Endotoxins
• Escherichia coli
• Hemodynamics (drug effects)
• Kinetics
• Lymph (metabolism)
• Prostaglandins E (metabolism)
• Prostaglandins F (metabolism)
• Pulmonary Artery (physiopathology)
• Quinazolines (pharmacology)
• Sheep
• Thromboxane B2 (metabolism)
• Thromboxane-A Synthase (antagonists & inhibitors)
• Toxemia (chemically induced, physiopathology)
• Vascular Resistance (drug effects)