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[Effect of dazoxiben on cerebrovascular resistance in rabbits]
Abstract:
The effects of dazoxiben, a TXA2 synthetase inhibitor, and indomethacin were compared on cerebrovascular resistance (CVR) and levels of serum TXB2, 6-keto-PGF1 alpha (the stable metabolites of TXA2 and PGI2, respectively) and on protection from acute brain ischaemia caused by ia arachidonic acid (AA) in rabbits. The flow represented the cerebral blood flow (CBF) in two internal jugular arteries were measured with electromagnetic flow meter after occlusion of bilateral vertebral arteries and external jugular arteries. CVR was represented as blood pressure/(CBF.100 g brain). Serum TXB2 and 6-keto-PGF1 alpha levels were determined by radioimmunoassay. The results showed that CVR and BP, EEG, ECG were not affected by treatment with iv dazoxiben 2 or 10 mg/kg. The CVR was enhanced by 35.5 and 49.8% at 30 and 40 min, respectively after iv indomethacin 10 mg/kg. The serum TXB2 level (872 +/- 85) was inhibited to 511 +/- 169 pg/ml (n = 5, P less than 0.05) and 6-keto-PGF1 alpha increased from 668 +/- 309 to 890 +/- 357 pg/ml (n = 5, P less than 0.05) at 30 min after iv 2 mg/kg dazoxiben. However, both TXB2 and 6-keto-PGF1 alpha decreased by 26.4 and 32.7%, respectively at 40 min after iv indomethacin 10 mg/kg. In a model of cerebral ischaemia caused by ia AA in rabbits, the EEG change and enhancement of CVR were antagonized by iv dazoxiben 10 mg/kg completely, but only partly antagonized by indomethacin 10 mg/kg. The results suggest that PGI2 and TXA2 may play a minor role in the regulation of CVR in the physiological condition.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Dazoxiben, a TXA2 synthetase inhibitor, protected rabbits from brain ischemia, unlike indomethacin. This suggests prostacyclin (PGI2) and thromboxane A2 (TXA2) have minor roles in regulating cerebrovascular resistance under normal conditions.
Area of Science:
- Pharmacology
- Neuroscience
- Cardiovascular Physiology
Context:
- Cerebrovascular resistance (CVR) regulation is crucial for brain health.
- Thromboxane A2 (TXA2) and prostacyclin (PGI2) are key mediators in vascular tone.
- Understanding their roles in cerebral ischemia is vital for developing therapeutic strategies.
Purpose:
- To compare the effects of dazoxiben (TXA2 synthetase inhibitor) and indomethacin on CVR, serum TXB2 and 6-keto-PGF1 alpha levels, and protection against acute brain ischemia in rabbits.
- To investigate the physiological roles of PGI2 and TXA2 in cerebrovascular regulation.
Summary:
- Dazoxiben (2 or 10 mg/kg IV) did not affect CVR, BP, EEG, or ECG. Indomethacin (10 mg/kg IV) increased CVR.
- Dazoxiben inhibited serum TXB2 and increased 6-keto-PGF1 alpha at 30 min. Indomethacin decreased both metabolites.
- Dazoxiben completely antagonized EEG changes and CVR enhancement during arachidonic acid-induced ischemia, while indomethacin only partly antagonized them.
Impact:
- PGI2 and TXA2 appear to play minor roles in physiological CVR regulation.
- Dazoxiben demonstrated significant neuroprotective effects against cerebral ischemia in rabbits.
- These findings contribute to understanding the complex interplay of prostanoids in cerebrovascular function and ischemia.