Abstract
Bnzoyl-pyrimidopyrimidine derivatives (BZPP) has been demonstrated to alleviate hyperalgesia in experimental model of of peripheral neuropathic pain. Activation of iNOS causes hyperalgesia and that adenosine contributes analgesia. In this connection, we investigated the mechanism of action of BZPP in vasculature as a model system, with reference to adenosine and iNOS induction/NO. BZPP prevented LPS- or IL-1β-primed initiation of L-arginine-induced relaxation and cGMP formation in rat thoracic aorta, and nitrite accumulation of cultured aortic smooth muscle cells. Treatment of rat aortic segments with LPS induced iNOS mRNA in 8 h. BZPP attenuated the expression of LPS-stimulated iNOS mRNA, assessed as iNOS/G3PDH ratio. In addition, BZPP potentiated adenosine-induced negative inotropic response of guinea-pig atria, adenosine-induced inhibition of guinea-pig ileum twitch response and adenosine-induced relaxation of rat aorta. Therefore, it is conceivable that inhibitory effect on iNOS induction and subsequent reduction of NO formation, and potentiating action on adenosine-induced effects may be responsible for the analgesic effect of BZPP.
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