NITRIC-OXIDE AND CYCLIC-GMP ATTENUATE SENSITIVITY OF THE BLOOD-TUMOR BARRIER PERMEABILITY TO BRADYKININ

Intracarotid infusion of bradykinin and its analogue, RMP-7, selective ly increase the permeability of brain tumor capillaries though the nit rix oxide (NO) and cyclic GMP pathway. Maximum blood-tumor barrier (BT B) permeability induced by bradykinin is observed at 15 min after intr acarotid infusion and this effect is decreased even ii the infusion co ntinues. The mechanism for this decreased effect with long term infusi on has not been clearly defined. This study sought to determine:the in volvement of the NO-cyclic GMP pathway in this event. Regional permeab ility was investigated in 44 Wistar rats with implanted RG2 gliomas, u sing quantitative autoradiography to determine the unidirectional tran sfer constant (Ki) of radiolabeled C-14-dextran. Tumor bearing rats we re treated by intracarotid infusion of bradykinin (10 mu g kg(-1) min( -1)) with or without pretreatment with bradykinin, the NO donor s-nitr osoglutathione (10 nmol kg(-1) min(-1)), or the cyclic GMP analogue, 8 Br-cyclic GMP (200 mu g kg(-1) min(-1)). At 30 min of bradykinin infus ion, BTB permeability was significantly lower compared to 15 min of br adykinin infusion (3.79+/-0.99 vs. 16.20+/-3.43 mu l g(-1) min(-1), p< 0.007). Pretreatment with an NO donor significantly decreased BTB perm eability in bradykinin infused rats (5.09+/-2.61 vs. 13.51+/-4.79 mu l g(-1) min(-1), p<0.001), as did pretreatment with a cyclic GMP analog ue (4.48 +/- 0.95 vs. 12.31 +/- 3.90 mu l g(-1) min(-1), p<0.001). The re was no increased permeability in nontumor brain areas. Increased tu mor permeability by bradykinin appears to be regulated by NO and cycli c GMP which are second messengers involved in the bradykinin B2 recept or mediated cascade.