Nitric oxide and cyclic GMP attenuate sensitivity of the blood-tumor barrier permeability to bradykinin.

Intracarotid infusion of bradykinin and its analogue, RMP-7, selectively increase the permeability of brain tumor capillaries though the nitrix oxide (NO) and cyclic GMP pathway. Maximum blood-tumor barrier (BTB) permeability induced by bradykinin is observed at 15 min after intracarotid infusion and this effect is decreased even if the infusion continues. The mechanism for this decreased effect with long term infusion has not been clearly defined. This study sought to determine the involvement of the NO-cyclic GMP pathway in this event. Regional permeability was investigated in 44 Wistar rats with implanted RG2 gliomas, using quantitative autoradiography to determine the unidirectional transfer constant (Ki) of radiolabeled 14C-dextran. Tumor bearing rats were treated by intracarotid infusion of bradykinin (10 micrograms kg-1 min-1) with or without pretreatment with bradykinin, the NO donor s-nitrosoglutathione (10 nmol kg-1 min-1), or the cyclic GMP analogue, 8Br-cyclic GMP (200 micrograms kg-1 min-1). At 30 min of bradykinin infusion, BTB permeability was significantly lower compared to 15 min of bradykinin infusion (3.79 +/- 0.99 vs. 16.20 +/- 3.43 microliters g-1 min-1, p < 0.001). Pretreatment with an NO donor significantly decreased BTB permeability in bradykinin infused rats (5.09 +/- 2.61 vs. 13.51 +/- 4.19 microliters g-1 min-1, p < 0.001), as did pretreatment with a cyclic GMP analogue (4.48 +/- 0.95 vs. 12.31 +/- 3.90 microliters g-1 min-1, p < 0.001). There was no increased permeability in nontumor brain areas. Increased tumor permeability by bradykinin appears to be regulated by NO and cyclic GMP which are second messengers involved in the bradykinin B2 receptor mediated cascade.