Bradykinin

BACKGROUND: ;Linoleic acid (LA) promotes monocyte chemotaxis and cell adhesion molecules such as MCP-1 and VCAM-1, which contribute to atherosclerogenesis. These molecules are restrained by endothelium-derived relaxing factors (EDRFs), such as nitric oxide (NO) and prostaglandin I2 (PGI2). Hence, the expressions of MCP-1 and VCAM-1 upregulated by LA may be partly attributable to decreased EDRF production. However, effect of LA on EDRF production remains controversial.;METHODS AND RESULTS: ;The present study aimed to examine the effects of LA and other free fatty acids on EDRF production and the endothelial Ca(2+) responses that mediate EDRF production, using primary cultured porcine aortic endothelial cells (PAECs). LA at 0.1-5 μmol/L attenuated bradykinin (BK)-induced NO and PGI2 production while suppressing the BK-induced Ca(2+) response dose-dependently. The inhibitory effect of LA on the Ca(2+) response was eliminated by adenylate cyclase inhibitor SQ22536, boosted by cAMP-hydrolyzing phosphodiesterase (PDE) inhibitor, rolipram, and mimicked by plasma membrane permeable 8-bromo-cAMP. Moreover, LA was confirmed to dose-dependently increase intracellular cAMP levels and selectively inhibit cAMP-hydrolyzing PDE activity in vitro.

PURPOSE: ;Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal vascular diseases. In the present study, the mechanisms underlying bradykinin vasodilation were examined and whether calcium-activated potassium channels of small (SK(Ca)) and intermediate (IK(Ca)) conductance are involved in regulation of endothelium-dependent vasodilation in retinal arterioles was investigated.;METHODS: ;Porcine retinal arterioles (diameter approximately 112 microm, N = 119) were mounted in microvascular myographs for isometric tension recordings. The arterioles were contracted with the thromboxane analogue, U46619, and concentration-response curves were constructed for bradykinin and a novel opener of SK(Ca) and IK(Ca) channels, NS309.;RESULTS: ;In U46619-contracted arterioles, bradykinin and NS309 induced concentration-dependent relaxations. In vessels without endothelium, bradykinin relaxation was abolished and NS309 relaxation was attenuated. Inhibition of NO synthase with asymmetric dimethylarginine and/or cyclooxygenase with indomethacin markedly reduced bradykinin and NS309 relaxation. NO synthase and cyclooxygenase inhibition together with oxyhemoglobin abolished bradykinin relaxation and attenuated NS309 relaxation.

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).