BRADYKININ B-2 RECEPTOR MODULATES RENAL PROSTAGLANDIN E(2) AND NITRIC-OXIDE

Bradykinin and lys-bradykinin generated intrarenally appear to be impo rtant renal paracrine hormones. However, the renal effects of endogeno usly generated bradykinin are still not clearly defined. In this study , we measured acute changes in renal excretory and hemodynamic functio ns and renal cortical interstitial fluid levels of bradykinin, prostag landin E(2), and cGMP in response to an acute intrarenal arterial infu sion of the bradykinin B-2 receptor antagonist Hoe 140 (icatibant), cy clooxygenase inhibitor indomethacin, or nitric oxide synthase inhibito r N-G-monomethyl-L-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icati bant caused a significant decrease in urine flow, urinary sodium excre tion, and renal plasma flow rate (each P<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produce d an unexpected large increase in renal interstitial fluid bradykinin (P<.0001) while decreasing renal interstitial fluid prostaglandin E(2) and cGMP (each P<.001). Both indomethacin and L-NMMA when given indiv idually caused significant antidiuresis and antinatriuresis and decrea sed renal blood flow (each P<.001). Glomerular filtration rate decreas ed during L-NMMA administration (P<.001) and did not change during ind omethacin administration. Combined administration of icatibant and ind omethacin or L-NMMA caused significant decreases in renal excretory an d hemodynamic functions, which were not different from changes observe d with icatibant alone. The failure of icatibant to change renal funct ion after inhibition of cyclooxygenase and nitric oxide synthase activ ity suggests that the effects of kinin B-2 receptor are mediated by in trarenal prostaglandin E(2) and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires furth er study of possible alterations in kinin synthesis, degradation, or c learance as a result of B-2 receptor blockade.