Bradykinin B2 receptor modulates renal prostaglandin E2 and nitric oxide.
Bradykinin and lys-bradykinin generated intrarenally appear to be important renal paracrine hormones. However, the renal effects of endogenously generated bradykinin are still not clearly defined. In this study, we measured acute changes in renal excretory and hemodynamic functions and renal cortical interstitial fluid levels of bradykinin, prostaglandin E2, and cGMP in response to an acute intrarenal arterial infusion of the bradykinin B2 receptor antagonist Hoe 140 (icatibant), cyclooxygenase inhibitor indomethacin, or nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icatibant caused a significant decrease in urine flow, urinary sodium excretion, and renal plasma flow rate (each P<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produced an unexpected large increase in renal interstitial fluid bradykinin (P<.0001) while decreasing renal interstitial fluid prostaglandin E2 and cGMP (each P<.001). Both indomethacin and L-NMMA when given individually caused significant antidiuresis and antinatriuresis and decreased renal blood flow (each P<.001). Glomerular filtration rate decreased during L-NMMA administration (P<.001) and did not change during indomethacin administration. Combined administration of icatibant and indomethacin or L-NMMA caused significant decreases in renal excretory and hemodynamic functions, which were not different from changes observed with icatibant alone. The failure of icatibant to change renal function after inhibition of cyclooxygenase and nitric oxide synthase activity suggests that the effects of kinin B2 receptor are mediated by intrarenal prostaglandin E2 and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires further study of possible alterations in kinin synthesis, degradation, or clearance as a result of B2 receptor blockade.
Siragy
H M
HM
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Jaffa
A A
AA
Margolius
H S
HS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D015232:Dinoprostone / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C065679:icatibant; D015232:Dinoprostone; D001920:Bradykinin; D007213:Indomethacin