Fate of bradykinin on the rat liver when administered by the venous or arterial route.
OBJECTIVE
Bradykinin (BK) infused into the portal vein elicits a hypertensive response via the B2 receptor (B2R) and is efficiently hydrolyzed by the liver. Our purpose was to characterize the mechanism of interaction between BK and the liver.


METHODS
BK, HOE-140 (a B2R antagonist), des-R(9)-BK (a B1R agonist) and enzyme inhibitors were used in monovascular or bivascular perfusions and in isolated liver cell assays.


RESULTS
Des-R(9)-BK did not elicit a portal hypertensive response (PHR); BK infused into the hepatic artery elicited a calcium-dependent PHR and a calcium-independent arterial hypertensive response (HAHR), with the latter being almost abolished by naproxen. BK has a predominant distribution in the extracellular space and an average hepatic extraction of 8% in the steady state. Hydrolysis products of infused BK (R(1)-F(5) and R(1)-P(7)) did not elicit PHR. Angiotensin converting enzyme (ACE) is concentrated in the perivenous region and B2R in the periportal region. Microphysiometry showed that BK (and not a B1 agonist) interacts with stellate cells and the endothelial sinusoidal/Kupffer cell fraction. This effect was inhibited by the B2R antagonist.


CONCLUSIONS
Events can be summarized as: the hypertensive action of BK on sinusoidal cells of the periportal region is followed by its hydrolysis by ACE which is primarily present in the perivenous region; there is no functional B1R in the normal liver; BK induces HAHR via eicosanoid release and PHR by a distinct pathway on the B2R. Our data suggest that BK may participate in the modulation of sinusoidal microvasculature tonus both in the portal and the arterial routes.
Gioli-Pereira
Luciana
L
Department of Biochemistry, Sao Paulo Federal University, Sao Paulo, Brazil.
Nascimento
Ecio Alves
EA
Santos
Edson Lucas
EL
Bracht
Adelar
A
Juliano
Maria Aparecida
MA
Pesquero
João Bosco
JB
Borges
Durval Rosa
DR
Kouyoumdjian
Maria
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006499:Hepatic Artery; D006868:Hydrolysis / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D013058:Mass Spectrometry; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects / Q000502:physiology; D011169:Portal Vein; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; C065679:icatibant; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin