Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro.
Twelve days following treatment with 50 mg/kg streptozotocin (STZ), male rats were diabetic, with a three-fold increase in blood glucose (P<0.001) and increased plasma bradykinin (BK) kininogen reserves of [high-(HK)- and low- (LK)-molecular-weight kininogens,+162%, P<0.01 and +63%, P=0.05, respectively], as determined by bioassay of BK released by trypsin from these precursors under standardized conditions. Administration of a single dose (10 U/kg i.v.) of regular insulin decreased plasma HK and LK to near non-diabetic values. Within 24 h these values had returned to levels characteristic of uncorrected diabetes. Prekallikrein (PK), the precursor of plasma kallikrein, an enzyme which releases BK from HK, was increased by 63.4% (P<0.05) in STZ-diabetes, but dropped to near normal levels following insulin treatment. Incubation of whole blood of normal or diabetic rats with 0.02-0.2 mU/ml regular insulin for 10 min at 37 C, decreased HK (P<0.01) and PK (P<0.05) and led to the appearance (P<0.05) of Arg-Pro-Pro-Gly-Phe, a partially stable product of BK metabolism, detected in the incubation media by an enzyme-linked immunosorbent assay (ELISA). Incubation of cell-free plasma insulin had no effect on these parameters, suggesting that blood cells, possibly neutrophils, are required by insulin for the activation of plasma PK to kallikrein leading to BK release. Insulin may be a factor modulating BK formation; its reduction in diabetes may explain increases of plasma kininogen and PK observed in this condition.
Rothschild
A M
AM
Laboratory of Pharmacology, School of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, Brazil.
Melo
V L
VL
Reis
M L
ML
Foss
M C
MC
Gallo
L
L
D000758:Anesthesia; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001920:Bradykinin / Q000097:blood / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007704:Kininogens / Q000097:blood*; D008297:Male; D011288:Prekallikrein / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D007704:Kininogens; D011288:Prekallikrein; D014357:Trypsin; D001920:Bradykinin