© 1995 American Heart Association, Inc.
Articles |
Characterization of Bradykinin B2 Receptors in Adult Myocardium and Neonatal Rat Cardiomyocytes
From the Departments of Pharmacology (R.D.M.), Anesthesiology (R.D.M., F.N., S.F.R), Physiology (S.F.R.), and Anatomy/Cell Biology (R.P.B.), University of Illinois College of Medicine at Chicago.
Correspondence to Sara F. Rabito, MD, Department of Anesthesiology and Critical Care, Cook County Hospital, Durand Building, Room 427, 637 S Wood St, Chicago, IL 60612.
Abstract Specific
[125I-Tyr8]bradykinin (BK) binding was
observed on myocardial membranes from adult guinea pigs, dogs, rats,
and rabbits that was displaced by unlabeled BK with an IC50
between 0.1 and 30 nmol/L. In the adult guinea pig ventricular
myocardium, which displays both high- and low-affinity binding,
guanosine 5'-O-(3-thiotriphosphate) (GTP
S; 100 µmol/L)
eliminated high-affinity binding and reduced total specific
[2,3-prolyl-3,4-3H(N)]BK
([3H]BK) binding by >60%. Agonist competition binding
to rat myocardial membranes was characterized as being of one affinity
for BK in the nanomolar range, and it was not altered by GTPS.
Saturation binding studies with [125I-Tyr8]BK
and [3H]BK, performed on cultured neonatal rat cardiac
myocytes, revealed a single class of BK binding sites with a
Kd and Bmax of 0.24±0.04 nmol/L and
18.4±1.1 fmol/mg protein, respectively (
1500 receptors per cell).
In competitive binding assays, unlabeled BK, Hoe 140 (a specific BK
B2 receptor antagonist), and
des-Arg9,[Leu8]BK (a BK B1
receptor antagonist) displaced [125I-Tyr8]BK
with an IC50 of 4.3, 0.041, and 307 nmol/L, respectively.
In the presence of 100 µmol/L GTPS, [3H]BK binding
to myocyte membranes was reduced by 40%, but the IC50 did
not change. Cardiac fibroblasts, evaluated in parallel to the myocytes,
contain a single class of [3H]BK binding sites (248±72
fmol/mg) with a 130-fold lower relative affinity (32.4±11.3 nmol/L)
than that determined in rat cardiomyocytes. BK stimulated the inositol
1,4,5-trisphosphate (IP3) production by cardiomyocytes,
which reached a maximum after 20 seconds of stimulation and increased
from a baseline of 138.4±23.2 pmol/mg protein to 1020.7±75.9 pmol/mg
with 1 µmol/L BK (EC50=15.3 nmol/L). The effect was
significantly blocked by 1 µmol/L Hoe 140. The IP3
response by cardiomyocytes was fourfold greater and sixfold more
sensitive than that by cardiac fibroblasts (EC50=92.3
nmol/L). These data suggest the presence of high-affinity BK
B2 receptors on cardiomyocytes, which are functionally
coupled via a G protein to the production of IP3.
Key Words: kininase II • angiotensin converting enzyme inhibitors • IP3 • myocardial membrane • bradykinin
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