Compensatory function of bradykinin B1 receptor in the inhibitory effect of captopril on cardiomyocyte hypertrophy and cardiac fibroblast proliferation in neonatal rats.
BACKGROUND
Bradykinin (BK) acts mainly on two receptor subtypes: B(1) and B(2), and activation of B(2) receptor mediates the most well-known cardioprotective effects of angiotensin converting enzyme inhibitors (ACEi), however, the role that B(1) receptor plays in ACEi has not been fully defined. We examined the role of B(1) receptor in the inhibitory effect of ACE inhibitor captopril on rat cardiomyocyte hypertrophy and cardiac fibroblast proliferation induced by angiotensin II (Ang II) and explored its possible mechanism.


METHODS
Neonatal cardiomyocytes and cardiac fibroblasts (CFs) were randomly treated with Ang II, captopril, B(2) receptor antagonist (HOE-140) and B(1) receptor antagonist (des-Arg(10), Leu(9)-kallidin) alone or in combination. Flow cytometry was used to evaluate cell cycle, size and protein content. Nitric oxide (NO) and intracellular cyclic guanosine monophosphate (cGMP) level were measured by colorimetry and radioimmunoassay.


RESULTS
After the CFs and cardiomyocytes were incubated with 0.1 micromol/L Ang II for 48 hours, the percentage of CFs in the S stage, cardiomyocytes size and protein content significantly increased (both P < 0.01 vs control), and these increases were inhibited by 10 micromol/L captopril. However, NO and cGMP levels were significantly higher than that with Ang II alone (both P < 0.01). 1 micromol/L HOE-140 or 0.1 micromol/L des-Arg(10), Leu(9)-kallidin attenuated the effects of captopril, which was blunted further by blockade of both B(1) and B(2) receptors.


CONCLUSIONS
Acting via B(2) receptor, BK contributes to the antihypertrophic and antiproliferative effects of captopril on cardiomyocytes and CFs. In the absence of B(2) receptor, B(1) receptor may act a compensatory mechanism for the B(2) receptor and contribute to the inhibition of cardiomyocyte hypertrophy and CFs proliferation by captopril. NO and cGMP play an important role in the effect of B(1) receptor.
Zou
Jun
J
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China. zoujun961@163.com
Ren
Jiang-hua
JH
Feng
Dan
D
Wang
Hong
H
Xu
Jiang
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002216:Captopril / Q000494:pharmacology*; D006332:Cardiomegaly / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D006152:Cyclic GMP / Q000032:analysis; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D043783:Receptor, Bradykinin B1; D009569:Nitric Oxide; D004247:DNA; D002216:Captopril; D006152:Cyclic GMP