Direct effects of the angiotensin-converting enzyme inhibitor ramiprilat on adult rat ventricular cardiomyocytes.
OBJECTIVE
Angiotensin-converting enzyme (ACE) inhibitors like ramiprilat bind to ACE expressed on the cell surface of endothelial cells and induce cell-specific signalling including the activation of activator protein (AP)-1. The present study addressed the question whether ramiprilat exerts a similar effect on adult ventricular cardiomyocytes, i.e. activates the AP-1 or modifies contractile performance. It was further aimed to decide whether such effects depend on bradykinin receptors or whether they are directly mediated via ACE.


METHODS
Adult rat ventricular cardiomyocytes were isolated and cultured. mRNA expression of ACE was investigated by RT-PCR, AP-1 activation by gel mobility shift assays, and cardiac contractile performance by electrical pacing of isolated cells and analysis of cell shortening via a line-camera.


RESULTS
Cardiomyocytes stably express ACE. Ramiprilat increased maximal contraction velocity and shortened the time-to-peak of contraction. In contrast to effects evoked by bradykinin, such effects caused by ramiprilat were not attenuated by HOE 140, a bradykinin-receptor antagonist. These effects were also not attenuated in the presence of l-nitro-arginine, used to mimic bradykinin-dependent signalling. In cardiomyocytes, bradykinin but not ramiprilat activated AP-1. Ramiprilat activates AP-1 in endothelial cells that are known to respond to ramiprilat in this way.


CONCLUSIONS
Ramiprilat exerts direct, bradykinin-receptor independent effects on cardiomyocytes that improve cellular function without a corresponding effect on AP-1 activation or induction of AP-1 dependent effects. This newly described effect of ramiprilat may contribute to the protective effects seen by application of ACE inhibitors.
Helmig
S
S
Justus-Liebig-Universität GieSSen, Physiologisches Institut, GieSSen, Germany.
Schuckenböhmer
P
P
Heger
J
J
Euler
G
G
Piper
H M
HM
Schlüter
K-D
KD
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D017257:Ramipril / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016276:Ventricular Function