Mechanism of beta-adrenergic receptor upregulation induced by ACE inhibition in cultured neonatal rat cardiac myocytes: roles of bradykinin and protein kinase C.
BACKGROUND
Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of beta-adrenergic receptors (beta-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes.


RESULTS
The density of beta-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 micromol/L) increased beta-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected beta-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on beta-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of beta-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours.


CONCLUSIONS
The results suggest that captopril enhances beta-AR responsiveness by inducing beta-AR upregulation and that the latter effect is mediated by activation of bradykinin B2 receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT1 receptor antagonists in the treatment of heart failure.
Yonemochi
H
H
Department of Laboratory Medicine, Oita Medical University, Japan. yonemo@pios.oita-med.ac.jp
Yasunaga
S
S
Teshima
Y
Y
Iwao
T
T
Akiyoshi
K
K
Nakagawa
M
M
Saikawa
T
T
Ito
M
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D002216:Captopril / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011943:Receptors, Adrenergic, beta; D018002:Receptors, Bradykinin; D013777:Tetrazoles; C065679:icatibant; D000803:Angiotensin I; D002216:Captopril; D011493:Protein Kinase C; D007545:Isoproterenol; C081643:candesartan; D001920:Bradykinin