Effect of captopril on lymphocytic beta-adrenergic receptors in normal and hypoxic conditions.
BACKGROUND
During heart failure, due to increased level of circulating norepinephrine, the number of beta-adrenergic receptors (beta-AR), both at the cardiac and the lymphocytic level, is reduced (down-regulation). Captopril, an ACE-inhibitor containing an SH group appears capable of resetting beta-AR when used in patients with heart failure. Our study was aimed at checking whether captopril exerts a direct effect upon the beta-AR, possibly through its SH group by disulphur binding with cysteine residues located at the binding sites for catecholamines.


METHODS
The study was carried out in vitro on human lymphocytes obtained from healthy volunteers: 10 males (mean age, 34 years; range, 25-45) and 10 females (mean age, 34 years; range 26-48). Lymphocytes were randomly divided in two groups of equal size. Group I were controls; in Group II cells were incubated with three different doses of captopril: 1, 10, and 100 microM. Control lymphocytes and those treated with 10 microM of captopril were exposed to 1 microM isoproterenol. The number of total and surface beta-AR, and the sequestration of beta-AR from isoproterenol under normoxic conditions and after 20 h of hypoxia were checked. Furthermore, the content of cAMP was assayed both in basal conditions and after stimulation with 10 microM and 100 microM isoproterenol and forskolin, respectively.


RESULTS
Total beta-AR: 1082 +/- 133 (controls) vs. 1174 +/- 94 (treatment with 1 microM captopril), vs. 1237 +/- 88 (10 microM captopril), vs. 1092 +/- 105 (100 microM captopril). Surface beta-AR: 84 +/- 4.41% (controls) vs. 90.5 +/- 2.1% (10 microM captopril). Basal cAMP: 1.21 +/- 0.4 (controls) vs. 1.23 +/- 0.5 pmol/10 cells (1 microM captopril), 1.05 +/- 0.6 pmol/10 cells (10 microM captopril), 1.15 +/- 0.4 pmol/10 cells (100 microM captopril). After 10 microM isoproterenol: controls 4.10 +/- 0.8 vs. 4.30 +/- 0.9 pmol/10 cells (1 microM captopril), 4.15 +/- 0.7 pmol/10 cells (10 microM captopril), 3.50 +/- 1.0 pmol/10 cells (100 microM captopril). After 100 microM forskolin: controls 13.2 +/- 3.1 vs. 11.2 +/- 3.1 pmol/10 cells (1 microM captopril), 13.1 +/- 4.2 pmol/10 cells (10 microM captopril), 12.6 +/- 2.9 pmol/10 cells (100 microM captopril). Neither of these differences were significant. Lymphocytic beta-AR exposed to hypoxia did not show any significant difference. Exposure to captopril did not cause any further alteration on beta-AR sequestration.


CONCLUSIONS
Captopril does not seem to exert any direct action upon lymphocyte beta-AR from healthy volunteers. Moreover, captopril does not modify cAMP storage either in basal conditions or after stimulation with isoproterenol or forskolin. Therefore our data suggest that action of captopril on beta-AR is probably due to the inhibition of both systemic and tissue ACE-system.
D'Amico
C
C
Istituto di Farmacologia, Università di Palermo, Italy.
Paterna
S
S
Di Pasquale
P
P
Antona
A
A
Palazzoadriano
M
M
Licata
G
G
D000328:Adult; D002216:Captopril / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D002216:Captopril; D000242:Cyclic AMP; D007545:Isoproterenol