EFFECT OF CAPTOPRIL ON LYMPHOCYTIC BETA-ADRENERGIC RECEPTORS IN NORMAL AND HYPOXIC CONDITIONS

Background: During heart failure, due to increased level of circulatin g norepinephrine, the number of beta-adrenergic receptors (beta-AR), b oth at the cardiac and the lymphocytic level, is reduced (down-regulat ion). Captopril, an ACE-inhibitor containing an SH group appears capab le of resetting beta-AR when used in patients with heart failure. Our study was aimed at checking whether captopril exerts a direct effect u pon the beta-AR, possibly through its SH group by disulphur binding wi th cysteine residues located at the binding sites for catecholamines. Methods: The study was carried out in vitro on human lymphocytes obtai ned from healthy volunteers: 10 males (mean age, 34 years; range, 25-4 5) 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 captopr il: 1, 10, and 100 mu M. Control lymphocytes and those treated with 10 mu M Of captopril were exposed to 1 mu M isoproterenol. The number of total and surface beta-AR, and the sequestration of beta-AR from isop roterenol under normoxic conditions and after 20 h of hypoxia were che cked. Furthermore, the content of cAMP was assayed both in basal condi tions and after stimulation with 10 mu M and 100 mu M isoproterenol an d forskolin, respectively. Results: Total beta-AR: 1082 +/- 133 (contr ols) vs. 1174 +/- 94 (treatment with 1 mu M captopril), vs. 1237 +/- 8 8 (10 mu M captopril), vs. 1092 +/- 105 (100 mu M captopril). Surface beta-AR: 84 +/- 4.41% (controls) vs. 90.5 +/- 2.1%(10 mu M captopril). Basal cAMP: 1.21 +/- 0.4 (controls) vs. 1.23 +/- 0.5 pmol/10 cells (1 mu M captopril), 1.05 +/- 0.6 pmol/10 cells(10 mu M captopril), 1.15 +/- 0.4 pmol/10 cells (100 mu M captopril). After 10 mu M isoprotereno l: controls 4.10 +/- 0.8 vs. 4.30 +/- 0.9 pmol/10 cells (1 mu M captop ril), 4.15 +/- 0.7 pmol/10 cells (10 mu M captopril), 3.50 +/- 1.0 pmo l/10 cells (100 mu M captopril). After 100 mu M forskolin: controls 13 .2 +/- 3.1 vs. 11.2 +/- 3.1 pmol/10 cells (1 mu M captopril), 13.1 +/- 4.2 pmol/10 cells (10 mu M captopril), 12.6 +/- 2.9 pmol/10 cells (10 0 mu M captopril). Neither of these differences were significant. Lymp hocytic beta-AR exposed to hypoxia did not show any significant differ ence. Exposure to captopril did not cause any further alteration on be ta-AR sequestration. Conclusions: Captopril does not seem to exert any direct action upon lymphocyte beta-AR from healthy volunteers. Moreov er, captopril does not modify cAMP storage either in basal conditions or after stimulation with isoproterenol or forskolin. Therefore our da ta suggest that action of captopril on beta-AR is probably due to the inhibition of both systemic and tissue ACE-system.