DIFFERENTIAL INHIBITORY EFFECTS OF ANTIDIABETIC DRUGS ON ARTERIAL SMOOTH-MUSCLE CELL-PROLIFERATION

We compared three drugs representing different classes of antidiabetic pharmacology (glyburide, a sulfonylurea; pioglitazone, a thiazolidine dione; and metformin, a biguanide) in terms of their direct effects on proliferation of cultured arterial smooth muscle cells (SMC). Rat aor tic SMC were seeded at 4 X 10(4)/35 mm well. After 24 h, they were tre ated every 2 to 4 days for 2 weeks with 5% fetal bovine serum (FBS) in normal culture medium containing either drug vehicles or a low and a high but nontoxic level of glyburide (0.5 and 2.5 mu mol/L), pioglitaz one (1 and 5 mu mol/L), and metformin (20 and 100 mu mol/L). Vehicle-t reated cells increased from 2 +/- 0 to 6 +/- 1 to 42 +/- 3 to 210 +/- 14 (cells per well x 10(4); 5 wells each) from day zero to 4 to 9 to 1 4. From day 9 to 14 these cell numbers were decreased an average of 20 % by the 2.5 mu mol/L glyburide (P <.05) and 43% by the 5 mu mol/L pio glitazone (P <.05). The low levels of glyburide and pioglitazone and b oth the low and high levels of metformin failed to influence cell numb ers. In a second experiment, even half the abovementioned high level o f pioglitazone (2.5 mu mol/L) still exerted a markedly greater antipro liferative effect on aortic SMC than a high level of 2.0 mu mol/L glyb uride (P <.05). In addition, neither drug's antiproliferative effect w as influenced by a high level of insulin added to the medium (10 mU/mL ). Similarly, a small but significant stimulatory effect of this high insulin on cell proliferation (P <.05) was not significantly affected by these two drugs (although pioglitazone tended to inhibit it). These results suggest that thiazolidinediones may be more useful antidiabet ic agents than sulfonylureas and biguanides in inhibiting abnormal art erial SMC proliferation associated with atherosclerosis and postangiop lastic restenosis which are common in diabetic patients.