ABSTRACT
We compared three drugs representing different classes of antidiabetic pharmacology (glyburide, a sulfonylurea; pioglitazone, a thiazolidinedione; and metformin, a biguanide) in terms of their direct effects on proliferation of cultured arterial smooth muscle cells (SMC). Rat aortic SMC were seeded at 4 x 10(4)/35 mm well. After 24 h, they were treated 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 mumol/L), pioglitazone (1 and 5 mumol/L), and metformin (20 and 100 mumol/L). Vehicle-treated 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 14. From day 9 to 14 these cell numbers were decreased an average of 20% by the 2.5 mumol/L glyburide (P < .05) and 43% by the 5 mumol/L pioglitazone (P < .05). The low levels of glyburide and pioglitazone and both the low and high levels of metformin failed to influence cell numbers. In a second experiment, even half the abovementioned high level of pioglitazone (2.5 mumol/L) still exerted a markedly greater antiproliferative effect on aortic SMC than a high level of 2.0 mumol/L glyburide (P < .05). In addition, neither drug's antiproliferative effect was 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 antidiabetic agents than sulfonylureas and biguanides in inhibiting abnormal arterial SMC proliferation associated with atherosclerosis and postangioplastic restenosis which are common in diabetic patients.
Subject(s)
Glyburide/pharmacology , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Muscle, Smooth, Vascular/cytology , Thiazoles/pharmacology , Thiazolidinediones , Animals , Aorta, Thoracic , Cattle/blood , Cell Division/drug effects , Cells, Cultured , Fetal Blood , In Vitro Techniques , Insulin/pharmacology , Muscle, Smooth, Vascular/drug effects , Pioglitazone , Rats , Rats, Inbred StrainsABSTRACT
High oral potassium (K) decreases stroke incidence in aging high salt-fed stroke-prone spontaneously hypertensive rats (SHRSP). We have seen high oral Ca increase stroke incidence in aging high salt-fed SHRSP without increasing blood pressure (BP) but with signs of K wasting. Therefore, we sought to determine whether high oral Ca suppresses the previously reported oral K-related enhancement of arterial endothelium-dependent relaxation as seen in younger high salt-fed SHRSP before the appearance of strokes. Four groups of female SHRSP were fed high-salt diets containing either low (0.4%) or high (1.6%) K with low (0.4%) and high (1.6%) Ca from age 1 to 4 mos. High oral K decreased BP independent of Ca intake (P < 0.05). High oral Ca did not affect BP. In contrast to aging SHRSP, high oral Ca neither increased urinary excretion nor decreased plasma concentration of K in these young adult SHRSP. However, high (vs. low) oral K only significantly reduced the half-maximal effective dose for acetylcholine-induced relaxation of aortic rings from rats fed low (18 +/- 3 vs. 38 +/- 6 nM, P < 0.05) not high Ca (25 +/- 5 vs. 31 +/- 3 nM). Neither oral K nor Ca affected nitroprusside-induced relaxation. Thus high oral Ca by itself does not impair endothelium-dependent relaxation in young adult high salt-fed SHRSP, but yet it suppresses the enhancing effect of high oral K on such relaxation and does so without altering BP, K balance, or endothelium-independent relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
