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.

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The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) was established by the NTP and the National Institute of Environmental Health Sciences (NIEHS) in 1998 to address the impact of chemical exposures on human reproductive and developmental health and to serve as an environmental and reproductive health resource for government agencies and the general public. The purpose of this report is to provide an overview of the Center activities and a summary of NTP conclusions on chemicals evaluated during this time period. CERHR evaluations involve the critical review of reproductive, developmental, and other relevant toxicity data by independent panels of scientists. The products of these evaluations are expert panel reports. The public has opportunities to provide oral comments at the panel meeting and written comments on draft and final expert panel reports. The NTP evaluates these comments, the conclusions of the expert panel, and any new data not available at the time of the panel meeting, and prepares an NTP brief that describes in plain language the NTP's conclusions on the reproductive and developmental hazard from specified chemical exposures. The NTP brief, expert panel report, and public comments comprise the NTP monograph on the chemical. Monographs are sent to federal regulatory agencies, the NTP Executive Committee, and the NTP Board of Scientific Counselors, and are publicly available. Over the last five years, CERHR conducted expert panel evaluations on 14 chemicals. At this time, 13 panel reports have been published and 12 NTP-CERHR monographs have been issued. Additionally, CERHR conducted a 2-day workshop on the role of thyroid hormones in reproductive and developmental health.

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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)