Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrimethamine's antifertility effects in the male mouse suggest that this agent has potential as a male contraceptive. This dihydrofolate reductase inhibitor was administered to 72 adult male Swiss-Webster mice over a 50-day period at dosages ranging from 10-200 mg/kg/day. During the last 10 days of drug administration, the study mice were exposed to 3 female mice who underwent 2 reproductive cycles. The female mice were examined for gravidity 19 days after the onset of the breeding cycle. Male infertility was dose-dependent, with no pregnancies occurring among the partners of mice who received the maximum dosage of pyrimethamine. Also inversely proportional to dosage were the number and motility of epididymal sperm in the treated mice and mean seminiferous tubule diameter and testicular and epididymal weights. Time course analysis revealed that the drug begins to exert its antifertility effect 33 days after administration and nearly complete infertility is achieved with 50 days, suggesting that pyrimethamine acts on early-midspermatogenesis. All mice returned to normal fertility status 44 days after treatment ended, and epididymal sperm reserves, sperm motility, and testicular and epididymal weights also returned to baseline values within this time period. Of particular interest was the finding that when pyrimethamine was administered to another group of mice for 80 days, infertility was significantly reduced beyond that achieved in 50 days, yet there were no further effects on testicular epididymal function. It would appear that pyrimethamine's mechanism of action is its antifolate action, with the main effect occurring on the testes rather than the epididymis.
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PMID:Pyrimethamine: an approach to the development of a male contraceptive. 230 8

The present study examines whether the antifertility effects of pyrimethamine (PYR), an inhibitor of dihydrofolate reductase, are mediated by a reduction in intratesticular testosterone (T) concentrations or whether PYR exerts its effect by a cytotoxic insult to spermatogenic cells that is independent of intratesticular testosterone. Adult male rats were treated daily with 100 mg/kg (n = 16) or 400 mg/kg (n = 16) of PYR in honey for 8 weeks. Control rats (n = 16) received honey without PYR. Eight weeks after treatment, five rats from each PYR-treated group and five control rats were mated with normal cycling female rats, and fertility was assessed. These rats were euthanized after the fertility trial; testis weight, testicular sperm, and epididymal sperm counts were determined, and serum levels of T, LH, FSH, and seminiferous tubule fluid T (STF-T) concentrations were measured by RIA. Testes from three rats per group were perfusion-fixed for histological evaluation. PYR was discontinued in the remaining rats for 8 weeks and similar parameters were evaluated after 8 weeks of recovery. PYR (100 mg/kg/day) treatment for 8 weeks did not have any effects on organ weights, testicular and epididymal sperm counts, and hormone levels when compared to controls. In contrast, PYR (400 mg/kg/day) treatment significantly reduced testis and epididymis weights, testicular and epididymal sperm counts, and fertility. Despite these effects, serum T, LH, FSH, and STF-T concentrations were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of chronic administration of pyrimethamine on spermatogenesis and fertility in male rats. 840 72

Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg(-1) per day, pravastatin 30 mg kg(-1) per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.
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PMID:Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model. 1946 50