PubMed · 4707410
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
R Paoletti, R Fumagalli, R Sirtori. 1973-04-14. [Hypolipemic agents].. https://pubmed.ncbi.nlm.nih.gov/4707410/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
The developing male rat reproductive system is highly sensitive to low doses of TCDD and p,p'-DDE (DDE), which exert antiandrogenic effects via different mechanisms. This study investigates the interactive effects of in utero and lactational exposure to a mixture of these compounds. Pregnant Holtzman rats received one of the following: vehicle on gestation day (GD) 14-18, 0.25 microgram/kg TCDD on GD15, 100 mg/kg DDE on GD 14-18, or 0.25 microgram/kg TCDD on GD15 and 100 mg/kg DDE on GD 14-18. Male offspring were euthanized on postnatal day (PND) 21 (weaning), PND 32 (prepuberty), PND 49 (puberty), and PND 63 (postpuberty). Coadministration of these doses of TCDD and DDE appeared to potentiate their individual actions on prostate weight on PND 21, while immunostaining for the prostatic androgen receptor exhibited patterns characteristic of the effects of both compounds individually. Cauda epididymal sperm number was reduced by each compound but was not further reduced by exposure to TCDD and DDE in combination. Anogenital distance, age at onset of puberty, daily sperm production, testicular and accessory sex organ weight (nonprostate), and levels of prostatic androgen-regulated gene transcripts are affected at higher doses of both compounds, but not at the doses used in the present study. Only DDE-treated animals retained nipples on PND 13. Serum androgen levels did not differ between treatment groups. In conclusion, the developing rat prostate is uniquely sensitive to the effects of TCDD and DDE, which may augment one another's effects in this organ.
Androgens and estrogens influence the maturation and function of numerous tissues in both male and female birds, especially the brains of the oscine songbirds. Although there exist a very large number of studies that have investigated circulating sex steroids in many species of wild and captive-held songbirds, there remain a significant number of questions about the sites of synthesis of the active steroids that act on the songbird brain. Estrogens are derived from androgen. Thus, the synthesis of androgen itself is critical for both androgen- and estrogen-dependent actions in both male and female songbirds. Therefore, we have undertaken studies of the enzyme 17alpha-hydroxylase/C17,20-lyase (Cyp17), the enzyme responsible for the synthesis of androgens from their progestin or pregnane precursors via their 17alpha-hydroxy intermediates. Here we have characterized optimal conditions for measuring Cyp17 in gonads of adult zebra finches via the conversion of tritiated [3H]progesterone into 17alpha-hydroxy P (17alpha-hydroxylase activity) and androstenedione and testosterone (C17,20-lyase) activity. Cyp17 activity is abundant in testis, with lesser amounts in ovary. Low levels of Cyp17 activity were also detected in male adrenals, but not in any other tissue, including brain. Testicular Cyp17 activity is readily inhibited in vitro by ketoconazole, a specific Cyp17 inhibitor. Ketoconazole works less well in vivo. In males castrated and/or treated with fadrozole, an inhibitor of aromatase, we detected no extragonadal sites of Cyp17 activity, although fadrozole appeared to increase circulating androgens in both castrated and intact males. Thus, we still do not know the site of androgen synthesis in these males. Further studies of Cyp17 will be useful in understanding more about the mechanisms of androgen delivery to neural circuits in adult and developing songbirds.