Abstract 246: Role Of Cytochrome P450 4a2 In Mediating The Elevated Blood Pressure In A Rat Model Of Polycystic Ovary Syndrome

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Chetan N Patil ◽  
Carolina Dalmasso ◽  
Richard Roman ◽  
Jane F Reckelhoff
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Elevated Blood Pressure ◽  
Elevated Blood ◽  
Renal Vasculature ◽  
Ovary Syndrome

Women with polycystic ovary syndrome (PCOS) often have elevated blood pressure (BP). PCOS is characterized in part by increases in androgens, and androgens can increase cytochrome P450 (CYP) 4A isoforms and 20-HETE synthesis. We have found that CYP4A2 expression is increased in renal vasculature of hyperandrogenemic female rats, a model of PCOS. In the present study we tested the hypothesis that androgen increase would not cause elevated BP in CYP4A2 -/- rats compared with wild type SS.Bn5 rats. CYP4A2 -/- and SS.Bn5 rats (n=6-8/grp) were treated from 4 wks of age with dihydrotestosterone pellets (DHT 7.5 mg/90 d) or placebo pellets until 14 wks, and then telemetry transmitters were implanted. After 2 wks, mean arterial pressure (MAP) was measured for 10 days. DHT increased MAP and decreased HR in SS.Bn5 compared with placebo controls (placebo: 104±2 vs. DHT: 126±6 mmHg, p<0.001). In contrast, while placebo-treated CYP4A2 -/- rats had higher MAP than WT, DHT did not increase BP in CYP4A2 -/- rats (Placebo: 120±1 vs. DHT: 118±1 mmHg, p=NS). These data suggest that CYP4A2 may be necessary for DHT to increase BP in our model of PCOS. However, by what mechanism(s) CYP4A2 -/- rats have higher MAP than SS.Bn5 WT remains to be determined. Supported by NIH R01HL66072, P01HL05971 and AHA 14POST18640015.

Abstract P040: Role of 20-HETE in Elevated Blood Pressure in Hyperandrogenemic Female Rats, a Model of Polycystic Ovarian Syndrome

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Chetan N Patil ◽  
Carolina Dalmasso ◽  
Rodrigo O Maranon ◽  
Huimin Zhang ◽  
Richard J Roman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Polycystic Ovary ◽  
Premenopausal Women ◽  
Female Rats ◽  
Elevated Blood Pressure ◽  
Female Rat ◽  
Elevated Blood ◽  
Reproductive Disorder ◽  
Consomic Strain

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in premenopausal women, is characterized by hyperandrogenemia, metabolic syndrome and inflammation. They also exhibit elevated blood pressure (BP) but may not be treated since they do not meet the criteria for hypertension (BP>130/90 mm Hg). We have characterized a female rat model of hyperandrogenemia (HAF) using dihydrotestosterone (DHT) that mimics many characteristics of women with PCOS. In the present study we tested the hypothesis that androgen-induced upregulation of the cytochrome P450 4A2 isoform (CYP4A2) and the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) in renal microvasculature contributes to the elevated BP in HAF rats. Female rats of SS.5BN consomic strain (wild type) rats and CYP4A2-/- rats on this same background were implanted with DHT (7.5mg/90d) or placebo pellets (n=5-8/grp) beginning at 6 wks of age; pellets were changed every 85 d. At 14 wks of age, rats were implanted with radiotelemetry transmitters, and mean arterial pressure (MAP) was measured for 10 days. Endogenous 20-HETE levels were measured using LC-MS in renal microvessels isolated using an Evans Blue sieving technique. DHT-treated HAF-SS.5BN rats had significantly higher MAP compared to placebo-SS.5BN (128±6 vs. 104±1 mmHg, p<0.004). In contrast, HAF-CYP4A2-/- rats had no change in MAP compared to placebo-CYP4A2-/- controls (120±4 vs 118±3 mmHg, p=NS). Endogenous 20-HETE levels in renal microvessels of HAF-SS.5BN rats were significantly increased compared to Placebo-SS.5BN (2.27±0.91 vs. 0.32±0.037 pmol/mg, p<0.01). The 20-HETE levels were lower in CYP4A2-/- than SS.5BN but DHT in HAF-CYP4A2-/- had no effect on 20-HETE levels compared to Placebo- CYP4A2-/-. These results suggest that androgen-mediated upregulation of the expression of CYP4A2 and the production of 20-HETE in renal microvessels contribute to elevated BP in HAF rats. These data also suggest that methods to attenuate 20-HETE may provide a novel therapeutic to reduce BP in women with PCOS. Work supported by NIH RO1HL66072 and PO1HL51971.

scholarly journals Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 943-952
Author(s):  
Noha M. Shawky ◽  
Chetan N. Patil ◽  
Carolina Dalmasso ◽  
Rodrigo O. Maranon ◽  
Damian G. Romero ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Female Rats ◽  
Ovary Syndrome ◽  
Uncomplicated Pregnancy ◽  
Age Related ◽  
Endothelin B

Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.

Abstract 245: Role Of Melanocortin-4-receptor In The Blood Pressure Regulation In Female Hyperandrogenemic Rats, A Model Of Polycystic Ovary Syndrome

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Roberta Lima ◽  
Jussara M do Carmo ◽  
Alexander Da Silva ◽  
John E Hall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Food Intake ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Sprague Dawley ◽  
Ovary Syndrome ◽  
Melanocortin 4 Receptor ◽  
Ad Libitum

Women with polycystic ovary syndrome (PCOS) are characterized by hyperandrogenemia, hirsutism, infertility, and enlarged cystic ovaries. Obesity and hypertension are also frequently found in women with PCOS, although the mechanisms responsible for the elevated blood pressure (BP) are unclear. Thus we tested the hypothesis that the melanocortin-4 receptor (MC4R), known to contribute to obesity hypertension in males, contributes to the elevated BP in hyperandrogenemic female rats, a model of PCOS. Female Sprague Dawley rats (4 wks) were implanted with dihydrotestosterone (DHT; 7.5mg/90 days sc) or placebo pellets (PL) (n=5/grp) and aged to 12 wks. Body weight and food intake (whether rats were pair fed or had ad libitum access) were measured daily. Two wks following implantation of radiotelemetry transmitters and intracerebroventricular cannulae, baseline mean arterial pressure (MAP) was measured for 5 days; then rats received MC3/4R antagonist, SHU-9119 (SHU; 1 nmol/h ICV) or vehicle for 7 days and MAP was recorded. DHT-treated rats had higher body weight and MAP than PL rats (BW: PL: 266.0±8.7; DHT: 348.5±10.4 g, p<0.01; MAP: PL rats: 102±5; DHT: 114±5 mmHg, p<0.05). SHU significantly increased food intake and body weights in both placebo (PL) and DHT-treated rats fed ad libitum (PL: 379.2±28.5; DHT: 451/3±7.3 g, p<0.01 DHT vs PL; 0.01 SHU vs control), but had no effect on MAP compared to controls (PL: 104±5; HAF rats: 114±5 mmHg; p<0.05, HAF vs PL; p=NS, SHU vs controls). However, in other rats, when pair fed with little increase in body weight (PL: 253.7±2.0, SHU: 261.0±0.6, p<0.05; DHT: 306.7±2.6, SHU: 316.7±1.5 g, p<0.05), SHU decreased MAP in DHT treated rats but not placebo controls (PL rats: 102±1, SHU: 103±2 mmHg; p=NS; DHT rats: 110±1 vs. SHU: 97±1 mmHg; p<0.001). Thus MC4R antagonist reduces MAP in DHT-treated rats only when food intake and body weight are controlled. These data suggest that activation of MC4R contributes to elevated BP in our model of PCOS and may also contribute to the elevated BP in women with PCOS. Supported by NIH R01HL66072, P01HL05971 and AHA 14POST18640015.

The role of vitamin D in metabolic and reproductive disturbances of polycystic ovary syndrome: A narrative mini-review

2020 ◽  
pp. 1-8
Author(s):  
Daniela Menichini ◽  
Gianpiero Forte ◽  
Beatrice Orrù ◽  
Giuseppe Gullo ◽  
Vittorio Unfer ◽  
...  
Keyword(s):  
Vitamin D ◽  
Polycystic Ovary Syndrome ◽  
Embryo Quality ◽  
Polycystic Ovary ◽  
Vitamin D Supplementation ◽  
Endometrial Receptivity ◽  
Metabolic Disturbances ◽  
Ovary Syndrome ◽  
Beneficial Role

Abstract. Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400–800 IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.

ROLE OF THE THYROID GLAND IN DEVELOPMENT AND MAINTENANCE OF RENAL HYPERTENSION IN RATS

1960 ◽  
Vol XXXIV (III) ◽  
pp. 411-429 ◽  
Author(s):  
Melvin J. Fregly ◽  
Kenneth M. Cook
Keyword(s):  
Blood Pressure ◽  
Rate Increase ◽  
Renal Hypertension ◽  
The Other ◽  
Elevated Blood Pressure ◽  
Unit Weight ◽  
Elevated Blood ◽  
Inhibition Of Growth ◽  
Testicular Size

ABSTRACT The anti-thyroid drugs, thiouracil, propylthiouracil, and methimazole, prevented both development of elevated blood pressure and cardiac hypertrophy usually accompanying kidney encapsulation with latex envelopes. These drugs also reduced elevated blood pressure of rats with hypertension of 13 to 40 weeks' duration prior to drug administration. Addition of desiccated thyroid powder to diet containing an anti-thyroid drug overcame the anti-hypertensive effect of the latter. Withdrawal of thyroid powder only was followed by return of blood pressure to previous low level within 3 weeks. The results suggest that the anti-hypertensive effect of these drugs is related directly to the hypothyroidism produced rather than to extrathyroidal effects of the drugs. Comparison of potencies of the 3 drugs in terms of anti-hypertensive effect, inhibition of growth rate, increase in testicular size, and increase in thyroid size suggests that propylthiouracil and methimazole are equally potent per unit weight of drug. Thiouracil has approximately half the potency of the other two.

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