Oestrogen inhibits salt-dependent hypertension by suppressing GABAergic excitation in magnocellular AVP neurons
| Autor: | Mi na Kim, Eun Hwa Hong, Yoon Sik Kim, Wan Joo Shim, Yang In Kim, Woong Kim, Xiangyan Jin, Won Woo Jung, Christopher S. Colwell, Young Beom Kim, Hyung Kyung Kang, Hee Chul Han |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Vasopressin medicine.medical_specialty Physiology medicine.drug_class Ovariectomy Blood Pressure Nephrectomy gamma-Aminobutyric acid Rats Sprague-Dawley Desoxycorticosterone Acetate Physiology (medical) Internal medicine medicine Animals Solute Carrier Family 12 Member 2 GABAergic Neurons Sodium Chloride Dietary Antihypertensive Agents Estradiol Symporters business.industry Receptor antagonist Arginine Vasopressin Disease Models Animal Endocrinology Blood pressure Vasoconstriction Estrogen Basal Nucleus of Meynert Hypertension Ovariectomized rat GABAergic Female Cardiology and Cardiovascular Medicine business hormones hormone substitutes and hormone antagonists Hormone medicine.drug |
| Zdroj: | Cardiovascular Research. 117:2263-2274 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvaa271 |
| Popis: | Aim Abundant evidence indicates that estrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. Methods and results To this end, we performed a series of in-vivo and in-vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1, D-Tyr(Et)2, Lys6, Arg8, des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. Conclusion Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons. Translational perspective Numerous studies have shown that sex steroids can impact blood pressure (BP) and premenopausal women have a lower incidence of hypertension than age-matched men. Postmenopausal women no longer enjoy this beneficial difference. The causal mechanisms are not clear and hormone replacement therapy with estradiol (E2) does not consistently lower BP in postmenopausal women. In this study we showed that rats treated with CLP290 to control GABAergic excitation in AVP neurons have the same phenotype as E2-supplemented rats in BP and plasma AVP level. This result indicates that CLP290 leverages the same pathway of E2 protective effects against salt-dependent hypertension, and therefore, raises the possibility that classes of drugs like CLP290 may have some utility as alternative antihypertensives in persons resistant to or contraindicated for E2 therapy. |
| Databáze: | OpenAIRE |
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