Estrogen Regulates Adrenal Angiotensin Type 1 Receptors by Modulating Adrenal Angiotensin Levels

Abstract

Estrogen inhibits adrenal angiotensin type 1 receptor (AT(1)R) binding sites and attenuates the adrenal responsivity to angiotensin II (Ang II). Ang II modulates AT(1)R expression. Here, we determined if estrogen-induced down-regulation of adrenal AT(1)Rs involves modulation of adrenal Ang II. Female rats were ovariectomized (OVX) and injected with 17beta-estradiol benzoate (E(2); 40 micro g/kg) or vehicle for 7 d. Adrenal Ang II was separated from other angiotensin peptides by HPLC and measured by RIA. Scatchard analysis of radioligand binding curves showed that E(2) or captopril (Cap; 0.5 g/liter water) significantly reduced adrenal AT(1)R binding (maximum binding capacity) by 22% and 19%, respectively, compared with OVX (276 +/- 2.09 fmol/mg protein). E(2) and Cap lowered adrenal Ang II levels by 39% and 21%, respectively, compared with OVX (4.10 +/- 0.44 pmol/g). E(2) caused no further reductions in adrenal AT(1)R binding or in Ang II levels in Cap-treated OVX rats. High-dose Ang II infusion (1000 ng/kg.min) increased adrenal Ang II levels by 71% and lowered AT(1)R binding by 18%. Under these infusion conditions, E(2) did not reduce adrenal Ang II or AT(1)R binding. No differences in AT(1)R affinity (dissociation constant) were observed among groups. These data suggest that E(2) regulates the number of adrenal AT(1)R binding sites indirectly by modulating adrenal Ang II.

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

“…In humans and experimental animals, estrogen facilitates vasodilation by stimulating prostacyclin and nitric oxide synthesis as well as by decreasing the production of vasoconstrictor substances, such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1 (3). Estrogen also reduces the number of adrenal angiotensin type I (AT 1 ) receptors, but indirectly, by modulating adrenal angiotensin II (4). In estrogen receptor-deficient states, there is evidence of increased atherosclerosis, an attenuated response to vascular smooth muscle cell proliferation in response to injury and reduced endothelial nitric oxide production (5).…”

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

“…Indeed, the incidence for ischemic stroke and dementia were higher for this population of postmenopausal women receiving either estrogen or combined hormone replacement therapy (40, 41). The results of WHI and HERS were surprising, in part, due to the generally accepted view that estrogen has beneficial actions on nitric oxide (NO), as well as an inhibitory influence on the components of the renin-angiotensin-aldosterone system (RAAS), including ACE and the angiotensin type 1 (AT1) receptor (6,12,17,26,33,45).Our studies in the congenic mRen2.Lewis strain of hypertensive rats support the beneficial role of estrogen since ovariectomy exacerbates the development of hypertension in this model of tissue renin overexpression (10). Early estrogen depletion almost abolishes the gender difference in blood pressure evident between male and female mRen2.Lewis rats (10), as well as in other hypertensive models (33).…”

“…Indeed, the incidence for ischemic stroke and dementia were higher for this population of postmenopausal women receiving either estrogen or combined hormone replacement therapy (40,41). The results of WHI and HERS were surprising, in part, due to the generally accepted view that estrogen has beneficial actions on nitric oxide (NO), as well as an inhibitory influence on the components of the renin-angiotensin-aldosterone system (RAAS), including ACE and the angiotensin type 1 (AT1) receptor (6,12,17,26,33,45).…”

PET Imaging of the AT1 receptor with [11C]KR31173

“…Dogs, baboons, and probably pigs can be used as animal models for human AT 1 R imaging since, in contrast to rodents in which two subtypes, AT 1a and AT 1b , have been discovered, dogs, baboons and pigs, like humans, possess only one subtype of these receptors, i.e., AT 1 R. The PET images showed high [ 11 C]KR31173 binding in the adrenal glands of dogs and a baboon, confirming the ex vivo binding studies performed in mice. The adrenals have a very high density of the AT 1 R which also undergoes hormonal regulation [7,29] and is involved in the regulation of the biosynthesis and secretion of aldosterone [30][31][32][33]. Of potential interest for imaging studies is the application of AT 1 R PET in aldosterone producing tumors.…”