Role of endothelin in mediating postmenopausal hypertension in a rat model

Abstract

Cardiovascular disease is the leading cause of death in women after menopause. Hypertension, a major cardiovascular risk factor, becomes more prevalent after menopause. The mechanisms responsible for the increase in blood pressure (BP) in postmenopausal women are unknown. We have recently characterized the aged, postestrous-cycling (PMR) spontaneously hypertensive rats (SHR) as a model of postmenopausal hypertension. The purpose of the present study was to determine whether endothelin plays a role in the increased BP in PMR. Premenopausal female SHR, aged 4 -5 mo (YF), and PMR, aged 16 mo, were studied. Expression of preproendothelin-1 mRNA was not different in either renal cortex or medulla between PMR and YF (n ϭ 7-8/group). In contrast, ET-1 peptide expression was significantly higher in renal cortex of PMR than in renal cortex of YF, but there was no difference in medullary ET-1. Expression of endothelin ET A receptor (ETAR) mRNA was lower in renal cortex and medulla of PMR than of YF. Additional groups of rats (n ϭ 6 -7/group) were treated for 3 wk with the ETAR antagonist ABT-627 (5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). BP was significantly higher in PMR than in YF. ETAR antagonist reduced BP in PMR by 20% to the level found in control YF. ETAR antagonist had no effect on BP in YF. These data support the hypothesis that the increase in BP in PMR is mediated in part by endothelin and the ET AR. ETA receptor; ETB receptor; kidney AFTER MENOPAUSE, blood pressure (BP) increases in women such that the prevalence of hypertension is higher in postmenopausal women than in age-matched men (5, 24). The reasons why BP increases in women after menopause are not known. However, endothelin has been suggested to play a role in the increase in BP in postmenopausal women because plasma levels of endothelin have been shown to be increased after menopause (15), and hypertensive postmenopausal women have higher endothelin levels than normotensive ones (25).Recently, we characterized a model of postmenopausal hypertension in the aging female spontaneously hypertensive rat (SHR). Throughout their reproductive lives, female SHR have lower BPs than males (17). However, the female SHR stops cycling at 10 -12 mo of age, and, by 16 -18 mo of age, BP levels are similar to or higher than those in age-matched male SHR (11). This loss of the sexual dimorphism in BP is due to an increase in BP in the females rather than any change in BP in the males after 8 mo of age (11). Postcycling female SHR (PMR) also exhibit increases in plasma renin activity, renal vasoconstriction, and renal injury when compared with premenopausal females (11), suggesting that a vasoconstrictor may be involved in the increase in BP in PMR.In the present study, we determined whether endothelin plays a role in mediating postmenopausal hypertension in PMR. Because the kidney is the major long-term controller of BP, we tested the hypothesis of whether there was an increase in the expression of endothelin-1 (ET-1) in the kidneys of PMR compared with young female rats and whether a s...

Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

“…With regard to oxidative stress, aging female SHR respond with reductions in blood pressure to chronic (8 mo) treatment with vitamins E and C (6), which suggests that oxidative stress plays a role in maintaining hypertension with aging in female SHR, although the present data do not indicate that ANG II is involved in mediating the oxidative stress in aging females. We found previously that the increase in blood pressure with aging in female SHR is associated with greater expression of intrarenal endothelin (ET) than in young females (23). In addition, a specific ET type A receptor antagonist decreased blood pressure in aging female SHR, but not to normotensive levels (23), similar to the effect of losartan in the present study.…”

Endothelin in the female vasculature: a role in aging?

“…Studies in intact animals have shown a modulatory effect of estrogen on ET-1 effects in the cardiovascular system. While neither male nor cycling female SHR rats show a role for ET-1 on hypertension, ET-1 protein levels are upregulated in postcycling SHR females with a consequent effect of ET-1 modulation on blood pressure (90,112). Similarly, in a rat model of DOCA-salt hypertension, ovariectomy worsened ET-1-mediated vasoconstriction, which could be reversed by supplementation with exogenous estrogen with or without progesterone (24).…”

Prevalence of metabolic syndrome in pre- and postmenopausal women

“…The oxidative stress markers are increased in women after menopause (37), and oxidative stress has caused the increase of blood pressure by decreasing the bioavailability of vasodilator (36). However, antioxidant therapy did not produce a reduction in blood pressure, in humans (38). The role of oxidative stress in hypertension in women after menopause has not been completely elucidated (35).…”