17β-Estradiol Increases Basal but Not Bradykinin-Stimulated Release of Active t-PA in Young Postmenopausal Women

Abstract

Abstract-Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17␤-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2Ϯ2.3 years) who were randomized to receive 17␤-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before and during intraarterial enalaprilat (0.33 g/min/100 mL forearm volume Key Words: estradiol Ⅲ angiotensin-converting enzyme inhibition Ⅲ postmenopausal women Ⅲ plasminogen activator Ⅲ bradykinin E strogen deficiency of menopause causes vascular and metabolic changes that increase the risk for cardiovascular disease. 1,2 In contrast to observational studies that suggest that hormone replacement therapy (HRT) reduces the risk of coronary heart disease (CHD), 3-5 recent randomized controlled trials indicate that treatment with conjugated estrogen plus progestin increases the risk of pulmonary emboli, CHD, and stroke, whereas treatment with conjugated estrogen alone increases risk of stroke without affecting embolic events or risk of CHD. 6 -8 This discrepancy in results has been attributed to the type of HRT used, the timing of intervention of HRT after menopause, 9,10 or the route of administration. 11 For example, the Heart and Estrogen/progestin Replacement Study (HERS) 8 and the Women's Health Initiative (WHI) 6,7 study assessed the effect of treatment with conjugated equine estrogens, a mixture of estrogens extracted from horse urine that also contains progestins and androgens, whereas estradiol is the major endogenous estrogen. 12 Differences in the outcomes of epidemiological studies and clinical trials are best interpreted in the context of an understanding of the biological effects of estrogen. On the one hand, oral HRT increases circulating fibrin split products (FSP), concentrations of inflammatory cytokines, and C-reactive protein. [13][14][15] On the other, estradiol exerts many salutary effects on the vasculature, including improving endothelial-dependent vasodilation, 16 decreasing fibrinogen and plasminogen activator inhibitor (PAI)-1 (PAI-1), [17][18][19] increasing the secretion of nitric oxide from intact platelets, 20 and attenuating platelet-derived growth factor (PDGF) receptor-activated smooth muscle cell migration and proliferation. 21 HRT decreases circulating t-PA antigen in parallel with PAI-1 antigen, to which it is complexed. Circulating t-PA antigen does not reflect the capacity of the vasculature to release t-PA, however, and the effect of HRT or estrogen on endothelial fibrinolytic function has not been studied exten-

Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular Tissue-Type Plasminogen Activator Release

“…The increase in bradykinin-stimulated t-PA release in the presence of L-NMMA was significantly greater in women compared with men (F ϭ 6.7, P ϭ 0.02). jpet.aspetjournals.org estrogen-independent as, during ACE inhibition, bradykinin-stimulated t-PA release is increased in postmenopausal as well as premenopausal women compared with age-matched men and 17␤-estradiol treatment does not alter t-PA release in postmenopausal women (Pretorius et al, 2005(Pretorius et al, , 2008. We again observed a gender difference in the t-PA response to bradykinin in the current study.…”

Endothelial biology in the post-menopausal obese woman

“…28 Interestingly, the admisntistration of 17b-estradiol increases basal but not bradykinin-stimulated release of t-PA in young post-menopausal women. 29 …”

Sex differences in the coronary vasodilation induced by 17 β‐oestradiol in the isolated perfused heart from spontaneously hypertensive rats

“…The natural oestrogen 17 b-oestradiol may indirectly affect both vascular tone and vasoreactivity to different contractile or relaxant agonists, including the thromboxane A 2 receptor agonist U46619 (Yang et al 2009), bradykinin (Pretorius et al 2008) or serotonin (Moysés et al 2001). The ability of oestrogen to increase the bioavailability of the vasodilator, antiaggregating and anti-proliferative substance nitric oxide (NO) is a topic of intense current investigation (Bednarek-Tupikowska et al 2008).…”