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17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women.

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 17beta-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 48.2+/-2.3 years) who were randomized to receive 17beta-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 microg/min/100 mL forearm volume). 17Beta-estradiol significantly reduced baseline venous plasminogen activator inhibitor-1 antigen (4.4+/-1.4 versus 10.4+/-2.5 ng/mL, P=0.001) and t-PA antigen (5.5+/-0.6 versus 7.5+/-1.3 ng/mL, P=0.022) compared with placebo. 17Beta-estradiol increased basal forearm vascular release of active t-PA compared with placebo (1.2+/-0.3 IU/mL/min versus 0.4+/-0.1 IU/mL/min respectively, P=0.032), without increasing t-PA antigen release (P=0.761). Enalaprilat significantly increased basal net t-PA antigen release (from -0.8+/-1.0 to 3.2+/-1.2 ng/min/100 mL, P=0.012), but not the release of active t-PA, during either placebo or 17beta-estradiol. Enalaprilat potentiated bradykinin-stimulated vasodilation and t-PA antigen and activity release similarly during placebo and 17beta-estradiol treatment. 17Beta-estradiol treatment does not alter the effect of angiotensin-converting enzyme inhibition on basal t-PA antigen or on bradykinin-stimulated t-PA antigen or activity release. 17Beta-estradiol increases basal release of active t-PA in young postmenopausal women, consistent with enhanced vascular fibrinolytic function.

SUBMITTER: Pretorius M

PROVIDER: S-EPMC2673569 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women.

Pretorius Mias M van Guilder Gary P GP Guzman Raul J RJ Luther James M JM Brown Nancy J NJ

Hypertension (Dallas, Tex. : 1979) 20080207 4

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 17beta-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 48.2+/-2.3 years) who were randomized to receive 17beta-e ...[more]

PMID: 18259028

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Project description:Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.

Project description:Estrogen can significantly influence CD16 expression and alter monocytic cytokine release upon CD16 receptor activation. However, the function of the estrogen receptor (ER) alpha and beta in this response is unclear. To test whether estrogen binds ERalpha and/or ERbeta to affect CD16 expression, monocytic cells were treated with and without physiological levels of 17beta-estradiol and various doses of the ERalpha and ERbeta antagonist fulvestrant followed by measurement of CD16 transcript levels. To determine how estrogen induced changes in TNF-alpha and IL-1beta release due to CD16 activation we quantitated the amount of cytokines after treatment with estrogen, fulvestrant and antibodies that specifically bind and activate the CD16 receptor. Interaction of ERalpha and the CD16 promoter was then determined by chromatin immunoprecipitation. Furthermore, specific promoter elements utilized by estrogen to control CD16 expression were mutated and expression from a luciferase reporter quantitated after transfection. Using the luciferase reporter construct containing a wild type CD16 promoter, the role of ERalpha and ERbeta in the estrogen response was tested by treating transfected monocytes with an ERalpha specific agonist or an ERbeta specific agonist and measuring expression. Our results show that CD16 transcript levels significantly decreased in monocytic cells due to estrogen and that the observed decrease in message was blocked by the antagonist fulvestrant. Estrogen reduced CD16 expression and decreased TNF-alpha and IL-1beta release upon CD16 activation but the administration of fulvestrant blocked this decrease. ERalpha was found to interact with a region 5' of the CD16 gene in the presence of estrogen, and site-directed mutational analysis of this region indicated the necessity for an estrogen response element in modulating estrogen effects on CD16 expression. Moreover, both an ERalpha and an ERbeta agonist reduced expression of the CD16 reporter construct suggesting both receptors can play a role in CD16 regulation. In conclusion, CD16 expression can be altered by the activity of ERalpha or ERbeta and our results also show that ERalpha can associate with a region within the CD16 promoter that is important in production of transcript.

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17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women.

Publications

17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women.

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