Testosterone inhibits bradykinin-induced intracellular calcium kinetics in rat aortic endothelial cells in culture

Rubio-Gayosso, Iván; Garcia-Ramirez, Olga; Gutierrez-Serdan, Ruth; Guevara‐Balcazar, Gustavo; Muñoz-Garcia, Olga; Morato-Cartajena, Tomas; Zamora-Garza, Miguel; Ceballos, Guillermo

doi:10.1016/s0039-128x(01)00192-1

Cited by 30 publications

(17 citation statements)

References 19 publications

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“…35 Taken together with our prior observation that basal and bradykinin-stimulated t-PA release are increased in ACE inhibitor-treated postmenopausal women compared with age-matched men, the data support an estrogenindependent effect of gender on vascular t-PA release during ACE inhibition. In this regard, decreased bradykininstimulated t-PA release in men compared with women during ACE inhibition could reflect a reported negative effect of testosterone on bradykinin-stimulated calcium influx, 36 a prospect that merits further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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-

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…Metabolites of DHEA include estradiol, which also induces vascular endothelial proliferation by activation of MAPKs (86). Testosterone, another metabolite of DHEA, does not acutely activate ERK 1/2 or increase vascular proliferation (87,88). Additionally, there are many other metabolites of DHEA (89), some of which have known biological activities, e.g.…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone Stimulates Endothelial Proliferation and Angiogenesis through Extracellular Signal-Regulated Kinase 1/2-Mediated Mechanisms

et al. 2007

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“…Several lines of investigation, however, suggest that regulated secretion maintains basal plasma t-PA concentrations. 17,19 To the extent that endogenous BK contributes to basal t-PA release during ACE inhibition via its B 2 receptor 7 and that testosterone decreases BK-induced calcium influx, 20 decreased basal t-PA release in men during ACE inhibition may reflect an effect of testosterone on BK signaling.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men

Pretorius

Luther

Murphey

et al. 2005

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Objective-Angiotensin-converting enzyme inhibition (ACEI) increases vascular tissue plasminogen activator (t-PA) release through endogenous bradykinin (BK). We tested the hypothesis that gender influences the effect of ACEI on t-PA release. Methods and Results-We measured the effect of intra-arterial enalaprilat (0.33 g/min per 100 mL forearm volume) on forearm blood flow (FBF) and net t-PA release before and during BK (25 to 400 ng/min) and methacholine (3.2 to 12.8 g/min) in premenopausal women, postmenopausal women not using hormone replacement, young men, and older men. Baseline net t-PA release was similar among groups. Enalaprilat increased basal t-PA release in premenopausal (from 0.9Ϯ1.0 to 5.1Ϯ1.7 ng/min per 100 mL, Pϭ0.023) and postmenopausal women (from Ϫ3.9Ϯ2.2 to 3.9Ϯ1.1 ng/min per 100 mL, Pϭ0.010) but not in young or older men (Pϭ0.028 men versus women). Enalaprilat potentiated the effect of exogenous BK on FBF similarly in all groups. However, during enalaprilat, BK-stimulated t-PA release was greatest in premenopausal women (339.9Ϯ86.4 ng/min per 100 mL at the 100 ng/min dose, PϽ0.05 versus any other group), intermediate in postmenopausal women (243.8Ϯ51.1 ng/min per 100 mL, PϽ0.05 versus either male group), and least in young (111.9Ϯ19.2 ng/min/100 mL) and older men (103.4Ϯ27.6 ng/min/100 mL). Conclusion-ACEI enhances basal t-PA release in women, independent of menopausal status, but not in men. During ACEI, both gender and menopausal status affect BK stimulated t-PA release. (Arterioscler Thromb Vasc Biol. 2005;25:2435-2440.)Key Words: angiotensin Ⅲ inhibitors Ⅲ plasminogen activators Ⅲ women A ngiotensin-converting enzyme (ACE) inhibition improves endothelial function 1 and favorably alters fibrinolytic balance by decreasing angiotensin II (Ang II), a potent stimulus to plasminogen activator inhibitor-1 (PAI-1) synthesis 2-4 and by increasing bradykinin (BK), a potent stimulus to tissue plasminogen activator (t-PA) secretion. 5,6 For example, a recent study from this group using the specific BK B 2 receptor antagonist HOE 140 indicates that ACE inhibition increases baseline vascular t-PA release in humans through endogenous BK. 7 Unexpectedly, ACE inhibition increased basal t-PA release only in the female subjects studied. Moreover, ACE inhibition did not increase basal t-PA release in 2 earlier studies in predominantly male populations. 5,8 Coronary BK concentrations increase during myocardial ischemia 9 and ACE inhibitors potentiate BK-stimulated coronary 8 as well as forearm t-PA release. 5 Thus BK-stimulated t-PA release may be important in limiting thrombosis during myocardial infarction. Whereas the previous data of Pretorius et al 7 suggested that gender influences the effect of ACE inhibition on basal t-PA release, that study was not designed to test such a hypothesis. Study groups were not prospectively matched for gender. More importantly, the dose of enalaprilat was not normalized per forearm volume. Thus women, who have a smaller forearm volume than men, were given a higher effecti...

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Testosterone inhibits bradykinin-induced intracellular calcium kinetics in rat aortic endothelial cells in culture

Cited by 30 publications

References 19 publications

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

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

Dehydroepiandrosterone Stimulates Endothelial Proliferation and Angiogenesis through Extracellular Signal-Regulated Kinase 1/2-Mediated Mechanisms

Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men

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