N J Brown

..Bradykinin had no effect on PAI-1 antigen levels. These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1...

..Interruption of the RAAS decreases both PAI-1 expression and fibrosis in animal models. These findings have implications for the clinical management of renal disease...

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..Aldosterone receptor antagonism decreases both PAI-1 expression and fibrosis in animal models. These findings have implications for the clinical management of cardiovascular and renal disease...

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..Taken together, these data support the hypothesis that aldosterone modulates the effect of Ang II on PAI-1 expression in vitro and in vivo in humans...

..Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences...

..These data demonstrate that bradykinin stimulates tPA release in the human vasculature...

..The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1...

..Angiotensin-converting enzyme (ACE) inhibitors are associated with an increased risk of angioedema, but the risk of recurrent angioedema if treatment is continued is not known...

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..038) or during bradykinin (P=0.03). Increased SBP or vascular resistance may contribute to increased left ventricular mass reported previously in individuals with the BE1+9/+9 genotype...

..We conclude that Ang II stimulates PAI-1 expression in part through the AT(1b) receptor in the kidney and liver. Further, norepinephrine induces PAI-1 expression in vivo with AT(1a) receptor deficiency modulating the effect...

..Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease...

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..31, P=0.014) or low (R(2)=0.37, P=0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS...

..62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis...

..05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1(-/-) mice. PAI-1 contributes to aldosterone-induced glomerular injury...

..05 +/- 0.01) and demonstrates a significantly lower frequency in African Americans compared with Caucasians (0.05 vs. 0.25, respectively, chi 2 = 30.7, p < < 0.001, 1 df)...

..2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction...

..This study supports the idea that interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PA and PAI-1...

..These data suggest that endogenous bradykinin contributes to t-PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D-dimer concentrations during EACA treatment...

..By contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARBs may be safely continued until the day of surgery...

..9 kb promoter...

..This assay provides the first accurate and precise method using MS to quantify BK1-5 in human blood as a marker for the production of systemic bradykinin in humans...

..Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro...

..More-effective methods are needed to improve medication use in this vulnerable population...

..One study has reported an increased incidence of ACE inhibitor-associated angioedema among transplant patients compared to published rates, while several case series report angioedema in patients taking specific immunosuppressant agents...

..75 v. 0.62, P = .009). Thus, this B2 receptor promoter polymorphism may represent a susceptibility marker for essential hypertension in African-Americans...

..This study tests the primary hypothesis that blocking the bradykinin B(2) receptor would attenuate protamine-related hypotension...

..Emerging evidence suggests a role for cortisol in essential hypertension, and preliminary reports indicate that urinary free cortisol (UFC) may be an intermediate phenotype...

..These data support an important role for genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension...

..HOE-140 augmented the heart rate response to chronic valsartan (P = 0.04). These data suggest that endogenous bradykinin does not contribute significantly to the blood pressure-lowering effect of valsartan through its B(2) receptor...

..In contrast, angiotensin II-induced oxidative stress, as measured by F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent...

..It is concluded that inhibition of aldosterone by SP not only slows development of glomerulosclerosis but also induces regression in some rats of existing glomerulosclerosis...

..By inhibiting thrombin-induced platelet aggregation without causing vasodilation, bradykinin 1-5 may provide a model for small molecule substrate-selective thrombin inhibitors...

..During angiotensin-converting enzyme inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance in normotensive salt-replete subjects...

..The authors evaluate the impact of the VPSD and VCRS programs on early career outcomes of physician-scientists...

..These data support a role for renal monooxygenases and 20-hydroxyeicosatetraenoic acid in the regulation of BP and renal function in men...

..Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF...

..17Beta-estradiol increases basal release of active t-PA in young postmenopausal women, consistent with enhanced vascular fibrinolytic function...

..We propose that genotype analyses with sufficient homozygous CC will establish definitive relationships among 20-HETE, salt sensitivity of blood pressure, and insulin resistance...

..In conclusion, the BDKRB2 BE1 polymorphism influences bradykinin type 2 receptor-mediated vasodilation during angiotensin-converting enzyme inhibition...

..Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema...

..We have initiated a large-scale population-based study to characterize the genetic architecture of plasma t-PA and PAI-1 in Blacks from Sunyani, Ghana...

..Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND)...

..This study tests the hypothesis that biomarkers predict the development of postoperative AF...

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..These findings provide a mechanism for the D(1) receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension...

..Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment...

..With hypertension, these modulating effects are diminished or lost, supporting a role for both systems in the development/maintenance of hypertension...

..943). These data indicate that a polymorphism in the gene encoding carbamoyl-phosphate synthetase 1 influences nitric oxide production as well as vascular smooth muscle reactivity...

..Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG...

..2 +/- 4.4 to 58.9 +/- 6.6 pg/ml, p=0.83). Acute Ang II infusion increases oxidative stress in vivo in hypertensive humans. The renin-angiotensin system may contribute to oxidative stress in human cardiovascular disease...

..2 ng/ml (9.8, 28.6), P = 0.974 vs. baseline, P < 0.05 vs. candesartan, spironolactone or furosemide alone]. This study evidences an interactive effect of endogenous Ang II and aldosterone on PAI-1 production in humans...

..This review provides an overview of the pharmacology, efficacy, and safety of a new, more selective aldosterone receptor antagonist, eplerenone, in the context of emerging concepts of the role of aldosterone in cardiovascular toxicity...

..005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine. CONCLUSION: ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin...

..RT-PCR amplification of human kidney RNA followed by restriction fragment analysis showed that CYP4A11 is the predominant isoform expressed in kidney...

..However, the data suggest that ALDO may be an important factor contributing to the variability of PAI-1 levels in individual hypertensive subjects...

..The vascular tissue plasminogen activator response to bradykinin, but not methacholine, is impaired in smokers. Stimulated tissue plasminogen activator release may be a more sensitive measure of endothelial function than vasodilation...

..While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension...

..One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation...

..TH146 and MAP4-TH146 inhibit human and mouse platelet aggregation and mouse thrombosis. Analogs of RPPGF are model compounds to develop PAR1 activation antagonists as well as direct inhibitors to thrombin and factor VIIa...

..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...

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..Confirmation of these findings in additional populations is warranted...

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..We combined molecular and biochemical approaches to identify a functional variant of the CYP4A11 20-HETE synthase and determine its association with hypertensive status in 2 independent human populations...

..PAI-1 inhibition significantly attenuated Ang II-induced aortic medial and wall thickening, but not cardiac hypertrophy, and enhanced Ang II/salt-induced cardiac fibrosis...

..This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors potentiate activation of the kallikrein-kinin system during cardiopulmonary bypass (CPB)...

..Larger studies that use clinical outcomes are needed to determine whether PAI-1 4G/5G genotype should influence the choice of conjugated estrogens or ACE inhibition for the treatment of healthy postmenopausal women...

..The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II...

..57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r(2) = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans...

..2 . [potassium]-28.9; r2=0.609; P=0.008) but not during vehicle (P=0.313). These data suggest that endogenous NO modulates aldosterone synthesis in humans...

..These data show that the influence of thyroid function on blood pressure homeostasis extends into euthyroid range and likely reflects the action of thyroid hormone on peripheral vasculature...

..With respect to APP activity, there was no difference between groups. These results suggest that DPPIV activity is depressed in individuals with hypertension during acute ACEI-associated angioedema...

..0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi...

..037). These data suggest that the BK-dependent alterations in vascular fibrinolytic function are preserved in black Americans compared with white Americans...

..ACE and DPPIV degrade substance P, an edema-forming peptide. The contribution of impaired degradation of substance P by DPPIV to the pathogenesis of ACE inhibitor-associated angioedema is unknown...

..Defective degradation of vasoactive peptide substrates of ACE, such as bradykinin or substance P, may contribute via non-ACE pathways to the pathogenesis of ACE inhibitor-associated angioedema...

..Importantly, this association could only be detected with an intermediate and not a distant phenotype...

..These studies suggest that thrombin-stimulated t-PA release is Galphaq-, PLC-beta-, IP3-, and 5,6-EET-dependent while being prostacyclin-, NO- and K+ channel-independent in HMECs...