24 research outputs found
Bradykinin: vasomotor tone and endogenous fibrinolysis in man
No full textBradykinin is a nonapetide released into plasma during the contact phase of blood
coagulation. It has a wide variety of physiological effects including vasodilatation,
tissue-type plasminogen activator (t-PA) release, inflammatory mediator, ischaemic
preconditioning and vasculogenesis. It is inactivated in plasma by angiotensinconverting enzyme (ACE). Inhibition of this enzyme has been shown to be beneficial
in a variety of cardiovascular disorders including heart failure and hypertension, and
it is clear that this benefit is not due entirely to reduction in the bioavailability of
angiotensin II. We hypothesised that• bradykinin is a vasodilator and stimulates endothelial t-PA release via a
specific receptor and that this effect is augmented by ACE inhibition• in patients with heart failure, bradykinin contributes to peripheral and
systemic vascular tone during treatment with ACE inhibition.Forearm blood flow was measured using bilateral forearm plethysmography during
intrabrachial drug infusion. Bilateral venous cannulae were inserted to perform blood
sampling for estimation of plasma t-PA and plasminogen activator inhibitor 1 (PAI1) concentrations. Cardiac output was measured with pulmonary artery
catheterisation. The novel peptide bradykinin receptor antagonist, B9340, was used
to oppose the effects of bradykinin.Studies were performed in healthy volunteers•
to demonstrate the pharmacodynamics of B9340 and to demonstrate the
selectivity of B9340 in opposing bradykinin-induced t-PA release.•
to demonstrate the safety and tolerability of systemic intravenous B9340
administration.Studies were performed in patients with heart failure•
to demonstrate the effect of ACE inhibition on endothelial t-PA release.•
to demonstrate the effect of bradykinin antagonism on peripheral and
systemic vascular tone in patients treated with ACE inhibition and
angiotensin receptor blockade.RESULTS
In healthy volunteers• Bradykinin and substance P caused dose-dependent vasodilatation in the
infused forearm (p<0.001). B9340 caused a dose-dependent inhibition of
bradykinin-induced forearm vasodilatation and t-PA release (p<0.001)
without affecting substance P-induced vasodilatation or t-PA release (p=NS).
B9340 caused a reversible inhibition of bradykinin-induced vasodilatation
(p<0.001) with a rapid onset and offset of action. Intravenous systemic
B9340 administration inhibited the local bradykinin-induced forearm
vasodilatation in a dose-dependent mannerIn patients with heart failure•
bradykinin and substance P caused dose-dependent vasodilatation and release
of t-PA from the infused forearm (p<0.05). Long-term ACE inhibitor therapy
caused an increase in forearm vasodilatation (p<0.05) and t-PA release
(p<0.001) during bradykinin, but not substance P, infusion.•
incremental doses of B9340 caused a dose-dependent reduction in forearm
blood flow (p<0.01). After withdrawal of ACE inhibitor therapy, B9340
produced no significant change in forearm blood flow.•
systemic intravenous B9340 administration resulted in greater mean arterial
pressure, systemic vascular resistance, pulmonary arterial wedge pressure,
and mean pulmonary arterial pressure during ACE inhibitor therapy
compared with losartan therapy (p<0.005, p<0.07, p<0.0001, and p<0.05
respectively) or placebo infusion (p<0.005 for all).We have shown that bradykinin is a potent vasodilator that stimulates endogenous
t-PA release and that these effects are receptor specific and can be blocked by a
bradykinin receptor antagonist. We have also shown that bradykinin does not
contribute to peripheral or systemic vascular tone in health but does contribute to
peripheral and systemic vascular tone in patients with heart failure treated with
chronic ACE inhibition. We believe this suggests that many of the beneficial actions
of ACE inhibition are mediated through bradykinin
A Group of Teenagers Posing with Copies of SCLC's Soul Force Magazine, 1972
No full textA group of teenagers are shown posing with copies of an issue of the Southern Christian Leadership Conference's (SCLC) publication "Soul Force" that features Angela Davis on the cover. The teenagers are standing outside of the SCLC headquarters building on Auburn Avenue in Atlanta, Georgia. Caption information identifying individuals is found in the 15th Annual SCLC Convention Souvenir Journal: "from left, Theodore Frambro, Janet Worthy, Michael Huff, Linda Holland, Debra Witherow, Waynefield Barrett, and Janice Mitchell".The Atlanta University Center Robert W. Woodruff Library acknowledges the generous support of the Joseph & Evelyn Lowery Institute for Justice and Human Rights, the Joseph Echols Lowery Irrevocable Trust, and other donors in supporting the processing and digitization of Morehouse College's Joseph Echols and Evelyn Gibson Lowery Collection
Local and Systemic Effects of Intra-arterial Desmopressin in Healthy Volunteers and Patients with Type 3 von Willebrand Disease
No full textSummaryIntra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin ≥70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses ≥300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001; r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.</jats:p
1129-212 Endothelial, coagulation, and platelet function in atrial fibrillation: Effect of direct current cardioversion
No full textMarked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy
No full textAbstractObjectivesThe aim of the present study was to assess the contribution of angiotensin-converting enzyme (ACE) inhibitor therapy to bradykinin-induced tissue-type plasminogen activator (t-PA) release in patients with heart failure (HF) secondary to ischemic heart disease.BackgroundBradykinin is a potent endothelial cell stimulant that causes vasodilatation and t-PA release. In large-scale clinical trials, ACE inhibitor therapy prevents ischemic events.MethodsNine patients with symptomatic HF were evaluated on two occasions: during and following seven-day withdrawal of long-term ACE inhibitor therapy. Forearm blood flow was measured using bilateral venous occlusion plethysmography. Intrabrachial bradykinin (30 to 300 pmol/min), substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables.ResultsOn both study days, bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p < 0.05 by analysis of variance [ANOVA]). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p < 0.05 by ANOVA) and t-PA release (p < 0.001 by ANOVA) during bradykinin, but not substance P, infusion. Maximal local plasma t-PA activity concentrations approached 100 IU/ml, and maximal forearm protein release was ∼4.5 μg/min.ConclusionsLong-term ACE inhibitor therapy augments bradykinin-induced peripheral vasodilatation and local t-PA release in patients with HF due to ischemic heart disease. Local plasma t-PA activity concentrations approached those seen during systemic thrombolytic therapy for acute myocardial infarction. This may contribute to the primary mechanism of the anti-ischemic effects associated with long-term ACE inhibitor therapy
Drug-eluting stents with biodegradable polymer for the treatment of patients with diabetes mellitus: clinical outcome at 2 years in a large population of patients
No full textMarcus Wiemer,1 Gian Battista Danzi,2 Nick West,3 Vassilios Voudris,4 René Koning,5 Stefan Hoffmann,6 Mario Lombardi,7 Josepa Mauri,8 Rade Babic,9 Fraser Witherow10On behalf of the NOBORI 2 Investigators 1Department of Cardiology, Heart and Diabetes Center North Rhine–Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany; 2Ospedale Maggiore Policlinico, Milan, Italy; 3Papworth Hospital, Cambridge, UK; 4Onassis Cardiac Surgery Center, Athens, Greece; 5Clinique Saint Hilaire, Rouen, France; 6Vivantes Netzwerk für Gesundheit GmbH, Berlin, Germany; 7Azienda Ospedaliera Villa Sofia, Palermo, Italy; 8Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 9Institute for Cardiovascular Diseases Dedinje, Belgrade, Serbia; 10Dorset County Hospital, Dorchester, UK Objective: This study investigates the safety and efficacy of a third-generation drug-eluting stent (DES) with biodegradable polymer in the complex patient population of diabetes mellitus (DM). Clinical trial registration: ISRCTN81649913. Background: Percutaneous coronary interventions in patients with DM are associated with a higher incidence of death, restenosis, and stent thrombosis as compared to non-diabetic patients. The use of a DES has been shown to improve outcomes in diabetic patients. Methods: Out of 3,067 patients, enrolled in 126 centers worldwide in the NOBORI 2 registry, 888 patients suffered from DM, 213 of them (14%) being insulin-dependent DM (IDDM). Two years’ follow-up has been completed in this study. Results: At 1- and 2-year follow-up, 97% and 95% of the patients, respectively, were available. The reported target lesion failure (TLF) rates at 1- and 2-year follow-up were 6.0% and 7.2% in the DM group, respectively, and 3.0% and 4.2% in the non-DM group, respectively (P<0.001 for both years). Inside the DM group, the TLF rates of 9.9% and 11.7% at the 1- and 2-year follow-ups, respectively, in patients with IDDM were significantly higher than the TLF rates of 4.7% and 5.8%, respectively, in the non-IDDM subgroup (P<0.01 for both years). The rate of stent thrombosis at the 2-year follow-up was 1.0% in the DM group and 0.7% in non-DM patients. There were no cases of late, or very late stent thrombosis in IDDM patients. Conclusion: The Nobori DES performed well in patients with DM. As expected, patients with DM, particularly those with IDDM, had worse outcomes. However, the absence of late, and very late stent thrombosis in IDDM patients merits further investigation, as this finding might have significant clinical value. Keywords: diabetes mellitus, percutaneous coronary intervention, biodegradable polymer, drug-eluting stent
Microglia Control Vascular Architecture via a TGFβ1 Dependent Paracrine Mechanism Linked to Tissue Mechanics
No full text© 2020, The Author(s). Tissue microarchitecture and mechanics are important in development and pathologies of the Central Nervous System (CNS); however, their coordinating mechanisms are unclear. Here, we report that during colonization of the retina, microglia contacts the deep layer of high stiffness, which coincides with microglial bipolarization, reduction in TGFβ1 signaling and termination of vascular growth. Likewise, stiff substrates induce microglial bipolarization and diminish TGFβ1 expression in hydrogels. Both microglial bipolarization in vivo and the responses to stiff substrates in vitro require intracellular adaptor Kindlin3 but not microglial integrins. Lack of Kindlin3 causes high microglial contractility, dysregulation of ERK signaling, excessive TGFβ1 expression and abnormally-patterned vasculature with severe malformations in the area of photoreceptors. Both excessive TGFβ1 signaling and vascular defects caused by Kindlin3-deficient microglia are rescued by either microglial depletion or microglial knockout of TGFβ1 in vivo. This mechanism underlies an interplay between microglia, vascular patterning and tissue mechanics within the CNS
TCT-688 Treatment of bifurcation lesions with a Drug Eluting Stent with biodegradable polymer
No full textTCT-690 Safety and Clinical Efficacy of Sideguard® Stent for Treatment of Bifurcation Lesions: Interim Results from the European Sideguard® Bifurcation Registry Study
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