The effect of daily UVA phototherapy for 2 weeks on clinic and 24-h blood pressure in individuals with mild hypertension.

Latitude and season determine exposure to ultraviolet radiation and correlate with population blood pressure. Evidence for Vitamin D causing this relationship is inconsistent, and temperature changes are only partly responsible for BP variation. In healthy individuals, a single irradiation with 20 J/cm2 UVA mobilises NO from cutaneous stores to the circulation, causes arterial vasodilatation, and elicits a transient fall in BP. We, therefore, tested whether low-dose daily UVA phototherapy might be an effective treatment for mild hypertension. 13 patients with untreated high-normal or stage 1 hypertension (BP 130-159/85-99 mm Hg), confirmed by 24-h ambulatory blood pressure (ABP), were recruited. Using home phototherapy lamps they were either exposed to 5 J/cm2 full body UVA (320-410 nm) radiation each day for 14 days, or sham-irradiated with lamps filtered to exclude wavelengths <500 nm. After a washout period of 3 ± 1 week, the alternate irradiation was delivered. 24-h ABP was measured on day 0 before either irradiation sequence and on day 14. Clinic BP was recorded on day 0, and within 90 min of irradiation on day 14. There was no effect on 24-h ABP following UVA irradiation. Clinic BP shortly after irradiation fell with UVA (-8.0 ± 2.9/-3.8 ± 1.1 mm Hg p = 0.034/0.029) but not sham irradiation (1.1 ± 3.0/0.9 ± 1.5 mm Hg). Once daily low-dose UVA does not control mildly elevated BP although it produces a transient fall shortly after irradiation. More frequent exposure to UVA might be effective. Alternatively, UVB, which photo-releases more NO from skin, could be tried.

Prescribing Paradigm Shift? Applying the 2019 European Society of Cardiology-Led Guidelines on Diabetes, Prediabetes, and Cardiovascular Disease to Assess Eligibility for Sodium-Glucose Cotransporter 2 Inhibitors or Glucagon-Like Peptide 1 Receptor Agonists as First-Line Monotherapy (or Add-on to Metformin Monotherapy) in Type 2 Diabetes in Scotland.

OBJECTIVE: In 2019, the European Society of Cardiology led and released new guidelines for diabetes cardiovascular risk management, reflecting recent evidence of cardiovascular disease (CVD) reduction with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and some glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D). A key recommendation is that all those with T2D who are (antihyperglycemic) drug naïve or on metformin monotherapy should be CVD risk stratified and an SGLT-2i or a GLP-1RA initiated in all those at high or very high risk, irrespective of glycated hemoglobin. We assessed the impact of these guidelines in Scotland were they introduced as is. RESEARCH DESIGN AND METHODS: Using a nationwide diabetes register in Scotland, we did a cross-sectional analysis, using variables in our register for risk stratification at 1 January 2019. We were conservative in our definitions, assuming the absence of a risk factor where data were not available. The risk classifications were applied to people who were drug naïve or on metformin monotherapy and the anticipated prescribing change calculated. RESULTS: Of the 265,774 people with T2D in Scotland, 53,194 (20.0% of those with T2D) were drug naïve, and 56,906 (21.4%) were on metformin monotherapy. Of these, 74.5% and 72.4%, respectively, were estimated as at least high risk given the guideline risk definitions. CONCLUSIONS: Thus, 80,830 (30.4%) of all those with T2D (n = 265,774) would start one of these drug classes according to table 7 and figure 3 of the guideline. The sizeable impact on drug budgets, enhanced clinical monitoring, and the trade-off with reduced CVD-related health care costs will need careful consideration.

Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease.

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.

Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism.

BACKGROUND: Endothelin 1 (ET-1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET-1 peptides, endothelin-like domain peptide (ELDP) and C-terminal pro-ET-1 (CT-proET-1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists. METHODS AND RESULTS: We assessed plasma and urine ELDP and plasma CT-proET-1 in CKD patients with minimal comorbidity. Next, in a randomized double-blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT-proET-1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT-proET-1. Sitaxentan increased both plasma ELDP and CT-proET-1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT-proET-1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET-1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT-proET-1 correlated negatively with 24-hour urinary sodium excretion. CONCLUSIONS: ELDP and CT-proET-1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents. CLINICAL TRIAL REGISTRATION: URL: www.clinicalTrials.gov Unique identifier: NCT00810732.

Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension.

Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre- and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a double-blind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135.8 (SE 1.3) mmHg and diastolic BP was 81.5 (SE 0.9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of - 3.0 mmHg for systolic BP (95% CI - 6.5, 0.5) and - 1.4 mmHg for diastolic BP (95% CI - 3.5, 0.6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension.

Endothelin-A receptor antagonism modifies cardiovascular risk factors in CKD.

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease.

Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.

Exploring differential prescribing between anti-epileptic drugs in epilepsy patients with a history of mood disorders.

PURPOSE: To explore differential prescribing of anti-epileptic drugs (AEDs) to patients with epilepsy by history of mood disorder. METHODS: Epilepsy was defined as at least one diagnosis code and one AED prescription, and all patients must have been on the database 182 days before and after their first AED prescription. The Integrated HealthCare Information Services (IHCIS) insurance claims database included 44 557 patients with epilepsy between January 1997 and March 2007. The General Practice Research Database (GPRD) included 16 904 patients with epilepsy up to March 2007. Patients were categorized by their first use of specified AEDs. Mood disorders were defined as diagnosis codes for depression and bipolar disorder, or anti-depressant use. The unadjusted odds ratios and 95% confidence intervals for a history of mood disorder diagnosis ever or within the three months prior to AED use were calculated with carbamazepine and oxcarbazepine (CBZ) as the referent. RESULTS: In the US IHCIS, a history of mood disorders was significantly more common in new users of most AEDs compared to CBZ new users, indicating differential prescribing. Clonazepam and gabapentin were the most commonly prescribed AEDs in patients with epilepsy and a history of mood disorders.In the UK GPRD, there was less evidence of differential prescribing of AEDs, although gabapentin was prescribed most often to epilepsy patients with a history of mood disorders. CONCLUSIONS: Any observational studies of AEDs and suicidality would have to consider potential channeling bias by history of mood disorders, which is a major risk factor for suicide.

Blood pressure-independent reduction in proteinuria and arterial stiffness after acute endothelin-a receptor antagonism in chronic kidney disease.

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition.

The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS), yet the mechanisms responsible for the inhibition of Toll-like receptor (TLR) signaling by OxPAPC remain incompletely understood. Here, we examined the mechanisms by which OxPAPC inhibits TLR signaling induced by diverse ligands in macrophages, smooth muscle cells, and epithelial cells. OxPAPC inhibited tumor necrosis factor-alpha production, IkappaBalpha degradation, p38 MAPK phosphorylation, and NF-kappaB-dependent reporter activation induced by stimulants of TLR2 and TLR4 (Pam3CSK4 and LPS) but not by stimulants of other TLRs (poly(I.C), flagellin, loxoribine, single-stranded RNA, or CpG DNA) in macrophages and HEK-293 cells transfected with respective TLRs and significantly reduced inflammatory responses in mice injected subcutaneously or intraperitoneally with Pam3CSK4. Serum proteins, including CD14 and LPS-binding protein, were identified as key targets for the specificity of TLR inhibition as supplementation with excess serum or recombinant CD14 or LBP reversed TLR2 inhibition by OxPAPC, whereas serum accessory proteins or expression of membrane CD14 potentiated signaling via TLR2 and TLR4 but not other TLRs. Binding experiments and functional assays identified MD2 as a novel additional target of OxPAPC inhibition of LPS signaling. Synthetic phospholipid oxidation products 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine inhibited TLR2 signaling from approximately 30 microm. Taken together, these results suggest that oxidized phospholipid-mediated inhibition of TLR signaling occurs mainly by competitive interaction with accessory proteins that interact directly with bacterial lipids to promote signaling via TLR2 or TLR4.

Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans.

BACKGROUND: Aqueous extracts from tomatoes display a range of antiplatelet activities in vitro. We previously showed that the active components also alter ex vivo platelet function in persons with a high response to ADP agonist. OBJECTIVE: The objective was to evaluate the suitability of a tomato extract for use as a dietary supplement to prevent platelet activation. DESIGN: A randomized, double-blinded, placebo-controlled crossover study was conducted in 90 healthy human subjects selected for normal platelet function. Changes from baseline hemostatic function were measured 3 h after consumption of extract-enriched or control supplements. RESULTS: Significant reductions in ex vivo platelet aggregation induced by ADP and collagen were observed 3 h after supplementation with doses of tomato extract equivalent to 6 (6TE) and 2 (2TE) tomatoes [3 micromol ADP/L: 6TE (high dose), -21.3%; 2TE (low dose), -12.7%; P < 0.001; 7.5 micromol ADP/L: 6TE, -7.8%, 2TE, -7.6%; P < 0.001; 3 mg collagen/L: 6TE, -17.5%; 2TE, -14.6%; P = 0.007]. No significant effects were observed for control supplements. A dose response to tomato extract was found at low levels of platelet stimulation. Inhibition of platelet function was greatest in a subgroup with the highest plasma homocysteine (P < 0.05) and C-reactive protein concentrations (P < 0.001). CONCLUSION: As a functional food or dietary supplement, tomato extract may have a role in primary prevention of cardiovascular disease by reducing platelet activation, which could contribute to a reduction in thrombotic events.

Effects of antiplatelet components of tomato extract on platelet function in vitro and ex vivo: a time-course cannulation study in healthy humans.

BACKGROUND: Natural antithrombotic agents that influence platelet function are of potential interest for primary prevention of cardiovascular disease. Previous reports showed that tomato extracts inhibit platelet aggregation in vitro, but little is known of the active components, their mode of action, or their efficacy in vivo. OBJECTIVE: The objectives of the study were to examine the antiplatelet activity of specific tomato components by in vitro experimentation and to establish their ex vivo efficacy in healthy humans. DESIGN: The mechanisms of action of antiplatelet components isolated from tomato extracts were examined in vitro. A 7-h time-course study was carried out in cannulated human subjects (n = 23) to determine the ex vivo efficacy of a supplement drink containing tomato extract and the onset and duration of antiplatelet effects. RESULTS: The inhibition of ADP-, collagen-, thrombin-, and arachidonate-mediated platelet aggregation by tomato extract components appears to be linked to the inhibition of glycoprotein IIb/IIIa and platelet secretory mechanisms. We found a significant inhibition of baseline platelet function, from 2.9 +/- 1.4% (optimal ADP concentrations; P = 0.03) to 20.0 +/- 4.9% (suboptimal ADP concentrations; P < 0.001), 3 h after supplementation with a dose of tomato extract equivalent to 6 tomatoes. The observed effects persisted for >12 h. Coagulation variables were not affected. CONCLUSIONS: The ingestion of tomato components with in vitro antiplatelet activity significantly affects ex vivo platelet function. The reported cardioprotective effects of tomatoes are potentially linked to a modulation of platelet function.

Endothelial dysfunction in patients with recent myocardial infarction and hyperhomocysteinaemia: effects of vitamin supplementation.

Hyperhomocysteinaemia is a prothrombotic condition that may cause oxidative endothelial injury and impair endogenous fibrinolysis. Vitamin supplementation enhances endothelial function in hyperhomocysteinaemic patients, but responses in patients with co-existing coronary artery disease have been variable. It is also unknown whether hyperhomocysteinaemia is associated with reduced fibrinolytic responses in patients with coronary artery disease. The study aims were to test the hypothesis that patients with recent myocardial infarction and hyperhomocysteinaemia have impaired endothelium-dependent vasomotion and fibrinolysis that is rectified by vitamin supplementation. From a cohort of 120 patients admitted with acute myocardial infarction, 18 patients were recruited from the upper (n=9) and lower (n=9) plasma homocysteine quartiles into a randomized double-blind placebo-controlled crossover trial. Following a 4-week course of placebo or folate/cyanocobalamin/pyridoxine supplements, FBF (forearm blood flow) was measured using venous occlusion plethysmography during intra-arterial substance P (4-16 pmol/min), acetylcholine (5-20 microg/min) and sodium nitroprusside (2-8 microg/min) infusions. All vasodilators caused dose-dependent increases in infused FBF (P<0.05). Patients in the upper homocysteine quartile (16.8+/-2.9 compared with 7.9+/-0.7 micromol/l; P=0.003) had reduced vasodilatation to acetylcholine (P=0.01) and substance P (P<0.05), but not sodium nitroprusside. There were no differences in substance P-induced tissue plasminogen activator release. Vitamin supplementation increased serum folate and vitamin B12 concentrations (P<0.05), but did not significantly lower homocysteine, or affect FBF or fibrinolytic responses. In patients with recent myocardial infarction, hyperhomocysteinaemia is associated with impaired endothelium-dependent vasodilatation, but no alteration in the acute fibrinolytic capacity. This endothelial vasomotor dysfunction is unaltered by vitamin supplementation.

Nebivolol increases arterial distensibility in vivo.

Arterial stiffness is a key determinant of cardiovascular risk in hypertensive patients. beta-Blockers appear to be less effective than other drugs in improving outcome in hypertensive patients, and a potential explanation may be that beta-blockers are less effective in reducing arterial stiffness. The aim of this study was to assess the direct effect of beta-blockade on pulse wave velocity (PWV), a robust measure of arterial distensibility, using a local, ovine, hind-limb model. In addition, we hypothesized that the vasodilating beta-blocker nebivolol, but not atenolol, would increase arterial distensibility in vivo. All studies were conducted in anesthetized sheep. PWV was recorded in vivo using a dual pressure-sensing catheter placed in the common iliac artery. Intraarterial infusion of nebivolol reduced PWV by 6+/-3% at the higher dose (P<0.001), but did not alter mean arterial pressure (change of -1+/-3 mm Hg, P=0.1). In contrast, atenolol had no effect on PWV (P=0.11) despite a small drop in mean pressure (change of -5+/-3 mm Hg, P<0.01). Infusion of glyceryl trinitrate led to a dose-dependent fall in PWV, and 2 nmol/min produced a similar reduction in PWV to the higher dose of nebivolol (500 nmol/min). The effect of nebivolol on PWV was significantly attenuated during coinfusion of N(G)-monomethyl-L-arginine (P=0.003) and also during coinfusion of butoxamine (P=0.02). These results demonstrate that nebivolol, but not atenolol, increases arterial distensibility. This effect of nebivolol is mediated through the release of NO via a beta2 adrenoceptor-dependent mechanism. Thus, nebivolol may be of benefit in conditions of increased large artery stiffness, such as isolated systolic hypertension.

Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers.

Blood flow and plasma fibrinolytic factors were measured on five occasions in both forearms of eight otherwise healthy male smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min), and the endothelium-independent vasodilator, sodium nitroprusside (2 to 8 microg/min). On the first occasion, intra-arterial vitamin C was co-infused at 25 mg/min. On subsequent occasions, subjects attended after 28 and 35 days treatment with oral vitamin C (1 g daily) or placebo in a double-blind randomized crossover design still smoking but with and without acute smoke inhalation (3 cigarettes over 30 minutes). Basal plasma ascorbate concentrations increased from 37 +/- 6 micromol/L to 105 +/- 11 micromol/L following oral vitamin C supplementation (P = 0.002). Substance P caused dose-dependent increases in forearm blood flow (P < 0.001, ANOVA) and t-PA release (P < 0.05, ANOVA) that was unaffected by acute recent smoke inhalation, intra-arterial vitamin C, or oral vitamin C administration (p = ns). Likewise there were no effects on sodium nitroprusside-induced vasodilatation (p = ns). Neither acute local intra-arterial nor prolonged oral vitamin C supplementation reverses smoking-related endothelial dysfunction and impaired endogenous t-PA release. We conclude that the adverse vascular actions of smoking are not principally mediated through oxidative stress.

Bradykinin receptor antagonism and endothelial tissue plasminogen activator release in humans.

OBJECTIVE: We sought to assess pharmacodynamic responses to the bradykinin antagonist B9340 and to determine the contribution of the endothelial bradykinin receptor to stimulated tissue plasminogen activator (t-PA) release in humans. METHODS AND RESULTS: Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 volunteers during 100 minutes of intrabrachial infusions of saline placebo, B9340 at 4.5 nmol/min, or B9340 at 13.5 nmol/min. On each occasion, intra-arterial bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min) were coinfused for 10 minutes at each dose. To assess the onset and offset of action, 6 additional subjects on 2 occasions received intra-arterial bradykinin (100 pmol/min) for 60 minutes with a coinfusion of either saline placebo or B9340 (13.5 nmol/min) for 12 minutes. During placebo infusion, 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. CONCLUSIONS: B9340 is a potent, reversible, and selective competitive receptor antagonist of bradykinin-induced vasodilatation and t-PA release in humans.