Effects of acute methionine loading and vitamin Con endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0±0.1 to 4.7±0.4 ng/ml; P < 0.001) and activity (from 1.2±0.2 to 4.2±0.4 i.u./ml; P < 0.001), which were augmented during acute methionine loading (4.7±0.4 to 5.6±0.5 ng/ml and 4.2±0.4 to 5.5±0.9 i.u./ml respectively; P⩽0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P = 0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.

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Podávanie vitamínu C zlepšuje reológiu plnej krvi u zdravých ľudí / Vitamin C supplementation promotes whole blood rheology in healthy humans

Cardiology letters ◽

10.4149/cardiol_2020_4_9 ◽

2020 ◽

Vol 29 (04) ◽

pp. 348-255

Author(s):

J. Radošinská ◽

T. Jasenovec ◽

A. Púzserová ◽

J. Krajčír ◽

J. Laceková ◽

...

Keyword(s):

Vitamin C ◽

Whole Blood ◽

Blood Rheology ◽

Healthy Humans ◽

Vitamin C Supplementation

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A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.516 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A254-A254

Author(s):

Soraya Allas ◽

Michel Ovize ◽

Michael D Culler ◽

Clarisse Geraul ◽

Jeroen van de Wetering ◽

...

Keyword(s):

Serum Calcium ◽

Clinical Symptoms ◽

Phase 1 ◽

High Dose ◽

Single Administration ◽

Double Blind ◽

Double Blind Placebo ◽

Healthy Humans ◽

Dose Dependent

Abstract Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.

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The Acute and Chronic Cognitive and Cerebral Blood-Flow Effects of Nepalese Pepper (Zanthoxylum armatum DC.) Extract—A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Humans

Nutrients ◽

10.3390/nu11123022 ◽

2019 ◽

Vol 11 (12) ◽

pp. 3022 ◽

Cited By ~ 3

Author(s):

David Kennedy ◽

Emma Wightman ◽

Julie Khan ◽

Torsten Grothe ◽

Philippa Jackson

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Single Dose ◽

Frontal Cortex ◽

Task Performance ◽

Performance Measure ◽

Controlled Study ◽

Double Blind ◽

Zanthoxylum Armatum ◽

Healthy Humans

Background: Zanthoxylum armatum DC. (ZA) is a traditional Asian culinary spice and medicinal compound, which is rich in monoterpenes and hydroxy α-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. Objectives: To investigate the effects of a single dose and 56-days supplementation with a lipid extract of ZA on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. Design: Double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years. Assessments were undertaken pre-dose and at 1, 3 and 5 h post-dose on the first (Day 1) and last (Day 56) days of supplementation. Results: A single dose of ZA (Day 1) resulted in acute improvements on a ‘Speed of Attention’ factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. However, following ZA participants were less accurate on the name-to-face recall task. After 56 days of ZA consumption (Day 56), speed was enhanced on a global ‘Speed of Performance’ measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 h assessment and were less mentally fatigued throughout the day than participants consuming placebo. These effects were complemented on both Day 1 and Day 56 by modulation of CBF parameters, as assessed by Near Infrared Spectroscopy (NIRS). The primary finding here was a reduced hemodynamic response during the RVIP task. Conclusion: ZA improves aspects of cognitive performance, in particular the speed of performing tasks, in healthy humans and results in concomitant reductions in hemodynamic responses in the frontal cortex during task performance. The findings suggest an increase in neural efficiency following ZA.

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Role of Nitric Oxide towards Vasodilator Effects of Substance P and ATP in Human Forearm Vessels

Clinical Science ◽

10.1042/cs0920123 ◽

1997 ◽

Vol 92 (2) ◽

pp. 123-131 ◽

Cited By ~ 18

Author(s):

Masanari Shiramoto ◽

Tsutomu Imaizumi ◽

Yoshitaka Hirooka ◽

Toyonari Endo ◽

Takashi Namba ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Substance P ◽

Sodium Nitroprusside ◽

Forearm Blood Flow ◽

Dependent Manner ◽

Human Forearm ◽

Before And After ◽

Dose Dependent

1. It has been shown in animals that substance P as well as acetylcholine releases endothelium-derived nitric oxide and evokes vasodilatation and that ATP-induced vasodilatation is partially mediated by nitric oxide. The aim of this study was to examine whether vasodilator effects of substance P and ATP are mediated by nitric oxide in humans. 2. In healthy volunteers (n = 35), we measured forearm blood flow by a strain-gauge plethysmograph while infusing graded doses of acetylcholine, substance P, ATP or sodium nitroprusside into the brachial artery before and after infusion of NG-monomethyl-l-arginine (4 or 8 μmol/min for 5 min). In addition, we measured forearm blood flow while infusing substance P before and during infusion of l-arginine (10 mg/min, simultaneously), or before and 1 h after oral administration of indomethacin (75 mg). 3. Acetylcholine, substance P, ATP or sodium nitroprusside increased forearm blood flow in a dose-dependent manner. NG-Monomethyl-l-arginine decreased basal forearm blood flow and inhibited acetylcholine-induced vasodilatation but did not affect substance P-, ATP-, or sodium nitroprusside-induced vasodilatation. Neither supplementation of l-arginine nor pretreatment with indomethacin affected substance P-induced vasodilatation. 4. Our results suggest that, in the human forearm vessels, substance P-induced vasodilatation may not be mediated by either nitric oxide or prostaglandins and that ATP-induced vasodilatation may also not be mediated by nitric oxide.

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Assessment of microvascular endothelial function in human skin

Clinical Science ◽

10.1042/cs1010567 ◽

2001 ◽

Vol 101 (6) ◽

pp. 567-572 ◽

Cited By ~ 34

Author(s):

David J. NEWTON ◽

Faisel KHAN ◽

Jill J.F. BELCH

Keyword(s):

Blood Flow ◽

Substance P ◽

Endothelial Function ◽

Animal Studies ◽

Doppler Imaging ◽

Microvascular Blood Flow ◽

Coefficients Of Variation ◽

Forearm Skin ◽

Invasive Techniques ◽

Dose Dependent

Endothelial dysfunction is an important factor in many cardiovascular diseases, and is commonly associated with impaired endothelium-mediated vasodilatation. Information about the mechanisms behind this dysfunction has come largely from animal studies or, in humans, through invasive techniques that are not specific to one vascular bed. We have developed protocols to assess endothelial function non-invasively in the cutaneous microcirculation by measuring blood flow responses to four receptor-specific vasoactive compounds. Cumulative doses of acetylcholine, methacholine, bradykinin and substance P were administered iontophoretically to the forearm skin of healthy volunteers on two to three occasions. Dose-dependent increases in skin microvascular blood flow in response to these drugs were measured with laser Doppler imaging. Vascular responses to acetylcholine and methacholine were reasonably consistent, with coefficients of variation of approx. 17%. The coefficients of variation for bradykinin and substance P were much poorer, as high as 70% for some doses. This might partly be a consequence of the more unpredictable effects of histamine release in the vasoactive behaviour of these two agonists. Although it might be advantageous to find other agonists with which to test the function of different receptor pathways, we have shown that just acetylcholine and methacholine can currently be used with iontophoresis to allow sensitive and reproducible assessment of endothelial function.

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Vitamin C Supplementation and Salivary Immune Function Following Exercise-Heat Stress

International Journal of Sports Physiology and Performance ◽

10.1123/ijspp.3.4.516 ◽

2008 ◽

Vol 3 (4) ◽

pp. 516-530 ◽

Cited By ~ 2

Author(s):

Andres E. Carrillo ◽

René J. L. Murphy ◽

Stephen S. Cheung

Keyword(s):

Heat Stress ◽

Vitamin C ◽

Cell Function ◽

Immune Cell ◽

Linear Trend ◽

Upper Respiratory Tract ◽

Short Term ◽

Double Blind ◽

Significant Linear Trend ◽

Vitamin C Supplementation

Purpose:Prolonged physical exertion and environmental heat stress may elicit postexercise depression of immune cell function, increasing upper respiratory tract infection (URTI) susceptibility. We investigated the effects of acute and short-term vitamin C (VC) compared with placebo (PL) supplementation on URTI susceptibility, salivary immunoglobulin A (s-IgA), and cortisol responses in healthy individuals following prolonged exercise-heat stress.Methods:Twelve participants were randomized into the VC or PL group in a double-blind design. For 12 days, participants consumed 3 × 500 mg tablets of VC or PL per day, with testing completed at baseline, then following acute (1 d) and short-term (8 d) supplementation. Participants performed 120.1 ± 49.6 min of cycling at 54 ± 6% VO2max in a hot (34.8 ± 1.0°C and 13 ± 3% relative humidity) environment, with saliva samples collected at pre-, post-, and 72 h postexercise. Health logs specifying URTI symptoms were completed for 7 days postexercise.Results:A 2 × 3 × 3 mixed ANOVA with a post hoc Bonferroni correction factor revealed a significant linear trend in postexercise cortisol attenuation in the VC group, 21.7 ± 15.1 nmol/L (mean ± SD) at baseline, to 13.5 ± 10.0 at acute, to 7.6 ± 4.2 after short term (P = .032). No differences were detected in ratio of s-IgA to protein or URTI symptoms between groups.Conclusions:These data suggest that vitamin C supplementation can decrease postexercise cortisol in individuals performing exercise similar to that of a half-marathon or marathon in hot conditions. However, no changes in s-IgA and URTI were evident, possibly due to previous moderate training and reduced physical and psychological stress compared with athletes participating in ultramarathons.

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Role of Substance P in the Vascular Response of Nasal Mucosa in Nasal Allergy

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348949610500811 ◽

1996 ◽

Vol 105 (8) ◽

pp. 648-653 ◽

Cited By ~ 15

Author(s):

Akiyoshi Konno ◽

Toyoyuki Hanazawa ◽

Tsutomu Numata ◽

Hiroshi Nagata ◽

Nobuhisa Terada ◽

...

Keyword(s):

Blood Flow ◽

Substance P ◽

Sensory Stimulation ◽

Nasal Allergy ◽

Vascular Response ◽

Nasal Challenge ◽

C Fiber ◽

Capacitance Vessels ◽

Dose Dependent

The effects of topically administered substance P (SP) on nasal blood flow and nasal airway resistance (NAR) were evaluated in 11 subjects with perennial nasal allergy. The change in NAR induced by SP was compared with those induced by nasal challenge with histamine, leukotriene EM (LTD4), and antigen. In doses ⩾ 16 nmol, SP caused a significant increase of nasal blood flow within 5 minutes that lasted for less than 20 minutes. In doses ⩾16 nmol, SP caused a dose-dependent, short-lasting, significant increase in NAR. The magnitude of the increase in NAR was LTD4 > SP > histamine when compared on a molar basis. Our results may suggest that SP released from C fiber terminals is partially involved in an early nasal vascular response after antigen challenge by acting on adjacent vascular smooth muscle to cause a transient vasodilatation of both resistance and capacitance vessels only while sensory stimulation persists in subjects with nasal allergy.

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