ABSTRACT
Developing a hemostatic material suitable for rapid hemostasis remains a challenge. This study presents a novel aminated gelatin sponge cross-linked with dialdehyde starch, exhibiting excellent biocompatibility and hemostatic ability. This aminated gelatin sponge features hydrophilic surface and rich porous structure with a porosity of up to 80 %. The results show that the aminated gelatin sponges exhibit superior liquid absorption capacity and can absorb up to 30-50 times their own mass of simulated body fluid within 5 min. Compared with the commercial gelatin hemostatic sponge and non-aminated gelatin hemostatic sponge, the aminated gelatin hemostatic sponge can accelerate the hemostatic process through electrostatic interactions, demonstrating superior hemostatic performance in both in vitro and in vivo hemostasis tests. The aminated gelatin sponge can effectively control the hemostatic time within 80 s in the in vivo rat femoral artery injury model, significantly outperforming both commercial and non-aminated gelatin sponges. In addition, the aminated gelatin sponge also exhibits good biocompatibility and certain antibacterial properties. The proposed aminated gelatin sponge has very good application prospects for the management of massive hemorrhage.
Subject(s)
Biocompatible Materials , Gelatin , Hemostatics , Starch , Animals , Starch/chemistry , Starch/pharmacology , Starch/analogs & derivatives , Rats , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Hemostatics/chemistry , Hemostatics/pharmacology , Gelatin/chemistry , Gelatin/pharmacology , Male , Porosity , Rats, Sprague-Dawley , Hemorrhage/drug therapy , Hemostasis/drug effects , Gelatin Sponge, Absorbable/chemistry , Gelatin Sponge, Absorbable/pharmacology , Cross-Linking Reagents/chemistry , Femoral Artery/drug effects , HumansABSTRACT
Despite great progress in the hydrogel hemostats and dressings, they generally lack resistant vascular bursting pressure and intrinsic bioactivity to meet arterial massive hemorrhage and proheal wounds. To address the problems, we design a kind of biomimetic and wound microenvironment-modulating PEGylated glycopolypeptide hydrogels that can be easily injected and gelled in â¼10 s. Those glycopolypeptide hydrogels have suitable tissue adhesion of â¼20 kPa, high resistant bursting pressure of â¼150 mmHg, large microporosity of â¼15 µm, and excellent biocompatibility with â¼1% hemolysis ratio and negligible inflammation. They performed better hemostasis in rat liver and rat and rabbit femoral artery bleeding models than Fibrin glue, Gauze, and other hydrogels, achieving fast arterial hemostasis of <20 s and lower blood loss of 5-13%. As confirmed by in vivo wound healing, immunofluorescent imaging, and immunohistochemical and histological analyses, the mannose-modified hydrogels could highly boost the polarization of anti-inflammatory M2 phenotype and downregulate pro-inflammatory tumor necrosis factor-α to relieve inflammation, achieving complete full-thickness healing with thick dermis, dense hair follicles, and 90% collagen deposition. Importantly, this study provides a versatile strategy to construct biomimetic glycopolypeptide hydrogels that can not only resist vascular bursting pressure for arterial massive hemorrhage but also modulate inflammatory microenvironment for wound prohealing.
Subject(s)
Hemorrhage , Hydrogels , Polyethylene Glycols , Wound Healing , Animals , Hydrogels/chemistry , Hydrogels/pharmacology , Rats , Rabbits , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology , Wound Healing/drug effects , Hemorrhage/drug therapy , Rats, Sprague-Dawley , Male , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Glycopeptides/chemistry , Glycopeptides/pharmacology , Femoral Artery/injuries , Femoral Artery/drug effectsABSTRACT
BACKGROUND: Ilex pubescens Hook. et Arn (IP), traditionally known for its properties of promoting blood circulation, swelling and pain relief, heat clearing, and detoxification, has been used in the treatment of thromboangiitis obliterans (TAO). Despite its traditional applications, the specific mechanisms by which IP exerts its therapeutic effects on TAO remain unclear. AIM OF THE STUDY: This study aims to uncover the underlying mechanisms in the therapeutic effects of IP on TAO, employing network pharmacology and metabolomic approaches. METHODS: In this study, a rat TAO model was established by injecting sodium laurate through the femoral artery, followed by the oral administration of IP for 7 days. Plasma coagulation parameters were measured to assess the therapeutic effects of IP. The potential influence on the femoral artery and gastrocnemius muscle was histopathologically evaluated. Network pharmacology was employed to predict relevant targets and model pathways for TAO. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was used for the metabolic profile analysis of rat plasma. Immunohistochemistry (IHC) was used to verify the mechanisms by which IP promotes blood circulation in TAO. RESULTS: The study revealed that IP improved blood biochemical function in TAO and played a significant role in vascular protection and maintaining normal blood vessels and gastrocnemius morphologies. Network pharmacology showed that IP compounds play a therapeutic role in modulating lipids and atherosclerosis. Metabolomic analysis revealed that the pathways involved in sphingolipid metabolism and steroid biosynthesis were significantly disrupted. The joint analysis showed a strong correlation between lysophosphatidylcholine and IP components, including triterpenoid and iridoid components, which support the curative action of IP through the modulation of sphingolipid metabolism. Furthermore, decreased expression levels of SPHK1/S1PR1, TNF-α, IL-1ß, and IL-6 were observed in the IP-treated group, suggesting that IP exerts a protective effect on the vasculature primarily by regulating of the SPHK1/S1PR1 signaling pathway. CONCLUSION: In this study, we found that IP protects the vasculature against injury and treats TAO by regulating the steady-state disturbance of the sphingolipid pathway. These findings suggest that IP promotes vasculature by modulating sphingolipid metabolism and SPHK1/S1PR1 signaling pathway and reduce levels of inflammatory factors, offering new insights into its therapeutic potential.
Subject(s)
Ilex , Metabolomics , Network Pharmacology , Plant Extracts , Rats, Sprague-Dawley , Thromboangiitis Obliterans , Animals , Thromboangiitis Obliterans/drug therapy , Male , Ilex/chemistry , Rats , Plant Extracts/pharmacology , Plant Extracts/chemistry , Disease Models, Animal , Femoral Artery/drug effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/blood supply , Muscle, Skeletal/metabolism , Tandem Mass SpectrometryABSTRACT
We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 µM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 µM), or the Ca2+-sensitive K+ channel inhibitor paxilline (10 µM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 µM) and XE991 (10 µM), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 µM) and cyclopiazonic acid (10 µM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 µM) and KT5720 (1 µM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K+ (ATP-sensitive K+, inwardly rectifying K+, and Ca2+-sensitive K+) channels, cGMP/PKG-associated signaling, and the endothelium.
Subject(s)
Cyclic AMP-Dependent Protein Kinases , Femoral Artery , Glucosides , Sarcoplasmic Reticulum Calcium-Transporting ATPases , Signal Transduction , Thiophenes , Vasodilation , Animals , Rabbits , Femoral Artery/drug effects , Femoral Artery/physiology , Vasodilation/drug effects , Signal Transduction/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Thiophenes/pharmacology , Male , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Vasodilator Agents/pharmacology , Potassium Channels, Voltage-Gated/metabolism , Potassium Channels, Voltage-Gated/antagonists & inhibitorsABSTRACT
PURPOSE: To evaluate the incidence of distal embolism and local vascular responses after treatment with the Kanshas drug-coated balloon (DCB) in a preclinical model. MATERIALS AND METHODS: A total of 90 femoral arteries from 35 healthy swine were treated with a single-dose (×1) or triple-dose (×3) Kanshas DCB that applies the Unicoat technology with 3.2 µg/mm2 of paclitaxel. An uncoated Kanshas balloon was used as a control. The arterial wall, downstream skeletal muscle, and nontarget organs (kidneys, lungs, lymph nodes, liver, spleen, and heart) were histologically evaluated. For pharmacokinetic evaluation, a total of 40 healthy swine were treated with ×1 Kanshas DCB, and treated vessels were evaluated ex vivo with high-performance liquid chromatography-mass spectrometry. RESULTS: Arteries treated with the Kanshas DCB showed mild proteoglycan deposition accompanied by the loss of smooth muscle cells (SMCs). These changes increased in a dose-dependent manner (medial SMC loss at 28 days in the ×1 vs ×3 groups, in depth, 1 (0.75-1.38) vs 2 (1.63-2.44); P = .0008; in circumference, 0.83 (0.67-1) vs 1.5 (1.19-1.81); P = .0071). No evidence of distal embolization in skeletal muscles (0 of 210 histological sections) and nontarget organs (0 of 345 sections) was observed. The pharmacokinetic evaluation showed high paclitaxel concentration in the treated artery (912 ng/mg, peaking at 3 minutes), which remained detectable at up to 180 days (0.04 ng/mg). CONCLUSIONS: The Kanshas DCB showed a local drug effect in treated arteries up to 180 days with a high concentration of paclitaxel and no histological evidence of distal embolization.
Subject(s)
Femoral Artery , Peripheral Arterial Disease , Animals , Femoral Artery/drug effects , Femoral Artery/surgery , Peripheral Arterial Disease/drug therapy , Paclitaxel/therapeutic use , Cardiovascular Agents/therapeutic use , Swine , Angioplasty, BalloonABSTRACT
OBJECTIVE: Studies evaluating the association of metals with subclinical atherosclerosis are mostly limited to carotid arteries. We assessed individual and joint associations of nonessential metals exposure with subclinical atherosclerosis in 3 vascular territories. Approach and Results: One thousand eight hundred seventy-three Aragon Workers Health Study participants had urinary determinations of inorganic arsenic species, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten. Plaque presence in carotid and femoral arteries was determined by ultrasound. Coronary Agatston calcium score ≥1 was determined by computed tomography scan. Median arsenic, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten levels were 1.83, 1.98, 0.27, 1.18, 0.05, 9.8, 0.03, 0.66, and 0.23 µg/g creatinine, respectively. The adjusted odds ratio (95% CI) for subclinical atherosclerosis presence in at least one territory was 1.25 (1.03-1.51) for arsenic, 1.67 (1.22-2.29) for cadmium, and 1.26 (1.04-1.52) for titanium. These associations were driven by arsenic and cadmium in carotid, cadmium and titanium in femoral, and titanium in coronary territories and mostly remained after additional adjustment for the other relevant metals. Titanium, cadmium, and antimony also showed positive associations with alternative definitions of increased coronary calcium. Bayesian Kernel Machine Regression analysis simultaneously evaluating metal associations suggested an interaction between arsenic and the joint cadmium-titanium exposure. CONCLUSIONS: Our results support arsenic and cadmium and identify titanium and potentially antimony as atherosclerosis risk factors. Exposure reduction and mitigation interventions of these metals may decrease cardiovascular risk in individuals without clinical disease.
Subject(s)
Atherosclerosis/chemically induced , Carotid Artery Diseases/chemically induced , Coronary Artery Disease/chemically induced , Femoral Artery/drug effects , Metals/adverse effects , Occupational Exposure/adverse effects , Occupational Health , Adult , Antimony/adverse effects , Antimony/urine , Arsenic/adverse effects , Arsenic/urine , Asymptomatic Diseases , Atherosclerosis/diagnostic imaging , Atherosclerosis/epidemiology , Atherosclerosis/urine , Biomarkers/urine , Cadmium/adverse effects , Cadmium/urine , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/epidemiology , Carotid Artery Diseases/urine , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Coronary Artery Disease/urine , Cross-Sectional Studies , Female , Femoral Artery/diagnostic imaging , Humans , Male , Metals/urine , Middle Aged , Plaque, Atherosclerotic , Risk Assessment , Risk Factors , Spain/epidemiology , Titanium/adverse effects , Titanium/urineABSTRACT
BACKGROUND/OBJECTIVES: Drug-coated balloon therapy for diseased superficial femoral arteries remains controversial. Despite its clinical relevance, only a few computational studies based on simplistic two-dimensional models have been proposed to investigate this endovascular therapy to date. This work addresses the aforementioned limitation by analyzing the drug transport and kinetics occurring during drug-coated balloon deployment in a three-dimensional geometry. METHODS: An idealized three-dimensional model of a superficial femoral artery presenting with a calcific plaque and treated with a drug-coated balloon was created to perform transient mass transport simulations. To account for the transport of drug (i.e. paclitaxel) released by the device, a diffusion-reaction equation was implemented by describing the drug bound to specific intracellular receptors through a non-linear, reversible reaction. The following features concerning procedural aspects, pathologies and modelling assumptions were investigated: (i) balloon application time (60-180 seconds); (ii) vessel wall composition (healthy vs. calcified wall); (iii) sequential balloon application; and (iv) drug wash-out by the blood stream vs. coating retention, modeled as exponential decay. RESULTS: The balloon inflation time impacted both the free and specifically-bound drug concentrations in the vessel wall. The vessel wall composition highly affected the drug concentrations. In particular, the specifically-bound drug concentration was four orders of magnitude lower in the calcific compared with healthy vessel wall portions, primarily as a result of reduced drug diffusion. The sequential application of two drug-coated balloons led to modest differences (~15%) in drug concentration immediately after inflation, which became negligible within 10 minutes. The retention of the balloon coating increased the drug concentration in the vessel wall fourfold. CONCLUSIONS: The overall findings suggest that paclitaxel kinetics may be affected not only by the geometrical and compositional features of the vessel treated with the drug-coated balloon, but also by balloon design characteristics and procedural aspects that should be carefully considered.
Subject(s)
Angioplasty, Balloon/instrumentation , Drug Delivery Systems/instrumentation , Femoral Artery/surgery , Vascular Calcification/therapy , Coated Materials, Biocompatible , Drug Liberation , Equipment Design , Femoral Artery/drug effects , Humans , Models, Biological , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Tubulin Modulators/administration & dosage , Tubulin Modulators/pharmacokinetics , Vascular Calcification/surgeryABSTRACT
AIMS: Type 2 diabetes mellitus (T2DM) ranks in the top 10 causes of mortality worldwide. The key factor of T2DM vascular complications is endothelial dysfunction. It is characterized by the vessels motor activity disruption and endothelium-derived factors imbalance. The blood vessels morphological and molecular heterogeneity greatly affects the changes occurring in T2DM. Therefore, we conducted a comparative study of vascular bed changes occurring in T2DM. MAIN METHODS: Male Wistar rats were fed a high-fat diet for 20 weeks, followed by a single streptozotocin injection (20 mg/kg). T2DM was confirmed with an oral glucose tolerance test. KEY FINDINGS: A dose-dependent contraction study showed an increase in third-order mesenteric arterioles response to serotonin but not to phenylephrine. These vessels also exhibited a decrease in acetylcholine-dependent relaxation and an increase in guanylate cyclase function. At the same time, the femoral arteries showed a tendency for increased acetylcholine-dependent relaxation. The blood plasma analysis revealed low bioavailable nitric oxide and high levels of endothelin-1 and ROS. SIGNIFICANCE: This knowledge, in conjunction with the features of the T2DM course, can allow further targeted approaches development for the prevention and treatment of vascular complications occurring in the disease.
Subject(s)
Acetylcholine/pharmacology , Diabetes Mellitus, Type 2/physiopathology , Femoral Artery/physiopathology , Mesenteric Arteries/physiopathology , Muscle Tonus , Serotonin/pharmacology , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/physiopathology , Femoral Artery/drug effects , Glucose Tolerance Test , Male , Mesenteric Arteries/drug effects , Muscle Tonus/drug effects , Nitric Oxide/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Rats, Wistar , Vascular ResistanceABSTRACT
BACKGROUND: Insulin exerts vasculoprotective effects on endothelial cells (ECs) and growth-promoting effects on vascular smooth muscle cells (SMCs) in vitro, and suppresses neointimal growth in vivo. Here we determined the role of ECs and SMCs in the effect of insulin on neointimal growth. METHODS: Mice with transgene CreERT2 under the control of EC-specific Tie2 (Tie2-Cre) or SMC-specific smooth muscle myosin heavy chain promoter/enhancer (SMMHC-Cre) or littermate controls were crossbred with mice carrying a loxP-flanked insulin receptor (IR) gene. After CreERT2-loxP-mediated recombination was induced by tamoxifen injection, mice received insulin pellet or sham (control) implantation, and underwent femoral artery wire injury. Femoral arteries were collected for morphological analysis 28 days after wire injury. RESULTS: Tamoxifen-treated Tie2-Cre+ mice showed lower IR expression in ECs, but not in SMCs, than Tie2-Cre- mice. Insulin treatment reduced neointimal area after arterial injury in Tie2-Cre- mice, but had no effect in Tie2-Cre+ mice. Tamoxifen-treated SMMHC-Cre+ mice showed lower IR expression in SMCs, but not in ECs, than SMMHC-Cre- mice. Insulin treatment reduced neointimal area in SMMHC-Cre- mice, whereas unexpectedly, it failed to inhibit neointima formation in SMMHC-Cre+ mice. CONCLUSION: Insulin action in both ECs and SMCs is required for the "anti-restenotic" effect of insulin in vivo.
Subject(s)
Endothelial Cells/drug effects , Endothelium, Vascular/drug effects , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Neointima , Receptor, Insulin/agonists , Vascular System Injuries/drug therapy , Animals , Disease Models, Animal , Drug Implants , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelium, Vascular/injuries , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Femoral Artery/drug effects , Femoral Artery/injuries , Femoral Artery/metabolism , Femoral Artery/pathology , Male , Mice, Knockout , Muscle, Smooth, Vascular/injuries , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Vascular System Injuries/metabolism , Vascular System Injuries/pathologyABSTRACT
Magnetic iron oxide nanoparticles (IONP) present the promising instrument for broad-spectrum of clinical applications, for example, targeted drug delivery. Reactivity of nanoparticles depends on their surface area and material. In the blood plasma IONP are getting covered with an albumin crown, so it was decided to test this shell for biocompatibility. Male Wistar rats were anesthetized and underwent laparotomy. Abdominal aorta was connected to external hemodynamic loop with regulated blood flow. Hind body quarter got step-like blood flow changing from 30 to 150 mmHg and back. This was followed with i.v. injection of IONP, albumin solution or albumin-covered IONP and consequent similar flow changes. Central hemodynamics-heart rate and mean arterial pressure were registered throughout the experiment and no significant changes in these parameters were observed. Hind paw microcirculation level had the same dynamic in all groups under changing blood flow conditions. At the end, venous blood was collected for endothelin-1 and NO evaluation that showed similar changes and no endothelial damage. Mesenteric arteries and femoral artery reactivity were evaluated with wire myography. Mesenteric arteries had the most relaxing function preservation after albumin-covered IONP injection. Given data reveal advantage of albumin-coated IONP so this can be used for further investigations as a vascular-safe vehicle.
Subject(s)
Albumins/chemistry , Endothelial Cells/metabolism , Magnetic Iron Oxide Nanoparticles/administration & dosage , Acetylcholine/pharmacology , Animals , Area Under Curve , Arterial Pressure/drug effects , Biomarkers/metabolism , Endothelial Cells/drug effects , Endothelin-1/metabolism , Femoral Artery/drug effects , Femoral Artery/physiology , Heart Rate/drug effects , Hemodynamics/drug effects , Injections, Intravenous , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiology , Microcirculation/drug effects , Nitric Oxide/metabolism , Phenylephrine/pharmacology , Rats, Wistar , Regional Blood Flow/drug effectsABSTRACT
PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.
Subject(s)
Cardiovascular Agents/administration & dosage , Drug-Eluting Stents , Endovascular Procedures/instrumentation , Femoral Artery/drug effects , Paclitaxel/administration & dosage , Polymers , Animals , Cardiovascular Agents/adverse effects , Endovascular Procedures/adverse effects , Femoral Artery/diagnostic imaging , Femoral Artery/pathology , Neointima , Paclitaxel/adverse effects , Prosthesis Design , Swine , Swine, Miniature , Time Factors , Vascular Remodeling/drug effects , Wound Healing/drug effectsABSTRACT
Imatinib, a PDGF receptor tyrosine kinase inhibitor, has been shown to suppress intimal hyperplasia in different animal models under normal metabolic milieu, diabetic, and/or hypercholesterolemic conditions. However, the impact of imatinib treatment on injury-induced neointimal hyperplasia has not yet been investigated in the setting of insulin resistance without frank diabetes. Using a mouse model of high fat diet (HFD)-induced insulin resistance and guidewire-induced arterial injury, the present study demonstrates that intraperitoneal administration of imatinib (25 mg/kg/day) for ~3 weeks resulted in a marked attenuation of neointimal hyperplasia (intima/media ratio) by ~78% (n = 6-9 per group; P < 0.05). Imatinib treatment also led to significant improvements in key metabolic parameters. In particular, imatinib improved insulin resistance and glucose tolerance, as revealed by complete inhibition of HFD-induced increase in HOMA-IR index and AUCIPGTT, respectively. In addition, imatinib treatment led to diminutions in HFD-induced increases in plasma total cholesterol and triglycerides by ~73% and ~59%, respectively. Furthermore, imatinib decreased HFD-induced increase in visceral fat accumulation by ~51% (as determined by epididymal white adipose tissue weight). Importantly, imatinib treatment in HFD-fed mice enhanced plasma levels of high-molecular-weight adiponectin by ~2-fold without affecting total adiponectin. However, there were no significant changes in mean arterial pressure in insulin-resistant state or after imatinib exposure, as measured by tail-cuff method. Together, the present findings suggest that targeting PDGF receptor tyrosine kinase using imatinib may provide a realistic treatment option to prevent injury-induced neointimal hyperplasia and diet-induced insulin resistance in obesity.
Subject(s)
Diet, High-Fat/adverse effects , Femoral Artery/drug effects , Imatinib Mesylate/therapeutic use , Insulin Resistance , Neointima/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Femoral Artery/metabolism , Femoral Artery/pathology , Hyperplasia/drug therapy , Hyperplasia/etiology , Hyperplasia/pathology , Imatinib Mesylate/pharmacology , Insulin Resistance/physiology , Male , Mice , Mice, Inbred C57BL , Neointima/metabolism , Neointima/pathology , Protein Kinase Inhibitors/pharmacologyABSTRACT
AIM: The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was defined by applying the cardio-ankle vascular index (CAVI). We compared changes in stiffness of the two arteries in response to reduced BP, due to the non-selective α adrenergic blocker phentolamine and the ß1 adrenergic blocker atenolol, in rabbits. METHODS: Pressure waves at the origin (oA) and distal ends of the aorta (dA) and the distal end of the left femoral artery (fA) were recorded simultaneously using three pressure sensors in 25 anesthetized rabbits. Phentolamine (50 µg/kg/min) and atenolol (10 mg/kg/min) were infused for 2 min. The pulse wave velocity (PWV) in each artery was determined; aBeta, ifBeta, and whole Beta (aifBeta) were calculated by the following formula; Beta=2ρ/PP×ln(SBP/DBP)×PWV2 (ρ: blood density; SBP, SBP, and PP: systolic, diastolic, and pulse pressures, respectively). RESULTS: SBP and DBP at oA, dA, and fA decreased by the administration of phentolamine and atenolol, with and without decreased total peripheral vascular resistance. After phentramine infusion, cardiac output (CO), aBeta, and aifBeta increased, while ifBeta decreased. After infusion of atenolol, CO decreased, while aBeta, ifBeta, and aifBeta remained unchanged. CONCLUSION: The contradictory reactions of aBeta and ifBeta to phentolamine suggest that the stiffness of the aorta and ilio-femoral artery is regulated separately during decreased BP induced by phentolamine, but not by atenolol.
Subject(s)
Aorta , Atenolol/pharmacology , Blood Flow Velocity/drug effects , Femoral Artery , Phentolamine/pharmacology , Vascular Stiffness/drug effects , Animals , Antihypertensive Agents/pharmacology , Aorta/drug effects , Aorta/physiopathology , Blood Flow Velocity/physiology , Blood Pressure Determination/methods , Cardiac Output/drug effects , Cardiac Output/physiology , Disease Models, Animal , Femoral Artery/drug effects , Femoral Artery/physiopathology , Hypertension/drug therapy , Hypertension/physiopathology , Pulse Wave Analysis/methods , RabbitsABSTRACT
CONTEXT: Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. OBJECTIVE: We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response. METHODS: In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. RESULTS: Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. CONCLUSION: These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.
Subject(s)
Acetylcysteine/pharmacology , Aldosterone/pharmacology , Diabetes Mellitus, Type 2/physiopathology , Vasoconstriction/drug effects , Acetylcysteine/administration & dosage , Adult , Aldosterone/administration & dosage , Aldosterone/blood , Antioxidants/administration & dosage , Antioxidants/pharmacology , Case-Control Studies , Denmark , Diabetes Mellitus, Type 2/blood , Female , Femoral Artery/drug effects , Femoral Artery/physiopathology , Hemodynamics/drug effects , Humans , Leg/blood supply , Male , Middle Aged , Regional Blood Flow/drug effectsABSTRACT
Extracellular nucleotides play an important role in the regulation of vascular function, and an abnormal vascular function is an important participant in the development and progression of diabetic vascular complications. The purpose of this study was to determine whether contractile responses induced by extracellular nucleotides and a dinucleotide, uridine adenosine tetraphosphate (Up4A), in femoral arteries would be altered at the chronic stage of type 2 diabetes. We determined the changes in contractile reactivity induced by ATP, uridine triphosphate (UTP), uridine diphosphate (UDP), and Up4A in the femoral arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats (aged male type 2 diabetic rats) and, Long-Evans Tokushima Otsuka (LETO) rats (controls for OLETF rats). ATP-induced contractions were greater in OLETF rats than in LETO rats. UTP-induced contractions were lower in OLETF rats than in LETO rats. UDP- and Up4A-induced contractions were similar between OLETF and LETO rats. The femoral artery contractile changes induced by the extracellular nucleotides and dinucleotide were similar when nitric oxide synthase was inhibited. These results suggest that the extent of femoral artery contractile reactivity to nucleotides/dinucleotides differs during long-term duration of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Femoral Artery/drug effects , Femoral Artery/physiopathology , Muscle Contraction/drug effects , Nucleotides/pharmacology , Animals , Diabetes Mellitus, Type 2/genetics , Male , Muscle Contraction/physiology , Organ Culture Techniques , Rats , Rats, Inbred OLETF , Species SpecificityABSTRACT
INTRODUCCIÓN Y OBJETIVOS: A menudo se excluye de los ensayos clínicos a los pacientes hemodinámica o eléctricamente vulnerables, por lo que escasea la información sobre el acceso vascular y el tratamiento antitrombótico óptimos. En este trabajo se estudia la evolución de los pacientes vulnerables con síndrome coronario agudo tratados invasivamente según el acceso fuera radial o femoral y el tratamiento fuera con bivalirudina o con heparina no fraccionada (HNF). MÉTODOS: El estudio MATRIX aleatorizó a 8.404 pacientes a acceso radial o femoral y a 7.213 pacientes a bivalirudina o a HNF. Se consideró vulnerables a 934 pacientes (11,1%) debido a clase Killip avanzada (808), parada cardiaca (168) o ambas a la vez (42). El objetivo primario compuesto a 30 días fueron los eventos cardiovasculares y cerebrovasculares mayores (MACE: muerte, infarto de miocardio e ictus) y los eventos clínicos adversos netos (NACE: MACE o hemorragia grave). RESULTADOS: El acceso radial, comparado con el femoral, redujo los MACE y NACE de modo similar en pacientes vulnerables y no vulnerables. El acceso radial se asoció con un claro beneficio relativo en la mortalidad total y cardiovascular y las hemorragias BARC 3 o 5, con mayor beneficio absoluto en los pacientes vulnerables. Los efectos de la bivalirudina comparada con la HNF en MACE y NACE concuerdan entre pacientes vulnerables y no vulnerables. La bivalirudina se asoció con menores mortalidad cardiovascular y por todas las causas en pacientes vulnerables, pero no en los no vulnerables, con test de interacción en el límite. La bivalirudina redujo las hemorragias en ambos grupos de pacientes, con un beneficio absoluto mayor en el caso de los pacientes vulnerables. CONCLUSIONES: En pacientes con síndrome coronario agudo sometidos a tratamiento invasivo, los efectos de los tratamientos aleatorizados fueron concordantes entre los pacientes vulnerables y los no vulnerables, pero la reducción del riesgo absoluto del acceso radial y bivalirudina fue mayor en los vulnerables, con una reducción de 5 a 10 veces en el número de pacientes que es necesario tratar
INTRODUCTION AND OBJECTIVES: Patients who are vulnerable to hemodynamic or electrical disorders (VP) are often excluded from clinical trials and data on the optimal access-site or antithrombotic treatment are limited. We assessed outcomes of transradial vs transfemoral access and bivalirudin vs unfractionated heparin (UFH) in VP with acute coronary syndrome undergoing invasive management. METHODS: The MATRIX trial randomized 8404 patients to radial or femoral access and 7213 patients to bivalirudin or UFH. Among them, 934 (11.1%) were deemed VP due to advanced Killip class (n = 808), cardiac arrest (n = 168), or both (n = 42). The 30-day coprimary outcomes were major adverse cardiovascular and cerebrovascular events (MACE: death, myocardial infarction, or stroke) and net adverse clinical events (NACE: MACE or major bleeding). RESULTS: MACE and NACE were similarly reduced with radial vs femoral access in VP and non-VP. Transradial access was also associated with consistent relative benefits in all-cause and cardiovascular mortality or Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding with greater absolute benefits in VP. The effects of bivalirudin vs UFH on MACE and NACE were consistent in VP and non-VP. Bivalirudin was associated with lower all-cause and cardiovascular mortality in VP but not in non-VP, with borderline interaction testing. Bivalirudin reduced bleeding in both VP and non-VP with a larger absolute benefit in VP. CONCLUSIONS: In acute coronary syndrome patients undergoing invasive management, the effects of randomized treatments were consistent in VP and non-VP, but absolute risk reduction with radial access and bivalirudin were greater in VP, with a 5- to 10-fold lower number needed to treat for benefits
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Heparin/administration & dosage , Acute Coronary Syndrome/drug therapy , Vascular Access Devices/classification , Thrombin/antagonists & inhibitors , Out-of-Hospital Cardiac Arrest/epidemiology , Fibrinolytic Agents/administration & dosage , Heart Failure/drug therapy , Acute Coronary Syndrome/complications , Indicators of Morbidity and Mortality , Heart Arrest/epidemiology , Radial Artery/drug effects , Femoral Artery/drug effectsABSTRACT
It is known that a high level of uric acid (UA) in plasma, hyperuricemia (HU), is associated with the increased risk of cardiovascular diseases (CVDs). Endothelial damage has been suggested as a potential mechanism involved in HU-induced CVDs, especially in patients with the accumulation of other cardiovascular risk factors. However, the role of UA in the pathogenesis of endothelial dysfunction is still a matter of debate. It is unclear whether UA is a causative risk factor in endothelial dysfunction, an inert marker or an endothelium-protective molecule with respect to its antioxidant properties. Of note, only a few studies have been conducted to investigate the effect of UA on vascular endothelium-dependent relaxation. Therefore, we have studied the acute in vitro effects of high UA concentrations on the endothelial function of arteries isolated from aged rats. Experiments were performed in small mesenteric arteries (SMAs), femoral arteries and thoracic aortas isolated from 68-week-old and 57-week-old male Wistar-Kyoto rats. Vascular reactivity was investigated in isometric conditions using the wire myograph and organ chamber. Acetylcholine (ACh) was used to investigate endothelium-dependent vasorelaxation. Then, UA was added to the myograph or organ chamber at 600 µmol/l (arteries from 68-week-old rats) or 1200 µmol/l (arteries from 57-week-old rats) and incubated for 1 h, and this was followed by determining the ACh concentration-response curve. UA had no significant effect on ACh-induced vasorelaxation and pD2 values in all investigated groups. Likewise, no significant differences in noradrenaline- (SMAs), serotonin- (femoral arteries) and phenylephrine-induced (aortas) vasoconstriction were observed after UA pre-incubation. In conclusion, high concentrations of UA administered acutely failed to affect endothelial function and did not provoke endothelial dysfunction in resistant mesenteric arteries, medium-sized and large arteries from aged rats.
Subject(s)
Aorta, Thoracic/drug effects , Endothelium, Vascular/drug effects , Femoral Artery/drug effects , Mesenteric Arteries/drug effects , Uric Acid/pharmacology , Vasoconstriction/drug effects , Vasodilation/drug effects , Age Factors , Animals , Aorta, Thoracic/physiology , Endothelium, Vascular/physiology , Femoral Artery/physiology , In Vitro Techniques , Male , Mesenteric Arteries/physiology , Rats, Inbred WKY , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
Formaldehyde (FA) is a common, volatile organic compound used in organic preservation with known health effects of eye, nose, and throat irritation linked to oxidative stress and inflammation. Indeed, long-term FA exposure may provoke skin disorders, cancer, and cardiovascular disease. However, the effects of short-term FA exposure on the vasculature have yet to be investigated. We sought to investigate the impact of an acute FA exposure on 1) macrovascular function in the arm (brachial artery flow-mediated dilation, FMD), 2) microvascular function in the arm (brachial artery reactive hyperemia, RH) and leg (common femoral artery, supine passive limb movement, PLM), and 3) circulating markers of oxidative stress (xanthine oxidase, XO; protein carbonyl, PC; and malondialdehyde, MDA) and inflammation (C-reactive protein, CRP). Ten (n = 10) healthy females (23 ± 1 yr) were studied before and immediately after a 90-min FA exposure [(FA): 197 ± 79 ppb] in cadaver dissection laboratories. Brachial artery FMD% decreased following FA exposure (Pre-FA Exp: 9.41 ± 4.21%, Post-FA Exp: 6.74 ± 2.57%; P = 0.043), and FMD/shear decreased following FA exposure (Pre-FA Exp: 0.13 ± 0.07 AU, Post-FA Exp: 0.07 ± 0.03 AU; P = 0.016). The area under the curve for brachial artery RH (Pre-FA Exp: 481 ± 191 ml, Post-FA Exp: 499 ± 165 ml) and common femoral artery PLM (Pre-FA Exp: 139 ± 95 ml, Post-FA Exp: 129 ± 64 ml) were unchanged by FA exposure (P > 0.05). Circulating MDA increased (Pre-FA Exp: 4.8 ± 1.3 µM, Post-FA Exp: 6.3 ± 2.2 µM; P = 0.047) while XO, PC, and CRP were unchanged by FA exposure (P > 0.05). These initial data suggest a short FA exposure can adversely alter vascular function and oxidative stress, influencing cardiovascular health.NEW & NOTEWORTHY This study was the first to investigate the implications of acute formaldehyde (FA) exposure on adult female vascular function in the arms and legs. The main findings of this study were a decrease in conduit vessel function without any alteration to microvascular function following a 90-min FA exposure. Additionally, the oxidative stress marker malondialdehyde increased after FA exposure. Taken together, these results suggest acute FA exposure have deleterious implications for the vasculature and redox balance.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/formaldehyde-exposure-decreases-vascular-function/.
Subject(s)
Brachial Artery/drug effects , Femoral Artery/drug effects , Fixatives/adverse effects , Formaldehyde/adverse effects , Microcirculation/drug effects , Oxidative Stress/drug effects , Vasodilation/drug effects , Biomarkers/blood , Brachial Artery/physiopathology , Cadaver , Dissection , Female , Femoral Artery/physiopathology , Humans , Inflammation Mediators/blood , Time Factors , Young AdultABSTRACT
INTRODUCTION: Preeclampsia (PE) is a serious maternal inflammatory disease with endothelial cell dysfunction, and there is a lack of effective treatment and prevention. Tadalafil is considered to be a promising drug for PE. This study aimed to determine whether and how tadalafil use during early pregnancy alleviates PE induced by N-nitro-l-arginine-methyl-ester (l-NAME), an antagonist of nitric oxide synthase, in rats. METHODS: Twenty-eight Sprague-Dawley (SD) rats were randomly divided into 4 equal groups on gestational day 0 (GD0): a pregnant control group, an l-NAME-treated PE group and two prophylactic low-dose and high-dose tadalafil groups. Blood pressure was measured on GD0, 5, 10, 15 and 20. Proteinuria was assessed on GD0 and 18. Femoral artery ultrasound was performed on GD19. Tissue sampling was performed on GD20. The perinatal outcomes, placenta and kidney tissue morphology, and endothelial and inflammatory markers were examined. RESULTS: Prophylactic administration of low and high doses of tadalafil improved l-NAME induced hypertension, proteinuria, maternal weight loss during pregnancy, fetal growth restriction and flow-mediated dilatation, balanced endothelial-relative factors, and alleviated inflammation activation in placenta and kidney tissue. What's more, in some results, the HT group performed better than the LT group. DISCUSSION: Our results indicate that prophylactic use of tadalafil in l-NAME-induced PE-like rat models alleviates PE symptoms, promotes fetal growth, protects endothelial function and reduces inflammation, suggesting that tadalafil may be a potential drug for the prevention of PE.
Subject(s)
Phosphodiesterase 5 Inhibitors/therapeutic use , Placenta/drug effects , Pre-Eclampsia/drug therapy , Tadalafil/therapeutic use , Animals , Blood Pressure/drug effects , Cytokines/metabolism , Female , Femoral Artery/diagnostic imaging , Femoral Artery/drug effects , Femoral Artery/metabolism , Kidney/diagnostic imaging , Kidney/drug effects , Kidney/metabolism , NG-Nitroarginine Methyl Ester , Phosphodiesterase 5 Inhibitors/pharmacology , Placenta/diagnostic imaging , Placenta/metabolism , Pre-Eclampsia/chemically induced , Pre-Eclampsia/diagnostic imaging , Pre-Eclampsia/metabolism , Pregnancy , Rats , Rats, Sprague-Dawley , Tadalafil/pharmacology , UltrasonographyABSTRACT
Background Basal release of nitric oxide (NO) from the vascular endothelium regulates the tone of muscular arteries and resistance vasculature. Effects of NO on muscular arteries could be particularly important during exercise when shear stress may stimulate increased NO synthesis. Methods and Results We investigated acute effects of NO synthase inhibition on exercise hemodynamics using NG-monomethyl-l-arginine (l-NMMA), a nonselective NO synthase -inhibitor. Healthy volunteers (n=10, 5 female, 19-33 years) participated in a 2-phase randomized crossover study, receiving l-NMMA (6 mg/kg, iv over 5 minutes) or placebo before bicycle exercise (25-150 W for 12 minutes). Blood pressure, cardiac output (measured by dilution of soluble and inert tracers) and femoral artery diameter were measured before, during, and after exercise. At rest, l-NMMA reduced heart rate (by 16.2±4.3 bpm relative to placebo, P<0.01), increased peripheral vascular resistance (by 7.0±1.4 mmHg per L/min, P<0.001), mean arterial blood pressure (by 8.9±3.5 mmHg, P<0.05), and blunted an increase in femoral artery diameter that occurred immediately before exercise (change in diameter: 0.14±0.04 versus 0.32±0.06 mm after l-NMMA and placebo, P<0.01). During/after exercise l-NMMA had no significant effect on peripheral resistance, cardiac output, or on femoral artery diameter. Conclusions These results suggest that NO plays little role in modulating muscular artery function during exercise but that it may mediate changes in muscular artery tone immediately before exercise.