scholarly journals Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor

Toxics ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 49
Author(s):  
Claudia Reyes-Goya ◽  
Álvaro Santana-Garrido ◽  
Estefanía Soto-Astacio ◽  
Óscar Aramburu ◽  
Sonia Zambrano ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitor ◽  
Vascular Remodeling ◽  
Kinase Inhibitor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Superoxide Anion Production ◽  
Vascular Toxicity

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

scholarly journals Pulsatile flow enhances endothelium-derived nitric oxide release in the peripheral vasculature

2000 ◽  
Vol 278 (4) ◽  
pp. H1098-H1104 ◽  
Author(s):  
Toshihide Nakano ◽  
Ryuji Tominaga ◽  
Ichiro Nagano ◽  
Hayato Okabe ◽  
Hisataka Yasui
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Pulsatile Flow ◽  
Kinase Inhibitor ◽  
Reactive Hyperemia ◽  
No Synthase ◽  
Peripheral Vasculature ◽  
Nitric Oxide Release

The effects of pulsatility in blood flow on endothelium-derived nitric oxide (EDNO) release in the peripheral vasculature were investigated. The basal and flow-stimulated EDNO release were compared between pulsatile and nonpulsatile systemic flows before and after the administration of NO synthase inhibitor NG-monomethyl-l-arginine (l-NMMA). Peripheral vascular resistance (PVR) was significantly lower in pulsatile flow than in nonpulsatile flow, but this difference disappeared after l-NMMA. The percent increase in PVR by l-NMMA was significantly larger in pulsatile flow. In reactive hyperemia in the hindlimb, the peak flow did not differ; however, both the repayment flow and the duration were significantly larger in pulsatile flow. Percent changes of these parameters by l-NMMA were significantly larger in pulsatile flow. These data indicated that pulsatility significantly enhances the basal and flow-stimulated EDNO release in the peripheral vasculature under in vivo conditions. We also studied the involvement of the Ca2+-dependent and Ca2+-independent pathways in flow-induced vasodilation using calmodulin inhibitor calmidazolium and tyrosine kinase inhibitor erbstatin A. PVR was significantly elevated by erbstatin A but not by calmidazolium, suggesting that flow-induced vasodilation was largely caused by tyrosine kinase inhibitor-sensitive activation of NO synthase.

scholarly journals Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib

Blood ◽  
2019 ◽  
Vol 133 (14) ◽  
pp. 1597-1606 ◽  
Author(s):  
Yllka Latifi ◽  
Federico Moccetti ◽  
Melinda Wu ◽  
Aris Xie ◽  
William Packwood ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Wall Motion ◽  
Platelet Adhesion ◽  
Kinase Inhibitor ◽  
Left Ventricular ◽  
Wild Type ◽  
Vascular Toxicity ◽  
Wall Motion Abnormalities ◽  
A1 Domain

Abstract The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE−/− mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE−/− mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE−/− mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.

scholarly journals Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Oren Pasvolsky ◽  
Avi Leader ◽  
Zaza Iakobishvili ◽  
Yishay Wasserstrum ◽  
Ran Kornowski ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Vascular Toxicity

scholarly journals Contrary Effects of the Receptor Tyrosine Kinase Inhibitor Vandetanib on Constitutive and Flow-Stimulated Nitric Oxide Elaboration in Humans

Hypertension ◽  
2011 ◽  
Vol 58 (1) ◽  
pp. 85-92 ◽  
Author(s):  
Erica L. Mayer ◽  
Susan M. Dallabrida ◽  
Maria A. Rupnick ◽  
Whitney M. Redline ◽  
Keri Hannagan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Receptor Tyrosine Kinase Inhibitor
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