Microvascular Perturbations in Rats Receiving the Maximum Tolerated Dose of Methotrexate or Its Major Metabolite 7-Hydroxymethotrexate

Abstract

Methotrexate (MTX) is a clinically important cytostatic antifolate. The study describes the acute effects of maximum tolerated doses of MTX or its major metabolite 7-hydroxymethotrexate (7-OH-MTX) on the ultrastructure of rat liver and kidneys. The ultrastructural changes in rats receiving MTX or 7-OH-MTX were, in principle, indistinguishable and their severity and extension increased with time of survival or doses of medication. All lesions were focal, microvascular, or parenchymal. Microvascular changes were more severe in nature when blood cells were present. The endothelial cells were swollen with loss of pinocytotic vesicles, their luminal plasma membrane formed blebs or were disrupted. Partly detached endothelial cells or deendothelialized areas, various types of white blood cells, in particular, neutrophil granulocytes, were observed in the microcirculation. Single platelets or small platelet aggregates were found either in the lumen or adhering to deendothelialized areas of injured endothelial cells. Hepatocytes exhibited steatosis, edema, and manifest single cell necrosis. There were also nuclear changes, marked proliferation of smooth endoplasmatic reticulum, increased amounts of intracellular lipid vacuoles, and a decrease in glycogen particles in hepatocytes. The kidney presented the major changes in the tubules and in the interstitial part. MTX and 7-OH-MTX acute toxicity may primarily be related to microvascular perturbation.

Endothelial alterations in a canine model of immune thrombocytopenia

“…Most notably, pinocytotic vesicles decreased significantly in the thrombocytopenic endothelium. The exact mechanism of vesicle decrease is unknown but vesicle reduction is observed in several other examples of endothelial damage including methotrexate toxicity, hypoxia, and snake bite envenomation [25],[26], [27]. Pinocytotic vesicles provide a reserve of plasma membrane and can be translocated to the endothelial cell surface by exocytosis when there is a demand for increased membrane either due to cellular distention or membrane damage [25].…”

Influence of high‐dose methotrexate therapy (HD‐MTX) on glomerular and tubular kidney function

“…In spite of proper hydration and urine alkalization, serious renal dysfunction seldom occurs after the administration of HD-MTX. Therefore it can be assumed that a disturbance in preglomerular vascular resistance [7,15], direct damage to the glomeruli [5,12], or direct tubular toxicity [11,16] are further nephrotoxic mechanisms.…”

Methotrexate and Cardiovascular Protection: Current Evidence and Future Directions

“…Merkle et al 78 reported a reduction in bovine pulmonary artery endothelial cell integrity, consisting in the development of gaps between cells and endothelial cell death, after 4-day exposure to methotrexate. Similarly, Fuskevag et al 79 observed endothelial cell swelling and membrane disruption in rats receiving methotrexate as a bolus, followed by a continuous infusion more than 8 hours. However, as reported by Hirata et al, the antiproliferative effects of methotrexate on endothelial cells, observed in a model of corneal neovascularization, might be beneficial in the pathophysiology of RA and other autoimmune disorders, by preventing synovial neovascularization.…”