Memantine, an NMDA Receptor Antagonist, Prevents Thyroxin-induced Hypertension, but Not Cardiac Remodeling

Abstract

Stimulation of glutamatergic tone has been causally linked to myocardial pathogenesis and amplified systemic blood pressure (BP). Memantine, a noncompetitive N-methyl-D-aspartate glutamatergic receptor (NMDA-R) antagonist, has been proposed to be an active cardioprotective drug. However, the efficacy of memantine and subsequently the possible involvement of the NMDA-R in the thyroxin (T4)-induced cardiovascular complications have never been investigated. We examined the effect of memantine (30 mg·kg·d) on the T4 (500 μg·kg·d)-provoked increase in mouse BP, cardiac hypertrophy indicated by enlarged overall myocardial mass, and reformed reactions of the contractile myocardium both in vivo and ex vivo after 2 weeks of treatment. Memantine alone did not result in any cardiovascular pathology in mice. Instead, memantine significantly prevented the T4-triggered systemic hypertension. But, it did not reverse cardiac hypertrophy, coupled in vivo left ventricular dysfunction (LV) or ex vivo right ventricular (RV) papillary muscle contractile alterations of the T4-treated mice. Our results openly direct the cardiovascular safety and tolerability of memantine therapy. Yet, extra research is necessary to endorse these prospective advantageous outcomes. Also, we believe that this is the first study to inspect the possible role of NMDA-R in the T4-stimulated cardiovascular disorders and concluded that NMDA-R could play a key role in the T4-induced hypertension.

Mechanism of new optimized Sheng-Mai-San Formula to regulate cardiomyocyte apoptosis through NMDAR pathway

“…When the NMDA receptor pathway is open in the presence of sustained activation, large amounts of Ca 2+ enter the cell, causing calcium overload [ 39 ]and damage to cardiomyocytes via the mitochondrial and endoplasmic reticulum pathways [ 40 ]. The large amount of Ca 2+ in mitochondria opens the mitochondrial permeability transition pore (MPTP) and takes up large amounts of water through higher colloidal osmotic pressure, leading to swelling of mitochondria and rupture of the outer membrane, generating large amounts of ROS [ 41 ], resulting in irreversible cellular damage, the release of Cyt-c, decreased Bcl-2 protein expression, dissociation of Bcl-2/Bax heterodimers, increased Bax protein expression, and increased number of Bax/Bax homodimers [ 42 ], initiating the apoptotic process [ 43 , 44 ].…”

Effect of hypothyroidism on contractile performance of isolated end-stage failing human myocardium

“…For each heart, the left ventricle (LV) was rapidly transferred from the cardioplegic solution to a cold modified Krebs-Henseleit solution (K-H) containing 2,3-butanedione monoxime (BDM) [ 34 ], where uniform linear trabeculae were dissected by the aid of a stereo dissection microscope. Muscles were transferred into custom-made setups as previously described [ 35 ], and the perfusion solution was exchanged for a BDM-free K-H solution, circulating at 37°C.…”

Modeling heart failure in animal models for novel drug discovery and development

“…Administration of sodium-L-thyroxin induced cardiac left-ventricular hypertrophy and associated cardiac dysfunction, which was either not or only partially dependent on hemodynamic changes (e.g. increased blood pressure) [38][39][40] . Not only that, but also the variation in mouse species, sex, and age between these experiments 41 and others 42 obviously signifies that cardiac alterations following experimental hyperthyroidism appear to be model-dependent and need to be cautiously clarified 41 .…”