Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart

Abstract

(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3-100 microM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by alpha(1)-antagonist (1 microM prazosin) nor by beta(1)-adrenoceptor antagonist (3 microM atenolol), but significantly by a transient outward K(+) channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V(max)) and an increase in the recovery time constant of V(max). Voltage clamp study showed that (+)-MK801 (3 microM) reduced inward Na(+) current (I(Na)), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 microM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I(Ca)), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 microM of (+)-MK801 reduced the peak transient outward current (I(to)), steady-state outward current (I(ss)) and inward current through K(1) channels. The inhibition of I(to) was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K(1) channels was unaffected. These results indicate that (+)-MK801 may be a strong I(Na) and I(to) blocker with some I(Ca) blocking activity. The inhibition of I(to) and other K(+) efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia

“…The increase in iNOS induced sudden cardiomyocyte death and may lead to SCD (Mungrue et al, 2002). NMDA is a major excitatory neurotransmitter, and NMDA-R1 is present in the mammalian central nervous system (CNS, Lalo et al, 2006), in cardiomyocytes (Kraine et al, 1998;Huang & Su, 1999) and the endothelial cells Qureshi et al, 2005). The relative expression of the NMDA-receptor in heart, specifically expression in cardiomyocytes versus endothelial cells and neuronal tissue (sympathetic and parasympathetic nerve endings, for example) is in the order of neuronal >cardiomyocyte >endothelial cells.…”

“…Cardiac interstitial fibrosis is the result of HHcy and the combination of HHcy and hypertension (Miller et al, 2002). Both cardiac arrhythmias and neurological disorders contribute to SCD, and the blockade of NMDA-R1 mitigates SCD (Folbergrova, 1994;Huang & Su, 1999;Matsuoka et al, 2002;Simandle et al, 2005). Since the induction iNOS increases SCD (Mungrue et al, 2002), and Hcy increases iNOS, therefore, the use of iNOSKO mice to determine the contribution of inducible NO in Hcy-mediated E-M uncoupling (disruption of connexin-43 and fibrosis), and generation of arrhythmogenic substrate (Gutstein et al, 2001;Kitamua et al, 2003;Poelzing & Rosenbaum, 2004) is very important for the understanding of the mechanism of iNOS-NO-mediated cardiac dysfunction.…”

Deterioration in donepezil-induced PR prolongation after a coadministration of memantine in a patient with Alzheimer's disease

“…The NMDA receptor is known to cause bradycardia as a result of increased nitric oxide and L-glutamic acid [7]. In a study in which MK801, an NMDA receptor antagonist, was administered, tachycardia developed in rats and bradycardia in pigs [8]. However, the mechanism for the memantine-induced PR prolongation is unknown.…”

Autophagy and Heart Failure: A Possible Role for Homocysteine

“…NMDA-R1 is well-known as being expressed in neural tissue; however, NMDA-R1 is now known to be expressed in cardiomyocytes and endothelial cells [99][100][101]. Activation of NMDA-R1 increases intracellular calcium levels, and mitochondrial calcium levels, resulting in oxidative stress [98].…”