Acute inhibition of monoamine oxidase and ischemic preconditioning in isolated rat hearts: interference with postischemic functional recovery but no effect on infarct size reduction.

Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 µmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (-dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection.

Ageing-induced decrease in cardiac mitochondrial function in healthy rats.

It is widely recognized that mitochondrial dysfunction is a key component of the multifactorial process of ageing. The effects of age on individual components of mitochondrial function vary across species and strains. In this study we investigated the oxygen consumption, the mitochondrial membrane potential (Δψ), the sensitivity of mitochondrial permeability transition pore (mPTP) to calcium overload, and the production of reactive oxygen species (ROS) in heart mitochondria isolated from old compared with adult healthy Sprague-Dawley rats. Respirometry studies and Δψ measurements were performed with an Oxygraph-2k equipped with a tetraphenylphosphonium electrode. ROS production and calcium retention capacity were measured spectrofluorimetrically. Our results show an important decline for all bioenergetic parameters for both complex I and complex II supported-respiration, a decreased Δψ in mitochondria energized with complex I substrates, and an increased mitochondrial ROS production in the old compared with the adult group. Mitochondrial sensitivity to Ca²âº-induced mPTP opening was also increased in the old compared with the adult animals. Moreover, the protective effect of cyclosporine A on mPTP opening was significantly reduced in the old group. We conclude that healthy ageing is associated with a decrease in heart mitochondria function in Sprague-Dawley rats.

Magnesium orotate elicits acute cardioprotection at reperfusion in isolated and in vivo rat hearts.

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia-reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and MgCl2 treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R.

Monoamine oxidase--a inhibition reverses endothelial dysfunction in hypertensive rat aortic rings.

AIM: Monoamine oxidases (MAOs) are mitochondrial enzymes, with 2 isoforms, A and B that convert biogenic amines to their corresponding aldehydes via a reaction that produces hydrogen peroxide. Since MAO-A is the predominant form at vascular level we hypothesized that MAO-A-dependent H2O2 production may contribute to the development of endothelial dysfunction and, MAOs inhibition could improve the vascular function, respectively. MATERIAL AND METHODS: To this aim aortic rings were isolated from female adult spontaneously hypertensive rats (SHR) and their corresponding (Wistar-Kyoto) controls. The effect of MAO-A inhibitor, clorgyline (10 micromol/l) on endothelium-dependent relaxation (EDR) in response to acetylcholine and endothelium-independent relaxation in response to sodium nitroprusside, was studied in isolated phenylephrine-preconstricted aortic segments in the presence of indometacine (10 micromol/l). RESULTS: In hypertensive group EDR was significantly decreased - maximal relaxation (% of KCI, mean +/- SD) being 37 +/- 3.5 in SHR vs. 3.7 +/- 1.8 in controls. If experiments were done in the presence of clorgyline, EDR in control segments was unaffected. However, the compound restored normal EDR in aortic segments from hypertensive rats (maximal relaxation % of KCI, 13.7 +/- 2.3). CONCLUSIONS: Inhibition of the MAO-A isoform might be useful in restoring endothelium-dependent relaxation in this experimental model of hypertension in rat.