E. Kalenikova

Changes in antioxidant status of myocardium during oxidative stress under the influence of coenzyme Q10

Changes in myocardium were studied during oxidative stress induced by infusion of hydrogen peroxide in the coronary vessels of isolated rat heart. Moderate concentrations of H2O2 increased the heart rate but decreased the contractile force, whereas higher concentrations of H2O2 decreased both parameters and increased the end diastolic pressure. The effect of H2O2 was stable, cumulative, and was associated with disturbance in respiration of mitochondria, increased production of ROS in them, and decrease in activities of antioxidant enzymes in the myocardium. Changes in the antioxidant status of the myocardium induced by long-term addition of coenzyme Q10 into food was accompanied by decrease in the negative inotropic effect of H2O2, whereas the levels of superoxide dismutase and glutathione peroxidase after oxidative stress were virtually unchanged. The activities of these enzymes displayed a high positive correlation with the cardiac function. The findings suggest that coenzyme Q10 should increase resistance of the myocardium to oxidative stress not only by a direct antioxidant mechanism but also indirectly, due to increased protection of antioxidant enzymes.

Chronic administration of coenzyme Q10 limits postinfarct myocardial remodeling in rats

The effect of chronic coronary artery occlusion on the content of rat myocardial coenzymes Q (CoQ) and evaluation of the applicability of CoQ10 for limiting postinfarct remodeling have been investigated. Left ventricle myocardium hypertrophy was characterized by the decrease in CoQ9 (−45%, p < 0.0001), CoQ10 (−43%, p < 0.001), and α-tocopherol (−35%, p < 0.05). There were no differences between the parameters of postinfarction and sham-operated rats in plasma. Administration of CoQ10 (10 mg/kg) via a gastric probe for 3 weeks before and 3 weeks after occlusion maintained higher levels of CoQ in the postinfarction myocardium: the decrease in CoQ9 and CoQ10 was 25% (p < 0.05) and 23% (p < 0.05), respectively (versus sham-operated animals). Plasma concentrations of CoQ10 were more than 2 times higher (p < 0.05). In CoQ treated rats there was significant correlation between plasma levels of CoQ and the infarct size: r = −0.723 (p < 0.05) and r = −0.839 (p < 0.01) for CoQ9 and CoQ10. These animals were also characterized by earlier and more intensive scar tissue formation in the postinfarction myocardium and also by more pronounced cell regeneration processes. This resulted in the decrease in both the infarct size (16.2 ± 8.1 vs. 27.8 ± 12.1%) and also mass index of left ventricle (2.18 ± 0.24 vs. 2.38 ± 0.27 g/kg) versus untreated rats (p < 0.05). Thus, long-term treatment with ubiquinone increases plasma and myocardial CoQ content and this can improve the survival of myocardial cells during ischemia and limit postinfarct myocardial remodeling.

Role of Reactive Oxygen Species in the Sensitivity of Rat Hypertrophied Myocardium to Ischemia

The relationship between hydroxyl radical (OH·) generation in the zone of ischemia/reperfusion and the size of infarction formed was investigated in 18-22-week-old anaesthetized male SHRSP and Wistar rats using a myocardial microdialysis technique. The marker of OH· generation, 2,3-dihydroxybenzoic acid (2,3-DHBA), was analyzed in dialyzates by high performance liquid chromatography with electrochemical detection. Myocardial ischemia was induced by ligation of the descending branch of the left main coronary artery for 30 min. The mean value of basal 2,3-DHBA level in the dialyzate samples from SHRSP (243 ± 21 pg for 30 min) was significantly higher than that from Wistar rats (91 ± 4 pg for 30 min, p < 0.0002); it positively correlated with left ventricular hypertrophy (r = 0.806; p < 0.05). During reperfusion total 2,3-DHBA output was 1.8-fold higher in SHRSP than in Wistar rats (659 ± 60 pg versus 364 ± 66 pg for 60 min, respectively, p < 0.0002). At the same time, 2,3-DHBA increase above the basal level was the same in Wistar and SHRSP rats (181 ± 25 and 172 ± 36 pg for 60 min, respectively). The infarct size in SHRSP (45.4 ± 4.3%) was significantly higher (p < 0.05) than in Wistar rats (32.8 ± 3.3%). There was a significant positive correlation between basal level of 2,3-DHBA and total reperfusion 2,3-DHBA content in SHRSP (r = 0.752; p < 0.05). Thus, data obtained clearly indicate that the hypertrophied myocardium of SHRSP was less tolerant to ischemia/reperfusion than that of Wistar rats due to chronically increased OH· production and enhanced total OH· output during reperfusion. Greater myocardial damage in SHRSP than in Wistar rats following the equal increase in OH· production above the basal level suggests the existence of deficit of the antioxidant defense in the hypertrophied myocardium.

Intravenous treatment with coenzyme Q10 improves neurological outcome and reduces infarct volume after transient focal brain ischemia in rats

Abstract: Coenzyme Q10 (CoQ10) crosses the blood–brain barrier when administered intravenously and accumulates in the brain. In this study, we investigated whether CoQ10 protects against ischemia-reperfusion injury by measuring neurological function and brain infarct volumes in a rat model of transient focal cerebral ischemia. In male Wistar rats, we performed transient middle cerebral artery occlusion (tMCAO) for 60 minutes, followed by reperfusion for 24 hours or 7 days. Forty-five minutes after the onset of occlusion (or 15 minutes before reperfusion), rats received a single intravenous injection of solubilized CoQ10 (30 mg·mL−1·kg−1) or saline (2 mL/kg). Sensory and motor function scores and body weights were obtained before the rats were killed by decapitation, and brain infarct volumes were calculated using tetrazolium chloride staining. CoQ10 brain levels were measured by high-performance liquid chromatography with electrochemical detection. CoQ10 significantly improved neurological behavior and reduced weight loss up to 7 days after tMCAO (P < 0.05). Furthermore, CoQ10 reduced cerebral infarct volumes by 67% at 24 hours after tMCAO and 35% at 7 days (P < 0.05). Cerebral ischemia resulted in a significant reduction in endogenous CoQ10 in both hemispheres (P < 0.05). However, intravenous injection of solubilized CoQ10 resulted in its increase in both hemispheres at 24 hours and in the contralateral hemisphere at 7 days (P < 0.05). Our results demonstrate that CoQ10 is a robust neuroprotective agent against ischemia-reperfusion brain injury in rats, improving both functional and morphological indices of brain damage.

Perindopril effects on angiotensin I elimination in lung after experimental myocardial injury induced by intracoronary microembolization in rats

The objective of the study was to determine whether angiotensin (Ang) I elimination in lung circulation depends on the degree of myocardial damage with and without early long-term perindopril treatment in a rat model of myocardial injury induced by intracoronary microembolization. Twenty-one days after surgery, steady-state arterial [125I]-Ang I and [125I]-Ang II blood concentrations were measured after high-performance liquid chromatography separation during i.v. infusion of [125I]-Ang I in three groups of male Wistar conscious rats: (a) sham-operated rats receiving saline (sham group, n = 6); (b) rats after coronary microembolization receiving saline (saline group, n = 7); and (c) rats after coronary microembolization receiving perindopril (2 mg/kg/day; from days 2-20 after embolization; perindopril group, n = 6). Ang I clearance and the Ang I-to-Ang II concentration ratio (R) were estimated. The embolization per se resulted in focal fibrosis, appearance of hypertrophic and dystrophic cardiac myocytes, and was accompanied by increased Ang I clearance (1,479 vs. 314 ml/min in sham group), 1.8-fold decreased [125I]-Ang II arterial level, and decreased R (0.5 vs. 1.2 in sham group; p < 0.05). Only Ang I concentrations and R were correlated with number of scars (r = -0.77; p < 0.05; and r = -0.82; p < 0.01, respectively). Captopril bolus (1 mg/kg, i.v.) caused similar reduction in [125I]-Ang II blood concentration in both sham and saline groups, but a significant increase of [125I]-Ang I blood concentration was detected in the sham group only. Thus in rats with coronary microembolization, a higher proportion of Ang I in lung circulation is eliminated by pathways independent of angiotensin-converting enzyme. In the perindopril group, a reduced number of scars (seven vs. 17 per slice in the saline group; p < 0.05), density of dystrophic and hypertrophic cardiac myocytes, and increased content of cell glycogen were observed. It was accompanied by normalized arterial [125I]-Ang I concentration, Ang I clearance, and R; [125I]-Ang II concentration tended to that in sham group. Only in the sham and perindopril groups was there significant correlation between Ang I and Ang II concentrations. The clear relation between number of scars per slice and R (r = -0.83; p < 0.01) was observed in all rats with embolized coronary vessels (saline and perindopril groups together). In conclusion, in this experimental, model Ang I elimination in the lung circulation was directly related to the degree of myocardial damage. Early perindopril treatment prevented maladaptive changes in Ang I processing and led to significant reduction of the undesirable aftereffects of myocardial tissue damage. Our data demonstrate the cardioprotective action of perindopril based on its beneficial influence on the renin-angiotensin system disturbances.

Single Intravenous Injection of Coenzyme Q10 Protects the Myocardium after Irreversible Ischemia

Experiments were performed on the model of irreversible myocardial ischemia in Wistar rats. Coenzyme Q10 was injected intravenously 10 min after coronary artery occlusion. On day 21 after myocardial infarction the content of coenzyme Q10 in the left ventricle, liver, and plasma from animals of the treatment group was higher than that in untreated rats by 23, 1042, and 87%, respectively (p<0.05). The area of the necrotic zone was lower, and postinfarction hypertrophy of the left ventricle was less pronounced in coenzyme-receiving rats. Right ventricular hypertrophy did not develop in these animals. These rats were characterized by greater stroke volume (by 24.6%, p<0.05), stroke work (by 34.9%), cardiac output (by 37.8%, p<0.05), ejection fraction (by 35.7%, p<0.05), and contractility (by 22.5%, p<0.05), but lower end-diastolic pressure (by 25.8%, p<0.05) than untreated animals. These data indicate that the development of parenteral ubiquinone preparations holds much promise for urgent therapy of acute cardiovascular disorders.

Pharmacokinetics of coenzyme Q10

The pharmacokinetics of coenzyme Q10 powder and solution of solubilized form was studied after their oral administration to rats (10 mg/kg). Plasma concentrations of coenzyme Q10 were measured by HPLC with electrochemical detection over 48 hours. Solubilized coenzyme Q10 exhibited high absorption creating higher plasma concentrations of the drug, as a result of which its bioavailability constituted 264% of that for the powder.

Antioxidant and prooxidant action of nitric oxide donors and metabolites

Different nitric oxide donors and metabolites proved to have similar effects on the peroxidation in rat myocardium homogenate. PAPA-NONOate (synthetic nitric oxide donor), S-nitrosoglutathione, nitrite, and nitroxyl anion caused dose-dependent inhibition of the formation of malonic dialdehyde, a secondary product of lipid peroxidation. Dextran-bound dinitrosyl iron complexes and PAPA-NONOate were the most efficient inhibitors of lipid peroxidation. S-Nitrosoglutathione also inhibited the decline in coenzymes Q9 and Q10. Low-molecular-weight dinitrosyl iron complexes with cysteine accelerated lipid peroxidation, which could be caused by the release of iron ions upon their destruction. The antioxidant effect of nitric oxide donors appears to be due to the reduction of hemoprotein ferryl forms and the reaction of nitric oxide with lipid radicals.

Protection of rat myocardium by coenzyme Q during oxidative stress induced by hydrogen peroxide.

Ubiquinone Q10 (coenzyme Q) is an important component of the mitochondrial electron transport chain and an antioxidant. The purpose of this work was to find out whether an increase in the level of coenzyme Q in the heart changes its maximal working capacity and resistance to oxidative stress. Male Wistar rats were treated with coenzyme Q (10 mg/kg body weight per day) for six weeks, and this increased its content in the myocardium by 63%. The myocardial content of malonic dialdehyde and activities of key antioxidant enzymes were unchanged, except nearly 2.5-fold decrease in the activity of superoxide dismutase. The maximal working capacity of the isolated isovolumic heart did not change, but under conditions of oxidative stress induced by 45-min infusion of hydrogen peroxide (70 μM) into coronary vessels the contractile function of these hearts decreased significantly more slowly. This was associated with less pronounced lesions in the ultrastructure of cardiomyocytes and lesser disorders in the oxidative metabolism of mitochondria that suggested increased antioxidant protection of the myocardium.

The effect of histamine receptor antagonists on stress-induced catecholamine secretion: an adrenomedullary microdialysis study in the rat.

The effects of pretreatment with selective histamine receptor antagonists on changes in sympathoadrenal activity and haemodynamics, induced by 60-min immobilization stress, were studied in conscious rats. Using adrenomedullary microdialysis, it was shown that ranitidine (5 mg/kg, i.v.), a histamine H2 receptor antagonist, selectively suppressed stress-stimulated noradrenaline secretion without affecting adrenaline response, whereas triprolidine (10 mg/kg, i.v.), a histamine H1 receptor antagonist, had little effect on stress-induced secretion of both catecholamines. Neither triprolidine nor ranitidine changed the pressor response to 60-min stress. The stress-induced increase in heart rate was not altered by triprolidine, whereas ranitidine reduced it after 30 min of stress. To test whether the anti-secretory effect of ranitidine could be of peripheral origin, in a separate experimental series, a local catecholamine secretion was stimulated by histamine (0.5 mM) perfused through the adrenomedullary dialysis probe. It appeared that triprolidine, but not ranitidine, reduced this effect of histamine. Thus, the present results suggest that during stress, the activity of the central histaminergic system, via histamine H2-receptors, may selectively modulate noradrenaline secretion by the adrenal gland.