E. Gorodetskaya

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.

Cardioprotection with Intravenous Injection of Coenzyme Q10 is limited by Time of Administration after Onset of Myocardial Infarction in Rats

Objective: Coenzyme Q 10 (CoQ 10 ) levels are decreased in patients with cardiovascular diseases. The bioavailability of orally ingested CoQ 10 is limited to 2–3%, and long-term administration is required to increase the level of CoQ10 in myocardium for cardioprotection. Intravenous (IV) administration of solubilized CoQ10 immediately after coronary occlusion has been shown to increase myocardial levels rapidly and to protect against cardiac ischemia. The aim of this study was to determine the length of time following onset of myocardial infarction (MI) for which a single IV administration of CoQ 10 was cardioprotective. Methods: A single IV injection of solubilized CoQ10 (30 mg/kg, 1 ml/kg) or saline (1 ml/kg) was administered at either minute 60 or minute 180 after the onset of MI induced by coronary artery ligation in rats. Results: Twenty-one days after injection, CoQ 10 levels were still high in both the 60 and 180 minute groups. Rats treated with CoQ10 60 min after ligation had a significantly larger mass of viable left ventricle (LV) myocardium, limited LV dilatation, and improved cardiac contractile and relaxation capacity compared with controls. CoQ10 levels were significantly correlated with LV end-systolic volume (r=-0.65), end-diastolic volume (r=-0.56), ejection fraction (r-=0.67), and LV relaxation (r=-0.64) (p<0.001). IV administration of CoQ 10 180 min after occlusion prevented signs of right ventricle hypertrophy but did not limit LV damage. Conclusion: A single IV injection of solubilized CoQ 10 (30 mg/kg) at minute 60 effectively limited LV damage and deterioration of function after coronary ligation in rats; however, the same protective effects were not seen with CoQ 10 injection administered at minute 180.

Neuroprotective Effectiveness of Intravenous Ubiquinone in Rat Model of Irreversible Cerebral Ischemia

The neuroprotective effect of ubiquinone (coenzyme Q10)was demonstrated on the rats model of ischemic stroke provoked by persistent 24-h occlusion of the middle cerebral artery. Coenzyme Q10 (30 mg/kg) was injected intravenously in 60 min after artery occlusion. Ubiquinone crossed the blood-brain barrier, accumulated in the brain, and produced a neuroprotective effect: it alleviated ischemia-induced neurological deficit and reduced the size of necrotic zone by 49% in comparison with rats receiving physiological saline.

Hplc estimation of coenzyme Q(10) redox status in plasma after intravenous coenzyme Q(10) administration

The pharmacokinetics of the total pool of coenzyme Q(10) (Co(10)), its oxidized (ubiquinone) and reduced (ubiquinol, CoQ(10)H₂) forms have been investigated in rats plasma during 48 h after a single intravenous injection of a solution of solubilized CoQ(10) (10 mg/kg) to rats. Plasma levels of CoQ(10) were determined by HPLC with spectrophotometric and coulometric detection. In plasma samples taken during the first minutes after the CoQ(10) intravenous injection, the total pool of coenzyme Q(10) and proportion of CoQ(10)H₂ remained unchanged during two weeks of storage at -20°C. The kinetic curve of the total pool of coenzyme Q(10) corresponds to a one-part model (R² = 0.9932), while the corresponding curve of its oxidized form fits to the two-part model. During the first minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in the total plasma coenzyme Q(10) content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ(10) by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ(10) into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ(10) for the use in the treatment of acute pathological conditions.

Bioavailability of coenzyme Q10 in various pharmaceutical formulations

The bioavailability of coenzyme Q10(CoQ10) in various pharmaceutical formulations (solutions and tablets) containing solubilized CoQ10 in comparison to lipophilic powder of CoQ10 has been studied in rats. It is established that the bioavailability of solubilized CoQ10 in tablets and solution after peroral administration is higher than that of lipophilic CoQ10 powder. The time to reach peak CoQ10 concentrations in plasma was shorter for the solution of the solubilized form. Auxiliary swelling substances in tablets prolong and increase the absorption of CoQ10.