Dietary coenzyme Q10 supplementation alters platelet size and inhibits human vitronectin (CD51/CD61) receptor expression.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10, ubiquinone). Several mechanisms have been proposed to explain the effects of CoQ10, but a comprehensive explanation of its cardioprotective properties is still lacking. One attractive theory links ubiquinone with the inhibition of platelets. The effect of CoQ10 intake on platelet size and surface antigens was examined in human volunteers. Study participants received 100 mg of CoQ10 twice daily in addition to their usual diet for 20 days. Receptor expression was measured by flow cytometry with monoclonal murine anti-human antibodies CD9 (p24), CD42B (Ib), CD41b (IIb), CD61 (IIIa), CD41a (IIb/IIIa), CD49b (VLA-2), CD62p (P selectin), CD31 (PECAM-1), and CD51/CD61 (vitronectin). An increase of total serum CoQ10 level (from 0.6 +/- 0.1 to 1.8 +/- 0.3 micrograms/ml; p < 0.001) was found at protocol termination. Fluorescence intensity was higher for the large platelets when compared with the whole platelet population. Significant inhibition of vitronectin-receptor expression was observed consistently throughout ubiquinone treatment. Reduction of platelet size was observed at the end of CoQ10 supplementation. Inhibition of the platelet vitronectin receptor and a reduction of the platelet size are direct evidence of a link between dietary CoQ10 intake and platelets. These findings may not be fully explained by the known antioxidant and bioenergetic properties of CoQ10. Diminished vitronectin-receptor expression and reduced platelet size resulting from CoQ10 therapy may contribute to the observed clinical benefits in patients with cardiovascular diseases.

Could coenzyme Q10 affect hemostasis by inhibiting platelet vitronectin (CD51/CD61) receptor?

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10, ubiquinone). Several mechanisms have been proposed to explain the effects of CoQ10. One attractive theory links ubiquinone with the inhibition of platelets. The effect of CoQ10 intake on platelet surface antigens, and certain hemostatic parameters was examined in 15 humans and 10 swine. Study participants received 100 mg of CoQ10 twice daily in addition to their usual diet for 20 days resulting in a three-fold increase of total serum CoQ10 level. We observed a decline in plasma fibronectin (-20.2%), thromboxane B2 (-20.6%), prostacyclin (-23.2%), and endothelin-1 (-17.9%) level. Significant inhibition of vitronectin receptor expression was observed consistently throughout ubiquinone treatment. Inhibition of the platelet vitronectin receptor is a direct evidence of a link between dietary CoQ10 intake, platelets, and hemostasis. These findings may contribute to the observed clinical benefits by a diminished incidence of thrombotic complications in such patients.

Hemostatic changes after early versus late intracoronary magnesium during acute myocardial infarction in swine.

There has been some debate regarding the benefit of magnesium (Mg) in the treatment of acute myocardial infarction (AMI) because of conflicting results from recent clinical trials. Several different hypotheses have been advanced to explain the cardioprotective properties of Mg, including the influence of the timing of Mg administration during AMI. This experiment was designed to assess the effect of intracoronary Mg on certain hemostatic parameters that are known to change during an AMI. Yorkshire swine underwent thoracotomy and 50 min left anterior descending artery (LAD) occlusion, followed by 3 h of reperfusion. In the early group, 250 mg of MgSO4 was delivered at the onset of reperfusion (n = 6, Mg-early group). In the second group, MgSO4 was given after 1 h of reperfusion (n = 6, Mg-late group). Six animals received saline instead of Mg and served as controls. The dynamics of plasma antithrombin-III (AT-III), protein C, total protein S, fibronectin, endothelin-1 (ET-1), as well as the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGFla) were determined at baseline, twice during occlusion, and three times during reperfusion. Mg given at reperfusion onset was associated with a diminished ET-1 (32.9%), decreased fibronectin level (21.7-25.2%), and increased protein C concentrations (31.9-52.3%) when compared with both the control and late Mg group. In summary, intracoronary Mg administered at the onset of reperfusion favorably influenced hemostasis in swine. The beneficial effects of early Mg supplementation in an expanding array of clinical conditions, including AMI, may be directly related to the improved hemostatic profile in such patients.

Changes in the haemostatic profile during magnesium deficiency in swine.

Epidemiological studies of populations living in areas of low magnesium (Mg) intake have consistently shown a higher cardiovascular morbidity. Several hypotheses have been advanced to explain the cardioprotective properties of magnesium. Few studies, however, have analysed the relation of magnesium to haemostasis. The overall purpose of this project was to assess the association between certain haemostatic variables and magnesium deficiency. This experiment was designed to assess the effect of magnesium deficiency on various haemostatic variables which may relate to cardiovascular morbidity. Twelve female Yorkshire swine were fed for seven weeks on an Mg-sufficient or an Mg-deficient diet. Blood samples were obtained at baseline and after the termination of feeding in order to evaluate platelet aggregability and concentrations of antithrombin-III (AT-III), protein C, total protein S, fibronectin, endothelin-1 (ET-1), as well as the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha). In animals on an Mg-sufficient diet, there were no significant differences in any of the investigated haemostatic variables. In the Mg-deficient group, a significant decrease in serum magnesium was noted after the feeding period (from 2.0 +/- 0.1 to 1.3 +/- 0.1; P < 0.01). Mg-deficient swine showed significant increases in ADP-induced (33.3 per cent and 59.6 per cent) and collagen-induced (36.6 per cent) platelet aggregation, and decreased plasma antithrombin-III (17.7 per cent) and protein S (14.4 per cent) when compared to baseline. Plasma concentrations of TxB2 (28.7 per cent), protein C (57.2 per cent), and ET-1 (74.9 per cent) were dramatically increased. There were no significant differences in plasma fibronectin and 6-keto-PGF1 alpha levels in the magnesium-depleted animals. We conclude that magnesium deficiency is associated with significant proaggregatory and coagulation alterations. This may contribute to the increased cardiovascular morbidity found in magnesium-deficient populations. The beneficial effects of magnesium supplementation in an expanding array of clinical conditions including cardiovascular disease may, in part, be related to the improved haemostatic profile in such patients.

Hemostatic changes after dietary coenzyme Q10 supplementation in swine.

Improved cardiovascular morbidity and mortality have been observed in several clinical studies of dietary supplementation with coenzyme Q10 (CoQ10). We elucidated the effect of CoQ10 on certain hemostatic parameters that may influence the progression of heart disease. Twelve Yorkshire swine were randomized to receive diet supplementation with either CoQ10 or placebo for 20 days. Blood samples were obtained at baseline and at the end of the feeding period. At the end of the protocol, there were no significant differences in hemostatic parameters in the placebo group. A significant increase in total serum CoQ10 level (from 0.39 +/- 0.06 to 0.96 +/- 0.04 microgram/ml, p < 0.001) was noted after the feeding period in the CoQ10-supplemented group. We observed significant inhibition of ADP-induced platelet aggregation (-9.9%) and a decrease in plasma fibronectin (-20.2%), thromboxane B2 (TXB2, -20.6%), prostacyclin (-23.2%), and endothelin-1 (ET-1, -17.9%) level. There were no changes in the plasma concentrations of the natural antithrombotics [antithrombin-III (AT-III), protein S, and protein C] after CoQ10 supplementation. CoQ10 supplementation in a dose of 200 mg daily is associated with mild antiaggregatory changes in the hemostatic profile. Clinical beneficial effects of CoQ10 may be related in part to a diminished incidence of thrombotic complications.

Mac-1 inhibitor affects certain hemostatic parameters during myocardial stunning in swine.

Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.

Effects of magnesium supplementation in a porcine model of myocardial ischemia and reperfusion.

We tested the hypothesis that acute, intravenous (i.v.) magnesium (Mg2+) supplementation would protect against myocardial stunning in an in situ swine model of regional ischemia and reperfusion and that a concomitant inhibitory effect on platelet aggregation would be elicited. An open-chest model was used, with transient occlusion of the left anterior descending coronary artery (LAD) for 8 min. Regional contractile function was assessed by measuring wall thickening fraction with epicardial Doppler crystals. One control group (n = 6) and two treatment groups were studied: group I (n = 6) received 750 mg MgSO4 before occlusion; group II (n = 6) received 1 g MgSO4 after the occlusion. Both protocols produced significant hypermagnesemia. In group I, platelet aggregation was measured before and after Mg2+ treatment using platelet-rich plasma (PRP) and various agonists (ADP 5 and 10 mM and collagen 1 mg/ml). As compared with controls, both treatment groups experienced significantly less postischemic dysfunction, with systolic function returning more quickly to baseline. Furthermore, platelet aggregation was significantly decreased immediately after Mg2+ infusion. Inhibition of platelet aggregation induced by Mg2+ treatment occurs concomitantly with significant amelioration of postischemic myocardial dysfunction.

Effect of magnesium sulphate infusion on ex vivo platelet aggregation in swine.

The effect of magnesium sulphate infusion on ex vivo platelet aggregation in 11 female Yorkshire swine was observed using platelet-rich plasma and different agonists (ADP 5 mM; ADP 10 mM and collagen 1 mg/ml). Infusion of 1 g MgSO4 over 1 h produced a significant decrease in platelet aggregability. A dose-dependent effect of different ADP concentrations on platelet aggregation was noticed. Platelet inhibition was most consistent when using ADP 5 mM. We estimate this concentration of agonist as optimal in swine. The swine model is a good choice for investigation of in vivo platelet activation, especially with regard to cardiovascular research. We conclude that there is an inhibitory effect of supplemental magnesium on ex vivo platelet aggregation in swine with initial normomagnesaemia.

Coenzyme Q10 protects ischemic myocardium in an open-chest swine model.

Myocardial stunning, defined as a reversible decrease in contractility after ischemia and reperfusion, may be a manifestation of reperfusion injury caused by free oxygen radical damage. The aim of this study was to test the hypothesis that pretreatment with coenzyme Q10 (ubiquinone), believed to act as a free radical scavenger, reduces myocardial stunning in a porcine model. Twelve swine were randomized to receive either oral supplementation with coenzyme Q10 or placebo for 20 days. A normothermic open-chest model was used with short occlusion (8 min) of the distal left descending coronary artery followed by reperfusion. Regional contractile function was measured with epicardial Doppler crystals in ischemic and nonischemic segments by measuring thickening fraction of the left ventricular wall during systole. Stunning time was defined as the elapsed time of reduced contractility until return to baseline. Coenzyme Q10 concentrations were measured in blood and homogenized myocardial tissue by high performance liquid chromatography. Plasma levels of reduced coenzyme Q10 (ubiquinol) were higher in swine pretreated with the experimental medication as compared to placebo (mean 0.45 mg/l versus 0.11 mg/l, respectively). Myocardial tissue concentrations, however, did not show any changes (mean 0.79 micrograms/mg dry weight versus 0.74 micrograms/mg). Stunning time was significantly reduced in coenzyme Q10 pretreated animals (13.7 +/- 7.7 min versus 32.8 +/- 3.1 min, P < 0.01). In conclusion, chronic pretreatment with coenzyme Q10 protects ischemic myocardium in an open-chest swine model. The beneficial effect of coenzyme Q10 on myocardial stunning may be due to protection from free radical mediated reperfusion injury. This protective effect seems to be generated by a humoral rather than intracellular mechanism.