The mechanisms of coenzyme Q10 as therapy for myocardial ischemia reperfusion injury.

It has been hypothesized that CoQ10 (CoQ) pretreatment protects myocardium from ischemia reperfusion (I/R) injury by its ability to increase aerobic energy production as well as its activity as an antioxidant. Isolated hearts from rats pretreated with either CoQ 20 mg/kg i.m. and 10 mg/kg i.p. or vehicle 24 and 2 h prior to the experiment, were subjected to 15 min of equilibration (EQ), 25 min of ischemia, and 40 min of reperfusion (RP). Developed pressure, +/-dp/dt, myocardial oxygen consumption, and myocardial aerobic efficiency (DP/MVO2) were measured. 31P NMR spectroscopy was used to determine ATP and PCr concentrations. Lucigenin-enhanced chemiluminescence of the coronary sinus effluent was utilized to determine oxidative stress through the protocol. CoQ pretreatment improved myocardial function after ischemia reperfusion. CoQ pretreatment improved tolerance to myocardial ischemia reperfusion injury by its ability to increase aerobic energy production, and by preserving myocardial aerobic efficiency during reperfusion. Furthermore, the oxidative burst during RP was diminished with CoQ. Similarly it was hypothesized that CoQ protected coronary vascular reactivity after I/R via an antioxidant mechanism. Utilizing a newly developed lyposomal CoQ preparation given i.v. 15 min prior to ischemia, ischemia reperfusion was carried out on Langendorff apparatus as previously described. Just prior to ischemia and after RP, hearts were challenged with bradykinin (BK) and sodium nitroprusside (SNP) and change in coronary flow was measured. CoQ pretreatment protected endothelial-dependent and endothelial-independent vasodilation after I/R. We conclude that CoQ pretreatment protects coronary vascular reactivity after I/R via OH radical scavenger action.

Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats.

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.

Coenzyme Q10 protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect.

BACKGROUND: Cardiac ischemia reperfusion (I/R) injury causes coronary vascular dysfunction. Coenzyme Q10 (CoQ), which preserves cardiac mechanical function after I/R, recently has been recognized as a free radical scavenger. We hypothesized that CoQ protects coronary vascular reactivity after I/R via an antioxidant mechanism. METHODS: Rats were pretreated with either CoQ (20 mg/kg intramuscular and 10 mg/kg intraperitoneal [CoQ group]) or a vehicle (Control) before the experiment. Isolated perfused rat hearts were subjected to 25 minutes of global normothermic ischemia and 40 minutes of reperfusion. The reperfusion-induced oxidative burst was directly assessed by lucigenin enhanced chemiluminescence. Coronary flow was measured at equilibration and after reperfusion with or without bradykinin, an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator. The effect of intracoronary infusion of hydrogen peroxide (H2O2 0.1 mumol/gm body weight given over 5 minutes), simulating the free radical burst after I/R, also was evaluated. RESULTS: I/R decreased the bradykinin-induced change in coronary flow (-5% +/- 4% versus 26% +/- 3% at equilibration; p < 0.05) and the SNP-induced change (+20% +/- 6% versus +56% +/- 5% at equilibration; p < 0.05). The coronary vasculature after H2O2 infusion revealed a similar loss in vasodilatory responsiveness (+4% +/- 4% in response to bradykinin, +35% +/- 8% in response to SNP; p < 0.05 versus equilibration). Pretreatment with CoQ improved BK-induced vasorelaxation after I/R (+12% +/- 2%; p < 0.05 versus control I/R) or H2O2 infusion (18% +/- 4%; p < 0.05 versus control I/R) but failed to improve SNP-induced vasorelaxation. The CoQ pretreatment decreased the I/R-induced maximal free radical burst (9.3 +/- 0.8 x 10(3) cpm versus 11.5 +/- 1.1 x 10(3) cpm; p < 0.05) during the early period of reperfusion. CONCLUSIONS: Endothelium-dependent vasorelaxation is more sensitive than endothelium-independent relaxation to I/R injury. Via a direct antioxidant effect, CoQ preserved endothelium-dependent vasorelaxation by improving tolerance to I/R injury.