Mingxiao Hou

Nitric oxide modulates myocardial oxygen consumption in the failing heart.

Background—Endogenous nitric oxide (NO) has been reported to inhibit oxygen consumption in the normal heart, so that nonselective inhibition of NO synthase (NOS) caused an increase of myocardial oxygen consumption (M&OV0312;O2). Although endothelial NOS responses are depressed in congestive heart failure (CHF), inducible NOS (iNOS) may be expressed in failing myocardium. Methods and Results—This study tested the hypothesis that NOS inhibition would increase M&OV0312;O2 in the failing heart. CHF was produced in dogs by use of the rapid ventricular pacing model. In comparison with normal values, animals with CHF had reduced coronary blood flow and M&OV0312;O2 at rest, with a blunted response to treadmill exercise. Selective iNOS inhibition with S-methylisothiourea (1.5 mg/kg IC) increased left ventricular systolic pressure and left ventricular dP/dt and caused an increase in M&OV0312;O2 at rest and during exercise (P <0.05), with a parallel upward shift in the relationship between M&OV0312;O2 and rate-pressure product. In contrast, S-methylisothiourea had no effect on M&OV0312;O2 or coronary flow in normal animals, although nonselective NOS inhibition with NG-nitro-l-arginine did cause an increase of M&OV0312;O2 in normal and in CHF animals. Conclusions—The results indicate that endogenous NO can modulate M&OV0312;O2 in failing hearts, but unlike the normal heart, this NO appears to be produced, at least in part, by iNOS.

NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart.

Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability. This study tested the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in six dogs by ventricular pacing at 240 beats/min for 4 wk. Studies were performed at rest and during treadmill exercise under control conditions and after treatment with the NADPH oxidase inhibitor and antioxidant apocynin (4 mg/kg iv). Apocynin caused no significant changes in heart rate, aortic pressure, left ventricular (LV) systolic pressure, LV end-diastolic pressure, or maximum rate of LV pressure increase at rest or during exercise in normal or CHF dogs. Apocynin caused no change in coronary blood flow (CBF) in normal dogs but increased CBF at rest and during exercise in animals with CHF (P < 0.05). Intracoronary ACh caused dose-dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to ACh in normal dogs but augmented the response to ACh in CHF dogs (P < 0.05). The oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal were significantly greater in failing than in normal myocardium. Furthermore, coelenterazine chemiluminescence for O(2)(-) was more than twice normal in failing myocardium, and this difference was abolished by apocynin. Western blot analysis of myocardial lysates demonstrated that the p47(phox) and p22(phox) subunits of NADPH were significantly increased in the failing hearts, while real-time PCR demonstrated that Nox2 mRNA was significantly increased. The data indicate that increased ROS generation in the failing heart is associated with coronary endothelial dysfunction and suggest that NADPH oxidase may contribute to this abnormality.

Metformin Protects Against Systolic Overload–Induced Heart Failure Independent of AMP-Activated Protein Kinase α2

Activation of AMP-activated protein kinase (AMPK)-&agr;2 protects the heart against pressure overload–induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardioprotection acts independently of an AMPK&agr;2-dependent pathway. Because the role of AMPK&agr;1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPK&agr;1 and AMPK&agr;2 genes on the response to transverse aortic constriction–induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPK&agr;2 gene knockout significantly exacerbated the degree of transverse aortic constriction–induced LV hypertrophy and dysfunction, whereas AMPK&agr;1 gene knockout had no effect on the degree of transverse aortic constriction–induced LV hypertrophy and dysfunction. Administration of metformin was equally effective in attenuating transverse aortic constriction-induced LV remodeling in both wild-type and AMPK&agr;2 knockout mice, as evidenced by reduced LV and lung weights, a preserved LV ejection fraction, and reduced phosphorylation of mammalian target of rapamycin (p-mTORSer2448) and its downstream target p-p70S6KThr389. These data support the notion that activation of AMPK&agr;1 plays a negligible role in protecting the heart against the adverse effects of chronic pressure overload, and that metformin protects against adverse remodeling through a pathway that seems independent of AMPK&agr;2.

Acute effects of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in pacing induced heart failure.

We investigated whether xanthine oxidase inhibition with febuxostat enhances left ventricular (LV) function and improves myocardial high energy phosphates (HEP) in dogs with pacing-induced heart failure (CHF). Febuxostat (2.2 mg/kg over 10 minutes followed by 0.06 mg/kg/min) caused no change of LV function or myocardial oxygen consumption (MVO2) at rest or during treadmill exercise in normal dogs. In dogs with CHF, febuxostat increased LV dP/dtmax at rest and during heavy exercise (P < 0.05), indicating improved LV function with no change of MVO2. Myocardial adenosine triphosphate (ATP) and phosphocreatine (PCr) were examined using 31P nuclear magnetic resonance spectroscopy in the open chest state. In normal dogs, febuxostat increased PCr/ATP during basal conditions and during high workload produced by dobutamine + dopamine (P < 0.05). PCr/ATP was decreased in animals with CHF; in these animals, febuxostat (given after completing basal and high workload measurements with vehicle) tended to increase PCr/ATP during basal conditions with no effect during catecholamine stimulation. Thus, febuxostat improved LV performance in awake dogs with CHF, but caused only a trend toward increased PCr/ATP in the open chest state. It is possible that the antecedent high workload condition prior to drug administration blunted the effect of febuxostat on HEP in the CHF animals. Alternatively, beneficial effects of febuxostat on LV performance in the failing heart may not involve HEP.

ET-A receptor activity restrains coronary blood flow in the failing heart.

Circulating levels of the potent vasoconstrictor peptide endothelin-1 (ET-1) are increased in congestive heart failure (CHF). Coronary blood flow and myocardial oxygen consumption (MVO2) are decreased in some models of CHF. This study tested the hypothesis that ET-1 induced coronary vasoconstriction limits oxygen availability in the failing heart. The effects of selective ET-A receptor blockade with BQ610 (5 μg/min, intracoronary) and selective ET-B receptor blockade with BQ788 (5 μg/min, intracoronary) on coronary blood flow were examined at rest and during graded treadmill exercise in 8 dogs in which congestive heart failure (CHF) had been produced by rapid ventricular pacing for three to four weeks. In animals with CHF, ET-B receptor blockade caused no change in left ventricular (LV) pressure or coronary blood flow. In contrast, ET-A blockade with BQ610 resulted in modest significant increases of coronary blood flow at rest (from 22.4 ± 2.1 to 27.9 ± 3.0 mL/min) and during two exercise stages (from 26.9 ± 2.0 to 30.7 ± 1.9 during stage 1 exercise and from 28.5 ± 2.0 to 31.7 ± 1.3 mL/min during stage 2; all P < 0.05), with an upward shift in the relationship between coronary flow and rate-pressure product. The increase in coronary flow produced by ET-A blockade was not associated with an increase of either myocardial oxygen uptake or LV dP/dt. Thus, although ET-A receptor blockade caused a modest increase in coronary flow, this did not result in an increase of MVO2, implying that ET-A-mediated coronary vasoconstriction did not limit oxygen uptake by the failing heart.