Inhibition of arginase activity enhances inflammation in mice with allergic airway disease, in association with increases in protein S-nitrosylation and tyrosine nitration.

Pulmonary inflammation in asthma is orchestrated by the activity of NF-kappaB. NO and NO synthase (NOS) activity are important modulators of inflammation. The availability of the NOS substrate, l-arginine, is one of the mechanisms that controls the activity of NOS. Arginase also uses l-arginine as its substrate, and arginase-1 expression is highly induced in a murine model of asthma. Because we have previously described that arginase affects NOx content and interferes with the activation of NF-kappaB in lung epithelial cells, the goal of this study was to investigate the impact of arginase inhibition on the bioavailability of NO and the implications for NF-kappaB activation and inflammation in a mouse model of allergic airway disease. Administration of the arginase inhibitor BEC (S-(2-boronoethyl)-l-cysteine) decreased arginase activity and caused alterations in NO homeostasis, which were reflected by increases in S-nitrosylated and nitrated proteins in the lungs from inflamed mice. In contrast to our expectations, BEC enhanced perivascular and peribronchiolar lung inflammation, mucus metaplasia, NF-kappaB DNA binding, and mRNA expression of the NF-kappaB-driven chemokine genes CCL20 and KC, and lead to further increases in airways hyperresponsiveness. These results suggest that inhibition of arginase activity enhanced a variety of parameters relevant to allergic airways disease, possibly by altering NO homeostasis.

Myocardial infarction does not preclude electrical and hemodynamic benefits of cardiac resynchronization therapy in dyssynchronous canine hearts.

BACKGROUND: Several studies suggest that patients with ischemic cardiomyopathy benefit less from cardiac resynchronization therapy. In a novel animal model of dyssynchronous ischemic cardiomyopathy, we investigated the extent to which the presence of infarction influences the short-term efficacy of cardiac resynchronization therapy. METHODS AND RESULTS: Experiments were performed in canine hearts with left bundle branch block (LBBB, n=19) and chronic myocardial infarction, created by embolization of the left anterior descending or left circumflex arteries followed by LBBB (LBBB+left anterior descending infarction [LADi; n=11] and LBBB+left circumflex infarction [LCXi; n=7], respectively). Pacing leads were positioned in the right atrium and right ventricle and at 8 sites on the left ventricular (LV) free wall. LV pump function was measured using the conductance catheter technique, and synchrony of electrical activation was measured using epicardial mapping and ECG. Average and maximal improvement in electric resynchronization and LV pump function by right ventricular+LV pacing was similar in the 3 groups; however, the site of optimal electrical and mechanical benefit was LV apical in LBBB hearts, LV midlateral in LBBB+LCXi hearts and LV basal-lateral in LBBB+LADi hearts. The best site of pacing was not the site of latest electrical activation but that providing the largest shortening of the QRS complex. During single-site LV pacing the range of atrioventricular delays yielding > or =70% of maximal hemodynamic effect was approximately 50% smaller in infarcted than noninfarcted LBBB hearts (P<0.05). CONCLUSIONS: Cardiac resynchronization therapy can improve resynchronization and LV pump function to a similar degree in infarcted and noninfarcted hearts. Optimal lead positioning and timing of LV stimulation, however, require more attention in the infarcted hearts.

Left ventricular septal and left ventricular apical pacing chronically maintain cardiac contractile coordination, pump function and efficiency.

BACKGROUND: Conventional right ventricular (RV) apex pacing can lead to adverse clinical outcome associated with asynchronous activation and reduced left ventricular (LV) pump function. We investigated to what extent alternate RV (septum) and LV (septum, apex) pacing sites improve LV electric activation, mechanics, hemodynamic performance, and efficiency over 4 months of pacing. METHODS AND RESULTS: After AV nodal ablation, mongrel dogs were randomized to receive 16 weeks of VDD pacing at the RV apex, RV septum, LV apex, or LV septum (transventricular septal approach). Electric activation maps (combined epicardial contact and endocardial noncontact) showed that RV apical and RV septal pacing induced significantly greater electric desynchronization than LV apical and LV septal pacing. RV apex and RV septal pacing also significantly increased mechanical dyssynchrony, discoordination (MRI tagging) and blood flow redistribution (microspheres) and reduced LV contractility, relaxation, and myocardial efficiency (stroke work/myocardial oxygen consumption). In contrast, LV apical and LV septal pacing did not significantly alter these parameters as compared with the values during intrinsic conduction. At 16 weeks, acute intrasubject comparison showed that single-site LV apical and LV septal pacing generally resulted in similar or better contractility, relaxation, and efficiency as compared with acute biventricular pacing. CONCLUSIONS: Acute and chronic LV apical and LV septal pacing maintain regional cardiac mechanics, contractility, relaxation, and efficiency near native levels, whereas RV apical or RV septal pacing diminish these variables. Acute LV apical and LV septal pacing tend to maintain or improve contractility and efficiency compared with biventricular pacing.