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Deficiency of iNOS does not attenuate severe congestive heart failure in mice

¹Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and ²Department of Molecular and Cellular Physiology, ³Department of Surgery, and ⁴Division of Cardiology, Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and ⁵The Whitaker Cardiovascular Institute, Boston University Medical Center, Boston, Massachusetts

Submitted 11 March 2004 ; accepted in final form 19 August 2004

	ABSTRACT

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Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS^–/–) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type (n = 17), sham iNOS^–/– (n = 8), MI wild-type (n = 56), and MI iNOS^–/– (n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 ± 2.0% and 441 ± 20 µl·min^–1·g^–1) and iNOS^–/– (9.8 ± 1.3% and 471 ± 26 µl·min^–1·g^–1) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS^–/– mice. None of the indexes demonstrated any significant differences between iNOS^–/– and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.

myocardial infarction; nitric oxide; physiology; inducible nitric oxide synthase

One potential contributor to the progression of CHF is nitric oxide (NO) derived from the inducible form of NO synthase (iNOS). Since its identification as an endothelium-derived relaxing factor (EDRF) in 1980 (11), NO has been implicated in numerous pathological sequelae as both a beneficial and deleterious moiety. NO is constitutively synthesized at low levels by the vascular endothelium (endothelial NOS) with the general effect of maintaining vascular homeostasis (15). However, iNOS-derived NO has specifically been implicated as a contributor to the development of heart failure (6, 20, 22). Indeed, biopsies from human hearts with dilated cardiomyopathy (4, 5, 13) and ischemic cardiomyopathy (13) demonstrate robust iNOS expression. The upregulation of iNOS in heart failure is thought to contribute to the pathophysiology of CHF, and iNOS upregulation is thought to be the result of the generation of several proinflammatory cytokines such as tumor necrosis factor-, interleukin-1, and interferon- (10). These inflammatory cytokines impair vascular endothelial function and exacerbate the pathophysiology of CHF by limiting coronary blood flow. It has been suggested that overproduction of NO by iNOS during CHF aggravates the severity of CHF (6–8). However, the potential pathological targets of iNOS in CHF are numerous.

We hypothesized that genetic ablation of iNOS would attenuate the severity of CHF and improve survival in mice. We subjected iNOS-deficient (iNOS^–/–) mice to CHF and assessed CHF pathophysiology in terms of ventricular morphology, cardiac function, and survival to ascertain the role of iNOS in severe CHF.

	METHODS

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Mice. Male, C57BL/6 (wild type, n = 73) and iNOS^–/– (n = 56) mice were purchased from Jackson Laboratory (Bar Harbor, ME). The wild-type mice were randomized to sham occlusion (n = 17) of the coronary artery or permanent occlusion (n = 56) of the coronary artery. The iNOS^–/– mice were also randomized to sham (n = 8) or permanent occlusion (n = 48) of the coronary artery. Mice were entered into the CHF protocol at 3 mo of age. The individual performing the experiments was blinded to the mouse genotype until all data analyses were completed.

All experimental procedures complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 86-23, Revised 1985), approved by the Council of the American Physiological Society, and with federal and state regulations. All experimental procedures were approved by the Louisiana State University Medical Center Animal Care and Use Committee.

Myocardial infarction protocol. Ligation of the left anterior descending coronary artery (LAD) was performed as described previously (16, 17). Mice were anesthetized with intraperitoneal injections of ketamine (50 mg/kg) and pentobarbital sodium (50 mg/kg). Body temperature was maintained at 37°C using a rectal thermometer and infrared heating lamp. With the use of direct visualization through a fiber-optic ring light, the mice were orally intubated with polyethylene-90 tubing and connected via loose junction to a rodent ventilator (model 683, Harvard Apparatus). The ventilator was set at a tidal volume of 1.5 ml and a rate of 120 breaths/min and supplemented with 100% oxygen. A median sternotomy was performed, and the proximal left anterior descending (LAD) coronary artery was visualized and ligated with a 7-0 silk suture mounted on a tapered needle (BV-1, Ethicon). The LAD coronary artery was ligated at a proximal location under the left atrial appendage. Ischemia was confirmed by the appearance of hypokinesis, pallor distal to the occlusion, and depressed fractional shortening according to echocardiography. The occlusion remained intact throughout the 4-wk protocol. In several experiments, ischemia was also confirmed by profound electrocardiographic changes (e.g., ST segment elevation). The chest wall was closed, and the mice were given subcutaneous butorphanol tartrate (0.1 mg/kg) and were allowed to recover in a temperature-controlled area. Butorphanol tartrate (0.1 mg/kg sc) was administered every 12 h for 3 days after the acute myocardial infarction (MI) procedure.

Assessment of iNOS protein. Wild-type and iNOS^–/– mice (n = 3 mice/group) were subjected to the MI protocol. Three days after coronary ligation, hearts were harvested, rinsed, and snap frozen in liquid nitrogen. Whole hearts were homogenized, and proteins were extracted. Western blot analysis was performed according to conventional protocols. Briefly, 50 µg of total protein were loaded per sample. Even loading and transfer were confirmed by Ponceau and Coomassie stains. Primary iNOS antibody was used at a concentration of 1:4,000. Membranes were exposed to chemiluminescent (ECL) reagents, documented on ECL film, and scanned into a personal computer.

Evaluation of arterial and left ventricular hemodynamics. To assess the closed-chest hemodynamic status, a 1.4-Fr Millar (SPR-671, Millar; Houston, TX) pressure transduction catheter was inserted similar to methods described previously (16, 18). Mice were anesthetized with ketamine (50 mg/kg ip) and pentobarbital (50 mg/kg ip) and supplemented with oxygen via a nasal cone. The right common carotid artery was isolated, the catheter was inserted, and the catheter was advanced to the aorta. Approximately 10 s of data were recorded. Off-line assessment of these data yielded systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and heart rate.

The catheter was then advanced through the aortic valve into the left ventricle (LV). Approximately 10 s of data were recorded. Subsequent off-line evaluation provided LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), LV developed pressure, and the first derivative of the LV pressure curve (minimum and maximum dP/dt). Data for each animal were calculated from at least 10 s of chart recording (arithmetic mean).

Echocardiographic assessment of LV function. In vivo transthoracic echocardiography of the LV using a 15-MHz linear array transducer (15L8) interfaced with a Sequoia C256 (Acuson) was performed as described previously (16). The cardiac output values were corrected for the animals' weights (in µl·min^–1·g^–1). All data were calculated from 10 independent cardiac cycles/experiment.

Pulmonary edema. Accumulation of pulmonary fluid was assessed by weighing the (wet) lungs from mice subjected to MI (or sham). The lungs were then placed in a drying oven (Econotherm Laboratory Oven, Precision) for 7 days at 40°C. The lungs were weighed, and the dry weights were recorded. The difference between the wet and dry weights yielded the pulmonary fluid accumulation values.

Statistical analyses. Data were analyzed by Student's unpaired t-test or ANOVA with post hoc analysis (Bonferroni) using StatView (SAS Institute; Cary, NC) software. Data are reported as means ± SE with differences accepted as significant when P < 0.05.

	RESULTS

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Myocardial infact size in wild-type and iNOS^–/– mice. In a separate group of mice (n = 8 mice/group), myocardial infarct size was determined at 24 h after permanent proximal coronary artery ligation (Fig. 1). The area at risk per LV was similar [P = not significant (NS)] in the wild-type (48.0 ± 2.2%) and iNOS^–/– mice (50.8 ± 1.9%). The infarct size per LV was 41.5 ± 2.2% in the wild-type group and 42.7 ± 1.5% in the iNOS^–/– group (P = NS between groups). Finally, infarct size per area at risk was 86.5 ± 1.4% in wild-type mice and 84.5 ± 1.1% in the iNOS^–/– mice (P = NS between groups).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Myocardial infarct size at 24 h after permanent ligation of the proximal left anterior descending (LAD) coronary artery in wild-type (WT; n = 8) and inducible nitric oxide synthase-deficient (iNOS–/–; n = 8) mice. The area at risk (AAR) per left ventricle (LV) was similar in both study groups. Permanent LAD ligation resulted in a large area of infarction (INF) per AAR and infarct size per LV. No significant differences were observed between the study groups. Numbers per group are indicated within each bar. NS, not significant.

View larger version (24K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier survival curve for WT and iNOS–/– mice subjected to sham or permanent occlusion [myocardial infarction (MI)] of the LAD coronary artery for up to 1 mo. Ligation of the LAD coronary artery induced significant mortality (P < 0.01) in WT and iNOS–/– mice compared with sham groups. However, there was no significant (P = NS) difference in mortality between WT and iNOS–/– mice. Inset: representative (n = 3 mice/group) Western blot analysis of cardiac protein isolates from WT and iNOS–/– mice 3 days after coronary occlusion. Expression of iNOS is evident in WT hearts but not in iNOS–/– hearts.

Hemodynamics during CHF. Systemic and ventricular hemodynamics were measured after 1 mo of coronary artery occlusion (Table 1). Systemic hemodynamics were not significantly (P = NS) different among the sham groups, wild-type, and iNOS^–/– mice subjected to the CHF protocol. Although LVSP was not significantly different among the three experimental groups, LVEDP was significantly (P < 0.05) higher in the wild-type and iNOS^–/– hearts compared with sham hearts. In addition, LV developed pressure was significantly (P < 0.05) lower in the wild-type and iNOS^–/– hearts compared with sham hearts.

View larger version (18K): [in this window] [in a new window]   Fig. 3. A: cardiac hypertrophy as evidenced by heart-to-body weight ratios. WT and iNOS–/– mice exhibited significant (**P < 0.01) increases in cardiac hypertrophy compared with sham mice after 1 mo of LAD occlusion (MI). However, there was no significant (P = NS) difference in hypertrophy between the WT and iNOS–/– hearts. B: echocardiographic assessment of LV chamber dimensions in sham WT, sham iNOS–/–, MI WT, and MI iNOS–/– hearts after 1 mo of MI. LV end-diastolic and systolic diameters were significantly (**P < 0.01) greater in MI WT and MI iNOS–/– mice compared with sham groups. WT and iNOS–/– dimensions were not significantly (P = NS) different from one another. C: fractional shortening was also significantly (**P < 0.01) diminished in MI WT and MI iNOS–/– mice compared with sham groups. Fractional shortening was not significantly (P = NS) different between WT and iNOS–/– mice.

Cardiac performance during heart failure. MI and the resultant heart failure produced profound cardiac dysfunction in terms of LV dP/dt and cardiac output. With the use of in vivo cardiac catheterization, LV dP/dt measurements were obtained as an index of cardiac performance (Fig. 4). Maximum positive dP/dt was significantly (P < 0.05) attenuated in wild-type (3,850 ± 451 mmHg/s) and iNOS^–/– (3,983 ± 519 mmHg/s) hearts after 1 mo of coronary occlusion compared with sham (6,664 ± 619 mmHg/s) hearts. Similarly, minimum dP/dt was significantly blunted in wild-type (–3,770 ± 486 mmHg/s) and iNOS^–/– (–3,917 ± 724 mmHg/s) mouse hearts compared with sham (–6,864 ± 700 mmHg/s) hearts. Neither maximum nor minimum dP/dt were significantly different between wild-type and iNOS^–/– hearts.

View larger version (19K): [in this window] [in a new window]   Fig. 4. Maximum (+) and minimum (–) first derivatives of LV pressure (dP/dt) were assessed in sham, MI WT, and MI iNOS–/– mice after 4 wk of congestive heart failure. Although +dP/dt and –dP/dt were significantly (*P < 0.05) attenuated in both groups of mice subjected to MI compared with sham, there was no statistically significant difference between the WT and iNOS–/– values.

View larger version (17K): [in this window] [in a new window]   Fig. 5. Cardiac output was measured using in vivo Doppler mode echocardiography. Occlusion of the LAD coronary artery produced a significant (*P < 0.05) deficit in cardiac output in WT mice subjected to MI compared with sham mice, but no difference was apparent between MI WT and MI iNOS–/– mice.

View larger version (17K): [in this window] [in a new window]   Fig. 6. Pulmonary edema was measured by fluid accumulation in the lungs of sham wild-type (WT), sham iNOS–/–, MI WT, and MI iNOS–/– mice after 4 wk of congestive heart failure. The WT and iNOS–/– lungs exhibited increased pulmonary fluid accumulation (*P < 0.05 vs. sham groups). Deficiency of iNOS did not significantly (P = NS) affect pulmonary edema compared with WT mice.

	DISCUSSION

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Numerous studies have demonstrated the presence and/or activity of iNOS in various forms of heart failure. However, the association between enhanced iNOS-derived NO production and CHF may merely have been the demonstration of a coincidental phenomenon. It is possible that iNOS becomes upregulated during CHF as a compensatory response to alterations in peripheral vascular resistance and/or tissue perfusion. Considering evidence suggesting iNOS is constitutively expressed during fetal life (1, 2), the myocardium may revert to a fetal gene program during heart failure and the iNOS gene may be upregulated merely as a consequence.

In a recent study (19), mice with targeted overexpression of iNOS exhibited a phenotype supportive of the idea that iNOS exerts negative cardiac contractile effects. In this study (19), overexpression of iNOS (without infarction) caused increased mortality, cell death, and conduction disturbances. Although this study provides support for the idea that iNOS exerts injurious cardiac effects, another (nearly simultaneous) study published by Heger et al. (14) found no significant negative effects in terms of cardiac function in iNOS-overexpressing mouse hearts. It is possible that there were significant differences in the amount of NO being produced in the two lines of transgenic mice. In addition, the transgenic system or locus of integration into the genome may also have influenced the deleterious effects of iNOS overexpression in the Mungrue et al. (19) study. Nevertheless, our present findings coupled with those Heger and co-workers (14) cast serious doubt on the obligate role of iNOS-derived NO in the pathogenesis of cardiac dysfunction and heart failure. The Schrader laboratory subsequently performed additional informative studies with iNOS-overexpressing mice (12, 24). These studies revealed that myoglobin acts as a physiological barrier against the potential pathological effects of excessive iNOS production. Such studies provide additional support against the idea that iNOS-derived NO has the capacity to exert deleterious effects on cardiac function.

Although difficult to directly compare with our study, data regarding the potential protective effects of NOS inhibition in acute cardiogenic shock have been presented by Cotter et al. (3). Unlike our present study, such studies by Cotter et al. (3) involved small human populations with varied genetic/risk factor backgrounds. More problematic is the use of the pan-NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME). Because L-NAME can inhibit all NOS isoforms, any results would be difficult to interpret. Previous murine studies of infarct-induced heart failure found the loss (23) of endothelial NOS to exacerbate CHF and the overexpression (16) of endothelial NOS to improve CHF outcomes. On the basis of these studies, we would hypothesize that the use of L-NAME in our model would exacerbate the extent of heart failure. However, the data would be difficult to evaluate because of the lack of selectivity of L-NAME for a particular NOS isoform coupled with the potentially divergent roles of inducible and endothelial NOS isoforms.

More relevant to our present study, Feng et al. (9) subjected iNOS^–/– mice to coronary artery occlusion for 1 mo and found protective effects compared with wild-type mice. Interestingly, the authors demonstrated improved contractile function and survival in the iNOS^–/– mice (9). Such findings lend credence to the idea of iNOS (and excess NO production) as a negative modulator of contractile function during heart failure. Another study (21) of iNOS^–/– mice in heart failure did not find any significant differences between iNOS^–/– and wild-type mice at 1 mo postinfarction. However, the same authors (21) observed significant improvement in ventricular function and survival in iNOS^–/– mice at 4 mo after coronary artery ligation compared with wild-type mice. The percentage of mice surviving in the present study at 1 mo is about 32% compared with 75% reported by Sam et al. (21) in the previous study. Furthermore, the infarct size per LV is 42% in the present study in both wild-type and iNOS^–/– mice compared with about 30% in the study by Sam et al. (21). Thus our model of CHF is much more severe (35–50% larger infarcts) than that of the other authors (21). The fact that our model of CHF is more severe than that previously reported with iNOS^–/– mice may help to reconcile the differences that were observed. That is, our findings provide solid evidence that iNOS is not involved in the pathogenesis of severe, acute CHF, whereas Sam et al. (21) demonstrated the deleterious consequences of iNOS in a more moderate infarct-induced heart failure model. Although the present model induces severe heart failure in mice, we have recently demonstrated that it is indeed possible to observe significant improvements in survival in this model of CHF (16). In this regard, transgenic mice that overexpress endothelial NOS within the endothelium are protected against CHF after acute MI. Thus the contention that our model is too severe to observe improvements is invalid.

As with any experimental study in laboratory animals, study limitations exist. The populations used in the present study do not have the characteristics of human patients at risk of developing heart failure. The mice used are healthy, adult (not old) mice without any of the known risk factors for heart disease. Future studies should incorporate the investigation of animal models exhibiting clinically relevant risk factors. Also, the use of anesthesia may also affect the interpretation of the results. Specifically, anesthesia may negatively affect cardiac function and make subtle differences difficult to document.

Severe, acute MI without reperfusion induces profound cardiac dysfunction and decompensated CHF. Despite the preponderance of evidence suggesting the contrary, ablation of iNOS does not affect the extent of severe CHF in the present model. It is possible that iNOS is involved in models of moderate CHF, but the present findings certainly cast doubt on the causative role of iNOS in severe CHF.

	GRANTS

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This study was funded by National Institutes of Health Grants RO1 HL-60849 and PO1 DK-43785 (to D. J. Lefer).

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. J. Lefer, Dept. of Molecular and Cellular Physiology, Louisiana State Univ. Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 (dlefer{at}lsuhsc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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1. Bloch W, Fleischmann BK, Lorke DE, Andressen C, Hops B, Hescheler J, and Addicks K. Nitric oxide synthase expression and role during cardiomyogenesis. Cardiovascular Research 43: 675–684, 1999.[Abstract/Free Full Text]
2. Brahmajothi MV and Campbell DL. Heterogeneous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart: implications for mechanisms governing indirect and direct nitric oxide-related effects. Circ Res 85: 575–587, 1999.[Abstract/Free Full Text]
3. Cotter G, Kaluski E, Milo O, Blatt A, Salah A, Hendler A, Krakover R, Golick A, and Vered Z. LINCS: L-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock: a prospective randomized study. Eur Heart J 24: 1287–1295, 2003.[Abstract/Free Full Text]
4. De Belder AJ, Radomski MW, Why HJ, Richardson PJ, Bucknall CA, Salas E, Martin JF, and Moncada S. Nitric oxide synthase activities in human myocardium. Lancet 341: 84–85, 1993.[CrossRef][Web of Science][Medline]
5. De Belder AJ, Radomski MW, Why HJ, Richardson PJ, and Martin JF. Myocardial calcium-independent nitric oxide synthase activity is present in dilated cardiomyopathy, myocarditis, and postpartum cardiomyopathy but not in ischaemic or valvar heart disease. Br Heart J 74: 426–430, 1995.[Abstract/Free Full Text]
6. Drexler H. Nitric oxide synthases in the failing human heart: a double-edged sword? Circulation 99: 2972–2975, 1999.[Free Full Text]
7. Drexler H and Hornig B. Importance of endothelial function in chronic heart failure. J Cardiovasc Pharmacol 27: S9–12, 1996.
8. Fang ZY and Marwick TH. Vascular dysfunction and heart failure: epiphenomenon or etiologic agent? Am Heart J 143: 383–390, 2002.[CrossRef][Web of Science][Medline]
9. Feng Q, Lu X, Jones DL, Shen J, and Arnold JMO. Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104: 700–704, 2001.[Abstract/Free Full Text]
10. Ferdinandy P, Danial H, Ambrus I, Rothery RA, and Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87: 241–247, 2000.[Abstract/Free Full Text]
11. Furchgott RF and Zawadzki JV. The obligatory role of endothelial cells on the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373–376, 1980.[CrossRef][Medline]
12. Godecke A, Molojavyi A, Heger J, Flogel U, Ding Z, Jacoby C, and Schrader J. Myoglobin protects the heart from inducible nitric-oxide synthase (iNOS)-mediated nitrosative stress. J Biol Chem 278: 21761–21766, 2003.[Abstract/Free Full Text]
13. Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, Lewis NP, Byrne CD, Rickenbacher PR, Bishopric NH, Cooke JP, McKenna WJ, and Fowler MB. Expression of inducible nitric oxide synthase in human heart failure. Circulation 93: 1087–1094, 1996.[Abstract/Free Full Text]
14. Heger J, Godecke A, Flogel U, Merx MW, Molojavyi A, Kuhn-Velten WN, and Schrader J. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 90: 93–99, 2002.[Abstract/Free Full Text]
15. Ignarro LJ. Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res 65: 1–21, 1989.[Free Full Text]
16. Jones SP, Greer JJM, van Haperen R, Duncker DJ, de Crom R, and Lefer DJ. Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci USA 100: 4891–4896, 2003.[Abstract/Free Full Text]
17. Jones SP, Trocha SD, and Lefer DJ. Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol 21: 2059–2064, 2001.[Abstract/Free Full Text]
18. Lorenz JN and Robbins J. Measurement of intraventricular pressure and cardiac performance in the intact closed-chest anesthetized mouse. Am J Physiol Heart Circ Physiol 272: H1137–H1146, 1997.[Abstract/Free Full Text]
19. Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ, and Husain M. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109: 735–743, 2002.[CrossRef][Web of Science][Medline]
20. Paulus WJ, Frantz S, and Kelly RA. Nitric oxide and cardiac contractility in human heart failure: time for reappraisal. Circulation 104: 2260–2262, 2001.[Free Full Text]
21. Sam F, Sawyer DB, Xie Z, Chang DLF, Ngoy S, Brenner DA, Siwik DA, Singh K, Apstein CS, and Colucci WS. Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res 89: 351–356, 2001.[Abstract/Free Full Text]
22. Sawyer DB and Colucci WS. Nitric oxide in the failing myocardium. Cardiol Clinics 16: 657–664, 1998.[CrossRef][Medline]
23. Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT, Lindsey ML, Vancon AC, Huang PL, Lee RT, Zapol WM, and Picard MH. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 104: 1286–1291, 2001.[Abstract/Free Full Text]
24. Wunderlich C, Flogel U, Godecke A, Heger J, and Schrader J. Acute inhibition of myoglobin impairs contractility and energy state of iNOS-overexpressing hearts. Circ Res 92: 1352–1358, 2003.[Abstract/Free Full Text]

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