This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hare, J. M. Articles by Colucci, W. S. Search for Related Content PubMed PubMed Citation Articles by Hare, J. M. Articles by Colucci, W. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

(Circulation. 1998;97:161-166.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Increased Sensitivity to Nitric Oxide Synthase Inhibition in Patients With Heart Failure

Potentiation of ß-Adrenergic Inotropic Responsiveness

Joshua M. Hare, MD; Michael M. Givertz, MD; Mark A. Creager, MD; ; Wilson S. Colucci, MD

From the Cardiomyopathy Programs and Cardiovascular Divisions, Boston Medical Center, Boston, Mass (M.M.G., W.S.C.); Johns Hopkins Medical Institutions, Baltimore, Md (J.M.H.); Brigham and Women's Hospital, Boston, Mass (M.M.G., W.S.C.); Boston University School of Medicine, Boston, Mass (M.A.C.); Johns Hopkins School of Medicine, Baltimore, Md (J.M.H.); and Harvard Medical School, Boston, Mass (M.A.C.).

Correspondence to Wilson S. Colucci, MD, Cardiomyopathy Program, Boston Medical Center, 88 E Newton St, Boston, MA 02118. E-mail wcolucci{at}acs.bu.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—We previously showed that cardiac nitric oxide (NO) inhibits the positive inotropic response to ß-adrenergic stimulation in humans with left ventricular (LV) dysfunction. Whether this effect is specific to heart failure per se or is a generalized feature of normal human myocardium is unknown. We therefore tested the hypothesis that inhibition of cardiac NO potentiates the positive inotropic response to ß-adrenergic stimulation in patients with symptomatic LV failure but not in subjects with normal LV function.

Methods and Results—We studied 11 patients with LV failure due to idiopathic dilated cardiomyopathy and 7 control subjects with normal LV function. The ß-adrenergic agonist dobutamine was infused via a peripheral vein before and during concurrent intracoronary artery infusion of acetylcholine, which activates the agonist-coupled isoforms of NO synthase, and N^G-monomethyl-L-arginine, which inhibits all isoforms of NO synthase. Changes in contractility were assessed by measuring the peak rate of rise of LV pressure (+dP/dt). Dobutamine increased +dP/dt by 40±6% and 73±14% in patients with heart failure and control subjects, respectively. Acetylcholine inhibited the +dP/dt response to dobutamine to a similar degree in patients with heart failure and control subjects (-39±8% and -31±4%, respectively; P=NS). Infusion of N^G-monomethyl-L-arginine potentiated the +dP/dt response to dobutamine by 51±15% (P=.01 versus dobutamine) in patients with heart failure but had no effect in control subjects (-6±4%; P=NS versus dobutamine; P=.0002 versus heart failure patients).

Conclusions—Inhibition of cardiac NO augments the positive inotropic response to ß-adrenergic receptor stimulation in patients with heart failure due to idiopathic dilated cardiomyopathy but not in control subjects with normal LV function.

Key Words: nitric oxide • heart failure • cardiomyopathy • contractility • receptors, adrenergic, beta

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Nitric oxide is a ubiquitous signaling molecule formed by the action of a family of at least three NOSs on L-arginine.¹ At least two isoforms of NOS, termed NOS2 and NOS3, are present in human myocardium.^{2 3 4} NOS2 is not expressed in normal myocardium, but it is synthesized in response to inflammatory cytokines such as tumor necrosis factor-, resulting in high levels of myocardial NO production.^{5 6 7} In contrast to NOS2, NOS3 is expressed constitutively in normal myocardium² and cardiac myocytes,⁸ in which its activity is increased by a variety of agonists (eg, acetylcholine).

Both the induction of NOS2 by inflammatory cytokines^{6 9 10} and the activation of constitutively expressed NOS3 by muscarinic cholinergic agonists^{8 11} can inhibit the contractile response to ß-adrenergic stimulation in cardiac myocytes and myocardium in vitro (reviewed in ⁹ . There is evidence that the expression and activity of NOS2 are increased in myocardium obtained from patients with severe heart failure.^{3 4} Consistent with this thesis, we previously found that the intracoronary infusion of the NOS inhibitor L-NMMA potentiated the positive inotropic response to ß-adrenergic receptor stimulation in patients with various degrees of LV dysfunction.¹²

However, studies have not consistently shown that NOS2 activity is increased in failing human myocardium.^{3 4 13} Furthermore, inhibition of NOS potentiated the inotropic response to ß-adrenergic stimulation in normal cultured cardiac myocytes,¹⁴ and we found that intracoronary infusion of the NOS inhibitor L-NMMA potentiated the positive inotropic response to the ß-adrenergic agonist isoproterenol in normal dogs.¹⁵ Therefore, it is possible that our previous observation was not related to heart failure per se but reflects a general property of normal human myocardium.

To address this important issue, we hypothesized that increased myocardial NOS activity attenuates the positive inotropic response to ß-adrenergic receptor stimulation in humans with LV failure but not in those with normal LV function. To test this hypothesis and to examine the relative roles of NOS2 and NOS3 in failing myocardium, we determined the positive inotropic response to the ß-adrenergic agonist dobutamine alone and during concurrent intracoronary infusion of L-NMMA, an inhibitor of all isoforms of NOS in patients with LV failure due to idiopathic dilated cardiomyopathy and control subjects with normal LV function. In addition, because an alternative mechanism for increased NO in failing myocardium is increased expression of NOS3 (rather than NOS2), we examined the positive inotropic response to dobutamine during concurrent intracoronary infusion of acetylcholine, which activates NOS3 but not NOS2.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The study population consisted of 18 adults (8 men and 10 women; mean age, 49±14 years) who were undergoing diagnostic cardiac catheterization. All were in sinus rhythm and were found to be free of significant coronary artery disease during the diagnostic catheterization. Patients in the heart failure group (n=11) were referred for catheterization for evaluation of heart failure and were diagnosed with idiopathic dilated cardiomyopathy through exclusion of coronary artery disease or other known causes of dilated cardiomyopathy. Patients were in New York Heart Association functional class II (n=3), III (n=2), or IV (n=6). Cardiovascular medications in this group consisted of: diuretics (n=7), digitalis (n=9), an ACE inhibitor (n=11), and other vasodilators (n=2). The control group consisted of 7 patients who were being evaluated for chest pain (n=3) or single-lung transplantation (n=4). All were free of coronary artery disease and had normal LV function and hemodynamics. Cardiovascular medications in this group consisted of: ß-blockers (n=2) and calcium channel antagonists (n=4). For both groups, medications were withheld at least 12 hours before study. Partial data for 6 of the heart failure patients were reported previously.¹² The study protocol was approved by the Committee for the Protection of Human Subjects from Research Risks at the Brigham and Women's Hospital, and written informed consent was obtained before study.

Hemodynamic Measurements
Before the experimental protocol, all subjects underwent routine diagnostic left and right heart catheterization via the femoral approach. Coronary angiography was performed with nonionic contrast media, and the research protocol was begun a minimum of 20 minutes after completion of the diagnostic catheterization. The methods used for hemodynamic measurements and intracoronary drug infusions have been described previously.^{12 16 17 18} Briefly, heparin (5000 U IV) was administered just before placement of the catheters. A 6F L4 Judkins catheter (Cordis Laboratories) was advanced via the right femoral artery to the ostium of the left main coronary artery. The catheter was continuously flushed at a rate of 2 mL/min with 5% dextrose in water (D₅W) containing heparin. A 7F micromanometer-tipped pigtail catheter (Millar Instruments) was advanced from the opposite femoral artery and placed in the LV for measurement of LV pressure. The peak rate of LV pressure rise (+dP/dt) was computed online, and femoral artery pressure was monitored via a 7F sidearm sheath (Cordis Laboratories). A 5F bipolar pacing catheter was advanced to the right atrial appendage, and pacing was initiated at 15 bpm above the baseline heart rate and continued for the duration of the study. The ECG, femoral artery pressure, LV pressure, and +dP/dt were recorded on a strip-chart recorder (Electronics for Medicine, Honeywell). Each measurement was obtained as the mean of at least 10 consecutive sinus beats, except +dP/dt, which was the mean of at least 45 consecutive beats. LV developed pressure was calculated as LV systolic pressure- LV end-diastolic pressure. Full hemodynamic measurements were obtained in all control subjects and 10 of 11 heart failure patients. In 1 heart failure patient, the +dP/dt signal was technically inadequate and was not included in calculations.

Drug Infusions
Dobutamine (Lilly) was infused via a systemic vein. Five percent dextrose in water (D₅W), acetylcholine (Lolab), and L-NMMA (Calbiochem) were infused into the left main coronary artery via the Judkins catheter using a Harvard pump. The sequence of drug infusions was as follows: (1) Baseline measurements were obtained during the intracoronary infusion of D₅W at a rate of 2 mL/min. (2) Dobutamine diluted in D₅W was infused via a systemic vein and titrated to achieve a stable 40% to 70% increase in +dP/dt. Dobutamine infusion was begun at a rate of 5 µg · kg^-1 · min^-1 for 10 minutes, and if +dP/dt did not increase by at least 40%, the infusion rate was increased to 7.5, 10, 15, or 20 µg · kg^-1 · min^-1, respectively, at 5-minute intervals. Once a stable response was established, hemodynamic measurements were obtained and the infusion rate was maintained constant for the remainder of the protocol. (3) Acetylcholine was infused for 5 minutes at a rate calculated to achieve a final coronary artery concentration of 1 µmol/L, assuming a left coronary artery blood flow of 125 mL/min.¹⁸ (4) Acetylcholine infusion was stopped and D₅W infusion was resumed for at least 5 minutes and until +dP/dt was stable and had returned to the initial value during dobutamine infusion. (5) L-NMMA¹⁹ was infused for 5 minutes in all subjects. Three normal control subjects and 7 heart failure patients received L-NMMA for 15 minutes. L-NMMA was infused at a rate of 20 µmol/min to achieve a calculated steady state coronary artery concentration of 160 µmol/L (assuming a left main coronary artery blood flow of 125 mL/min). (6) After the fifth minute of L-NMMA infusion, acetylcholine was again infused (at the same rate as before) for 5 minutes. In the patients receiving L-NMMA for 15 minutes, acetylcholine was stopped for the last 10 minutes of the 15-minute infusion. Measurements for each intracoronary infusion were made after achieving a steady state response during the fifth or last minute of the indicated infusion period. At the completion of the drug infusions, radiographic contrast was injected into the coronary artery infusion catheter to confirm the continued position of the catheter in the left main coronary ostium.

Statistical Analysis
All data are presented as mean±SEM. Baseline variables were compared by t test. Corresponding to the prospective study design, the effects of acetylcholine and L-NMMA were analyzed independently. Inhibition of the +dP/dt response to dobutamine by acetylcholine was analyzed by a paired t test. The effect of the 5- and 15-minute infusions of L-NMMA on the +dP/dt response to dobutamine was analyzed by two-way ANOVA using a term for patient identification and posthoc analysis with the Student-Newman-Keuls test. The dose-dependent effects of L-NMMA in control subjects and heart failure patients were compared by ANOVA.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Patient Characteristics
The age, gender, and baseline hemodynamics of study subjects are listed in Table 1. Patients with dilated cardiomyopathy had a lower LV ejection fraction and cardiac index and a higher pulmonary artery wedge pressure than the control subjects, who by definition had normal LV hemodynamics. Baseline +dP/dt was 838±58 and 1366±152 mm Hg/s in the patients with heart failure and control subjects, respectively.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Study Population

Positive Inotropic Response to Dobutamine
Despite a higher dobutamine infusion rate (10.2±1.5 versus 5.9±0.6 µg · kg^-1 · min^-1, P<.04), the increase in +dP/dt was smaller (40±6% versus 73±14%, P=.02) in heart failure patients versus control subjects (Fig 1).

View larger version (19K): [in this window] [in a new window]   Figure 1. Effect of acetylcholine (Ach) and L-NMMA on the positive inotropic response to dobutamine (Dob) in subjects with normal LV function (A) and patients with LV failure due to idiopathic dilated cardiomyopathy (B). Dob was infused via a systemic vein. Ach was infused into the left main coronary artery for 5 minutes and L-NMMA was infused for 5 or 15 minutes. Depicted is the absolute change in LV peak +dP/dt from baseline. Baseline +dP/dt was 838±58 and 1366±152 mm Hg/s in the patients with heart failure and control subjects, respectively. *P<.01 versus Dob-1; P<.05 versus Dob-2.

Inhibitory Effect of Acetylcholine on the Positive Inotropic Response to Dobutamine
Intracoronary infusion of acetylcholine inhibited the +dP/dt response to dobutamine to a similar degree in the control and LV failure groups (Fig 1). Acetylcholine inhibited the dobutamine-stimulated increase in +dP/dt by 31±4% in the control subjects (P<.0001 versus dobutamine alone) and 39±8% in the LV failure patients (P<.001 versus dobutamine alone).

Effect of NOS Inhibition on the Positive Inotropic Response to Dobutamine
In control subjects, the concurrent intracoronary infusion of L-NMMA for 5 or 15 minutes did not affect the +dP/dt response to dobutamine (2282±196 with dobutamine alone versus 2307±184 and 2297±23 mm Hg/s, at 5 and 15 min, respectively) (Fig 1 and 2; Table 2). In contrast, in LV failure patients, the concurrent intracoronary infusion of L-NMMA increased +dP/dt from 1171±88 with dobutamine alone to 1235±94 and 1330±72 mm Hg/sec after 5 and 15 minutes of L-NMMA infusion, respectively (P<.05 versus dobutamine alone, for each time point). L-NMMA infusion increased the +dP/dt response to dobutamine in 9 of 10 LV failure patients, resulting in an average potentiation of 51±15% over dobutamine alone (P<.01 versus dobutamine alone).

View larger version (25K): [in this window] [in a new window]   Figure 2. Effect of L-NMMA on the positive inotropic response to dobutamine (Dob) in individual subjects with normal LV function (A) and patients with LV failure (B). Depicted is the percent change in +dP/dt with concurrent infusion of L-NMMA with Dob relative to the +dP/dt with Dob alone. The results depicted reflect the infusion of L-NMMA for at least 5 minutes in all subjects. *P<.01 versus dobutamine alone.

View this table: [in this window] [in a new window]   Table 2. Changes in Heart Rate, Loading Conditions, and LV +dP/dt With Dobutamine, Acetylcholine, and L-NMMA in 11 Patients With LV Failure and 7 Control Subjects

Effect of NOS Inhibition and Activation on Ventricular Loading Conditions
In control subjects, dobutamine did not affect LV end- diastolic or systolic pressure but increased LV developed pressure by 10±2 mm Hg (P<.05 versus baseline) (Table 2). In patients with LV failure, dobutamine decreased LV end-diastolic pressure by 9±2 mm Hg (P<.05 versus baseline) and increased LV developed pressure by 9±3 mm Hg (P<.05 versus baseline) but had no effect on LV systolic pressure. Concurrent infusion of L-NMMA with dobutamine led to an increase in systolic pressure in both control subjects and patients with LV failure. In addition, L-NMMA enhanced the dobutamine-stimulated increase in LV developed pressure in LV failure patients only. Acetylcholine, when added to dobutamine or dobutamine plus L-NMMA, did not affect LV systolic or end-diastolic pressures in normal control subjects but resulted in a small increase in LV end-diastolic pressure when added to dobutamine plus L-NMMA in patients with LV failure (P<.05 versus dobutamine plus L-NMMA).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major new finding of this study is that inhibition of the synthesis of NO in the heart potentiates the positive inotropic response to a ß-adrenergic agonist in patients with LV failure but not in control subjects with normal LV function. An important implication of this finding is that NO production in the heart is of functional significance in patients with LV failure by contributing to hyporesponsiveness of the myocardium to ß-adrenergic stimulation. Myocardial ß-adrenergic hyporesponsiveness, a characteristic feature of failing myocardium, has generally been attributed to downregulation of ß-adrenergic receptors or alterations in G proteins.^{16 20 21} Our findings suggest that cardiac NO production is an additional mechanism that may contribute to this pathophysiological feature of heart failure.

Our findings are consistent with recent studies that have shown that NOS expression and activity are increased in failing human myocardium.^{2 3 4} DeBelder et al² first demonstrated that human myocardium obtained from patients with idiopathic dilated cardiomyopathy contains NOS activity as detected by the conversion of L-arginine to L-citrulline and, furthermore, that the NOS activity is largely calcium independent, suggesting that it is due to NOS2.^{2 3} More recently, Haywood et al⁴ demonstrated that NOS2 mRNA and protein are expressed in failing myocardium from patients with idiopathic, ischemic, or valvular cardiomyopathy. However, not all studies have found evidence of increased NOS2 in failing myocardium. Habib et al²² found increased NOS2 immunoreactivity only in myocardium from patients with idiopathic cardiomyopathy and not in patients with ischemic cardiomyopathy, and Theones et al¹³ found increased myocardial NOS2 immunoreactivity only in patients with sepsis and not in those with idiopathic or ischemic cardiomyopathy.

The effects of NO on myocardial contractility are also controversial. Investigators using isolated adult rat ventricular myocytes,²³ perfused rat hearts,²⁴ or intact dogs^{25 26} have found that NO may have no effect on contractility, a stimulatory effect, or dose-dependent effects (stimulatory at low dose and inhibitory at high dose). Recently, Yamamoto et al²⁷ reported that increased NO induction in myocytes isolated from dogs with pacing-induced heart failure attenuated the positive inotropic response to isoproterenol, an effect that was not seen in control myocytes; and a preliminary report by Drexler et al²⁸ found that increased cardiac production of NO modulates ß-adrenergic hyporesponsiveness in explanted myocardium from humans with end-stage heart failure. Our findings are consistent with these in vitro studies and strongly suggest that there is a functionally important increase in NOS activity in patients with LV failure due to idiopathic dilated cardiomyopathy. It should be noted that we studied only patients with idiopathic dilated cardiomyopathy; therefore, our conclusions must be limited to such patients and may not be relevant to patients with other etiologies of LV failure. It should also be noted that the greater effect of L-NMMA in LV failure patients could be due to increased sensitivity to NO rather than increased NO activity per se.

A potential mechanism for increased NOS activity in failing myocardium is provided by the observation that plasma levels of TNF- and IL-6 are increased in patients with heart failure.^{29 30} Recently, Torre-Amione et al³¹ and Habib et al²² have further demonstrated that the expression of TNF- is increased in the myocardium of patients with severe heart failure. TNF- and IL-6 are potent stimuli for the induction of NOS2 in myocardium,⁵ cardiac myocytes,⁷ and cardiac microvascular endothelial cells.³²

Gulick et al³³ demonstrated that exposure of cardiac myocytes to inflammatory cytokines results in attenuation of the responsiveness to ß-adrenergic stimulation. Subsequently, Balligand et al⁶ demonstrated the role of myocardial NO activity in mediating this effect by showing that NOS inhibitors enhance the contractile response to ß-adrenergic stimulation in isolated beating myocytes induced to express NOS2 by exposure to immunological stimuli. There are several mechanisms by which NO might inhibit the positive inotropic response to ß-adrenergic stimulation. NO activates soluble guanylyl cyclase to produce cGMP, which inhibits cAMP-stimulated slow-inward calcium channels via activation of protein kinase G³⁴ and increases the degradation of cAMP by activation of a cGMP-dependent phosphodiesterase.³⁵ NO may also modify protein function through direct nitrosylation at sulfhydryl or tyrosine moieties³⁶ and may inhibit mitochondrial respiration.³⁷

Studies in cardiac myocytes⁸ and dogs¹¹ indicate that muscarinic receptor stimulation, which activates NOS3 in cardiac myocytes,⁸ inhibits the positive inotropic response to ß-adrenergic agonists by a mechanism that involves an increase in NO activity. We therefore examined the possibility that increased agonist-stimulated NO activity in the myocardium attenuates the contractile response to ß-adrenergic stimulation in failing myocardium. We previously used the intracoronary infusion technique to show that the muscarinic agonist acetylcholine inhibits the positive inotropic response to dobutamine in humans with normal LV function.¹⁸ Using this approach in the present study, we found that acetylcholine inhibits the positive inotropic response to dobutamine to a similar degree in patients with LV failure and control subjects with normal LV function. To the extent that this action of acetylcholine reflects agonist-stimulated NOS activity, this finding suggests that NOS3 is not increased in failing myocardium and is unlikely to account for the increased effect of L-NMMA in patients with heart failure. Interestingly, Drexler et al²⁸ reported a reduction in NOS3 mRNA in failing human myocardium. Our data provide agreement that NOS3 activity is not increased in heart failure, although we cannot exclude a decrease as reported by Drexler and coworkers. In this and other studies,^{8 11} inhibition of NOS does not fully inhibit the effect of acetylcholine; therefore, it is likely that cholinergic receptor activation increases cGMP by non-NO pathways as well.³⁸

Elucidation of the functional role of NO in humans is complicated by the systemic pressor effect of NOS inhibitors.³⁹ By using the direct intracoronary artery infusion of L-NMMA, we were able to avoid changes in loading conditions that might otherwise confound the interpretation of +dP/dt, and thus we were able to observe the effect of a selective inhibition of NOS in the myocardium. To avoid an indirect effect of L-NMMA on the coronary artery concentration of dobutamine due to changes in coronary blood flow, dobutamine was infused via a systemic vein. On the other hand, because acetylcholine was infused via the intracoronary route, it is possible that differential effects of L-NMMA on coronary blood flow could have had quantitative effects on the interpretation of our data.

In summary, this study demonstrates that inhibition of NO synthesis potentiates the positive inotropic response to ß-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy but not in control subjects with normal LV function. This finding suggests that increased myocardial NO activity in the failing human heart is of functional significance by attenuating ß-adrenergic responsiveness. Given the potential for excessive NO activity to cause cardiac myocyte death,⁴⁰ apoptosis of vascular smooth muscle cells,⁴¹ and inhibition of mitochondrial function,³⁷ it is possible that these observations have additional, broader implications for the role of myocardial NO in the pathophysiology of heart failure.

	Selected Abbreviations and Acronyms

 

IL = interleukin L-NMMA = NG-monomethyl-L-arginine LV = left ventricular NO = nitric oxide NOS = nitric oxide synthase TNF- = tumor necrosis factor-

	Acknowledgments

 
This work was supported by National Institutes of Health grants HL-52320 (W.S.C., M.A.C.) and HL-03238 (J.M.H.). Dr Hare was a Physician-Scientist of the American Heart Association, Massachusetts Affiliate. We wish to acknowledge Dr Thomas W. Smith for his intellectual guidance, support, and encouragement. We would also like to acknowledge the excellent technical support and patience of Diane Gauthier, RN, and the Staff of the Cardiac Catheterization Laboratory at the Brigham and Women's Hospital.

Received June 24, 1997; revision received September 22, 1997; accepted September 25, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Moncada SA. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329:2002–2012.[Free Full Text]

2. DeBelder AJ, Radomski M, Why HJ, Richardson PJ, Bucknall CA, Salas E, Martin JF, Moncada S. Nitric oxide synthase activities in human myocardium. Lancet. 1993;341:84–85.[Medline] [Order article via Infotrieve]

3. DeBelder AJ, Radomski MW, Why HJ, Richardson PJ, 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. 1995;74:426–430.[Abstract/Free Full Text]

4. 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, Fowler MB. Expression of inducible nitric oxide synthase in human heart failure. Circulation. 1996;93:1087–1094.[Abstract/Free Full Text]

5. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca²⁺-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105:575–580.[Medline] [Order article via Infotrieve]

6. Balligand J-L, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage- conditioned medium. J Clin Invest. 1993;91:2314–2319.

7. Balligand J-L, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein C, Davidoff AJ, Kelly RA, Smith TW, Michel T. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes: characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem. 1994;269:27580–27588.[Abstract/Free Full Text]

8. Balligand J-L, Kobzik L, Han X, Kaye DM, Belhassen L, O'Hara DS, Kelly RA, Smith TW, Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J Biol Chem. 1995;270:14582–14586.[Abstract/Free Full Text]

9. Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis. 1995;38:155–166.[Medline] [Order article via Infotrieve]

10. Brady AJB, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol. 1992;263:H1963–H1966.[Abstract/Free Full Text]

11. Hare JM, Keaney JF Jr, Balligand J-L, Loscalzo J, Smith TW, Colucci WS. Role of nitric oxide in parasympathetic modulation of ß-adrenergic myocardial contractility in normal dogs. J Clin Invest. 1995;95:360–366.

12. Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the contractile response to ß-adrenergic stimulation in humans with left ventricular dysfunction. Circulation. 1995;92:2198–2203.[Abstract/Free Full Text]

13. Theones MU, Forstermann U, Tracey WR, Bleese NM, Nussler AK, Scholz H, Stein B. Expression of inducible nitric oxide synthase in failing and non-failing human heart. J Moll Cell Cardiol. 1996;28:165–169.[Medline] [Order article via Infotrieve]

14. Balligand J-L, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993;90:347–351.[Abstract/Free Full Text]

15. Keaney JF Jr, Hare JM, Kelly RA, Loscalzo J, Smith TW, Colucci WS. Inhibition of nitric oxide synthase potentiates the positive inotropic response to ß-adrenergic stimulation in normal dogs. Am J Physiol. 1996;271:H2646–H2652.[Abstract/Free Full Text]

16. Colucci WS, Denniss AR, Leatherman GR, Quigg RJ, Ludmer PL, Marsh JD, Gauthier DF. Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure: dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition. J Clin Invest. 1988;81:1103–1110.

17. Parker JD, Landzberg JS, Bittl JA, Mirsky I, Colucci WS. Effects of ß-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle. Circulation. 1991;84:1040–1048.[Abstract/Free Full Text]

18. Landzberg JS, Parker JD, Gauthier DF, Colucci WS. Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility. Circulation. 1994;89:164–168.[Abstract/Free Full Text]

19. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide signaling system. Br J Pharmacol. 1990;101:746–752.[Medline] [Order article via Infotrieve]

20. Bristow MR, Ginsberg R, Minobe W, Cubicciotti RS, Sagman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human myocardium. N Engl J Med. 1982;307:205–211.[Abstract]

21. Feldman AM, Cates AW, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Van Dop C. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing heart. J Clin Invest. 1988;82:189–197.

22. Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM. Tumor necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet. 1996;347:1151–1155.[Medline] [Order article via Infotrieve]

23. Kojda G, Kottenberg K, Nix P, Schluter KD, Piper HM, Noack E. Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res. 1996;78:91–101.[Abstract/Free Full Text]

24. Klabunde RE, Kimber ND, Kuk JE, Helgren MC, Forstermann U. N^G-Methyl-L-arginine decreases contractility, cGMP and cAMP in isoproterenol-stimulated rat hearts in vitro. Eur J Pharmacol. 1992;223:1–7.[Medline] [Order article via Infotrieve]

25. Kaneko H, Endo T, Kiuchi K, Hayakawa H. Inhibition of nitric oxide synthesis reduces coronary blood flow response but does not increase cardiac contractile response to ß-adrenergic stimulation in normal dogs. J Cardiovasc Pharmacol. 1996;27:247–254.[Medline] [Order article via Infotrieve]

26. Parent R, Al-Obaidi M, Lavallee M. Nitric oxide formation contributes to ß-adrenergic dilation of resistance coronary vessels in conscious dogs. Circ Res. 1993;73:241–251.[Abstract/Free Full Text]

27. Yamamoto S, Tsutsui H, Tagawa H, Saito K, Takahashi M, Tada H, Yamamoto M, Katoh M, Egashira K, Takeshita A. Role of myocyte nitric oxide in ß-adrenergic hyporesponsiveness in heart failure. Circulation. 1997;95:1111–1114.[Abstract/Free Full Text]

28. Drexler H, Kastner S, Strobel A, Studer R, Brodde OE, Hassenfus G. Expression, activity and functional significance of endothelial and inducible nitric oxide synthase in the failing human heart. Circulation. 1996;94(suppl I):I-29. Abstract.

29. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;223:236–241.

30. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann D. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201–1206.[Abstract]

31. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–711.[Abstract/Free Full Text]

32. Balligand J-L, Ungureanu-Longrois D, Simmons WW, Kobzik L, Lowenstein CJ, Lama S, Kelly RA, Smith TW, Michel T. Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1ß and IFN-. Am J Physiol. 1995;268:H1293–H1303.[Abstract/Free Full Text]

33. Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci U S A. 1989;86:6753–6757.[Abstract/Free Full Text]

34. Mery PF, Lohmann SM, Walter U, Fishmeister R. Ca²⁺ current is regulated by cGMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci U S A. 1991;88:1197–1201.[Abstract/Free Full Text]

35. Mery PF, Pavoine C, Belhassen L, Pecker F, Fishmeister R. Nitric oxide regulates cardiac Ca²⁺ current. J Biol Chem. 1993;268:26286–26295.[Abstract/Free Full Text]

36. Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994;78:931–936.[Medline] [Order article via Infotrieve]

37. Shen W, Hintze TH, Wolin MS. Nitric oxide: An important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption. Circulation. 1995;92:3505–3512.[Abstract/Free Full Text]

38. Bartel S, Karczewski P, Krause EG. Protein phosphorylation and cardiac function: cholinergic-adrenergic interaction. Cardiovasc Res. 1993;27:1948–1953.[Medline] [Order article via Infotrieve]

39. Stamler JS, Loh E, Roddy MA, Currie KE, Creager MA. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation. 1994;89:2035–2040.[Abstract/Free Full Text]

40. Pinsky DJ, Cai B, Yang X, Rodriguez C, Sciacca RR, Cannon PJ. The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. J Clin Invest. 1995;95:677–685.

41. Fukuo K, Hata S, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S, Ogihara T. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension. 1996;27:823–826.[Abstract/Free Full Text]

This article has been cited by other articles:

				B. Olshansky, H. N. Sabbah, P. J. Hauptman, and W. S. Colucci Parasympathetic Nervous System and Heart Failure: Pathophysiology and Potential Implications for Therapy Circulation, August 19, 2008; 118(8): 863 - 871. [Full Text] [PDF]

				S. Moniotte, C. Belge, B. Sekkali, P.B. Massion, B. Rozec, C. Dessy, and J.-L. Balligand Sepsis is associated with an upregulation of functional {beta}3 adrenoceptors in the myocardium Eur J Heart Fail, December 1, 2007; 9(12): 1163 - 1171. [Abstract] [Full Text] [PDF]

				E. Takimoto, D. Belardi, C. G. Tocchetti, S. Vahebi, G. Cormaci, E. A. Ketner, A. L. Moens, H. C. Champion, and D. A. Kass Compartmentalization of Cardiac {beta}-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5 Circulation, April 24, 2007; 115(16): 2159 - 2167. [Abstract] [Full Text] [PDF]

				M. M. Givertz, C. Andreou, C. H. Conrad, and W. S. Colucci Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships Circulation, March 13, 2007; 115(10): 1218 - 1224. [Abstract] [Full Text] [PDF]

				S. Imbrogno, T. Angelone, C. Adamo, E. Pulera, B. Tota, and M. C. Cerra Beta3-Adrenoceptor in the eel (Anguilla anguilla) heart: negative inotropy and NO-cGMP-dependent mechanism J. Exp. Biol., December 15, 2006; 209(24): 4966 - 4973. [Abstract] [Full Text] [PDF]

				M. Obayashi, B. Xiao, B. D. Stuyvers, A. W. Davidoff, J. Mei, S.R. W. Chen, and H. E.D.J. ter Keurs Spontaneous diastolic contractions and phosphorylation of the cardiac ryanodine receptor at serine-2808 in congestive heart failure in rat Cardiovasc Res, January 1, 2006; 69(1): 140 - 151. [Abstract] [Full Text] [PDF]

				S. Mak, C. B. Overgaard, and G. E. Newton Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2424 - H2428. [Abstract] [Full Text] [PDF]

				E. Takimoto, H. C. Champion, D. Belardi, J. Moslehi, M. Mongillo, E. Mergia, D. C. Montrose, T. Isoda, K. Aufiero, M. Zaccolo, et al. cGMP Catabolism by Phosphodiesterase 5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism Circ. Res., January 7, 2005; 96(1): 100 - 109. [Abstract] [Full Text] [PDF]

				A. L. Taylor, S. Ziesche, C. Yancy, P. Carson, R. D'Agostino Jr., K. Ferdinand, M. Taylor, K. Adams, M. Sabolinski, M. Worcel, et al. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure N. Engl. J. Med., November 11, 2004; 351(20): 2049 - 2057. [Abstract] [Full Text] [PDF]

				D. Nordhaug, T. Steensrud, E. Aghajani, C. Korvald, and T. Myrmel Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure Eur J Heart Fail, October 1, 2004; 6(6): 705 - 713. [Abstract] [Full Text] [PDF]

				W. J. Paulus and J. G. F. Bronzwaer Nitric oxide's role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H8 - H13. [Abstract] [Full Text] [PDF]

				S. D. Prabhu Nitric Oxide Protects Against Pathological Ventricular Remodeling: Reconsideration of the Role of NO in the Failing Heart Circ. Res., May 14, 2004; 94(9): 1155 - 1157. [Full Text] [PDF]

				R. S. Ostrom, R. A. Bundey, and P. A. Insel Nitric Oxide Inhibition of Adenylyl Cyclase Type 6 Activity Is Dependent upon Lipid Rafts and Caveolin Signaling Complexes J. Biol. Chem., May 7, 2004; 279(19): 19846 - 19853. [Abstract] [Full Text] [PDF]

				S. Chowdhary, A. M. Marsh, J. H. Coote, and J. N. Townend Nitric Oxide and Cardiac Muscarinic Control in Humans Hypertension, May 1, 2004; 43(5): 1023 - 1028. [Abstract] [Full Text] [PDF]

				M. T. Ziolo, L. S. Maier, V. Piacentino III, J. Bossuyt, S. R. Houser, and D. M. Bers Myocyte Nitric Oxide Synthase 2 Contributes to Blunted {beta}-Adrenergic Response in Failing Human Hearts by Decreasing Ca2+ Transients Circulation, April 20, 2004; 109(15): 1886 - 1891. [Abstract] [Full Text] [PDF]

				S. Mak and G. E. Newton Redox modulation of the inotropic response to dobutamine is impaired in patients with heart failure Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H789 - H795. [Abstract] [Full Text] [PDF]

				Y. Ohsawa, H. Toko, M. Katsura, K. Morimoto, H. Yamada, Y. Ichikawa, T. Murakami, S. Ohkuma, I. Komuro, and Y. Sunada Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity Hum. Mol. Genet., January 15, 2004; 13(2): 151 - 157. [Abstract] [Full Text] [PDF]

				D. A. Wink, K. M. Miranda, T. Katori, D. Mancardi, D. D. Thomas, L. Ridnour, M. G. Espey, M. Feelisch, C. A. Colton, J. M. Fukuto, et al. Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2264 - H2276. [Abstract] [Full Text] [PDF]

				P.B. Massion, O. Feron, C. Dessy, and J.-L. Balligand Nitric Oxide and Cardiac Function: Ten Years After, and Continuing Circ. Res., September 5, 2003; 93(5): 388 - 398. [Abstract] [Full Text] [PDF]

				S. M. Lowson Nitric Oxide Signaling and Clinical Alternatives to Nitric Oxide Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 239 - 252. [Abstract] [PDF]

				M. M. El-Omar, R. Lord, N. J. Draper, and A. M. Shah Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy Eur J Heart Fail, June 1, 2003; 5(3): 229 - 239. [Abstract] [Full Text] [PDF]

				N. Paolocci, T. Katori, H. C. Champion, M. E. St. John, K. M. Miranda, J. M. Fukuto, D. A. Wink, and D. A. Kass From the Cover: Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: Independence from beta -adrenergic signaling PNAS, April 29, 2003; 100(9): 5537 - 5542. [Abstract] [Full Text] [PDF]

				R. M. Gomez, O. A. Levander, and L. Sterin-Borda Reduced inotropic heart response in selenium-deficient mice relates with inducible nitric oxide synthase Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H442 - H448. [Abstract] [Full Text] [PDF]

				J M Cotton, M T Kearney, and A M Shah Nitric oxide and myocardial function in heart failure: friend or foe? Heart, December 1, 2002; 88(6): 564 - 566. [Abstract] [Full Text] [PDF]

				Y. Chen, J. H. Traverse, R. Du, M. Hou, and R. J. Bache Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart Circulation, July 9, 2002; 106(2): 273 - 279. [Abstract] [Full Text] [PDF]

				T. Saito, F. Hu, L. Tayara, L. Fahas, H. Shennib, and A. Giaid Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H339 - H345. [Abstract] [Full Text] [PDF]

				W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]

				O. Gealekman, Z. Abassi, I. Rubinstein, J. Winaver, and O. Binah Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and {beta}-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure Circulation, January 15, 2002; 105(2): 236 - 243. [Abstract] [Full Text] [PDF]

				M. T. Ziolo, H. Katoh, and D. M. Bers Expression of Inducible Nitric Oxide Synthase Depresses {beta}-Adrenergic-Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes Circulation, December 11, 2001; 104(24): 2961 - 2966. [Abstract] [Full Text] [PDF]

				H. Post, R. Schulz, P. Gres, and G. Heusch No involvement of nitric oxide in the limitation of beta -adrenergic inotropic responsiveness during ischemia Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2392 - H2397. [Abstract] [Full Text] [PDF]

				W. J. Paulus, S. Frantz, and R. A. Kelly Nitric Oxide and Cardiac Contractility in Human Heart Failure: Time for Reappraisal Circulation, November 6, 2001; 104(19): 2260 - 2262. [Full Text] [PDF]

				J. M. Cotton, M. T. Kearney, P. A. MacCarthy, R. M. Grocott-Mason, D. R. McClean, C. Heymes, P. J. Richardson, and A. M. Shah Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo Circulation, November 6, 2001; 104(19): 2318 - 2323. [Abstract] [Full Text] [PDF]

				Q. Feng, X. Lu, D. L. Jones, J. Shen, and J. M. O. Arnold Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice Circulation, August 7, 2001; 104(6): 700 - 704. [Abstract] [Full Text] [PDF]

				I. S. Wittstein, D. A. Kass, P. H. Pak, W. L. Maughan, B. Fetics, and J. M. Hare Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., August 1, 2001; 38(2): 429 - 435. [Abstract] [Full Text] [PDF]

				H. SENZAKI, C. J. SMITH1, G. J. JUANG, T. ISODA, S. P. MAYER, A. OHLER, N. PAOLOCCI, G. F. TOMASELLI, J. M. HARE, and D. A. KASS Cardiac phosphodiesterase 5 (cGMP-specific) modulates {beta}-adrenergic signaling in vivo and is down-regulated in heart failure FASEB J, August 1, 2001; 15(10): 1718 - 1726. [Abstract] [Full Text] [PDF]

				M. O. Stojanovic, M. T. Ziolo, G. M. Wahler, and B. M. Wolska Anti-adrenergic effects of nitric oxide donor SIN-1 in rat cardiac myocytes Am J Physiol Cell Physiol, July 1, 2001; 281(1): C342 - C349. [Abstract] [Full Text] [PDF]

				C. Y. T. Hart, E. L. Hahn, D. M. Meyer, J. C. Burnett Jr., and M. M. Redfield Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H146 - H154. [Abstract] [Full Text] [PDF]

				A. Godecke, T. Heinicke, A. Kamkin, I. Kiseleva, R. H Strasser, U. K M Decking, T. Stumpe, G. Isenberg, and J. Schrader Inotropic response to {beta}-adrenergic receptor stimulation and anti-adrenergic effect of ACh in endothelial NO synthase-deficient mouse hearts J. Physiol., April 1, 2001; 532(1): 195 - 204. [Abstract] [Full Text] [PDF]

				S. Moniotte, L. Kobzik, O. Feron, J.-N. Trochu, C. Gauthier, and J.-L. Balligand Upregulation of {beta}3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium Circulation, March 27, 2001; 103(12): 1649 - 1655. [Abstract] [Full Text] [PDF]

				S. Mak and G. E. Newton Vitamin C Augments the Inotropic Response to Dobutamine in Humans With Normal Left Ventricular Function Circulation, February 13, 2001; 103(6): 826 - 830. [Abstract] [Full Text] [PDF]

				T. Ukai, C.-P. Cheng, H. Tachibana, A. Igawa, Z.-S. Zhang, H.-J. Cheng, and W. C. Little Allopurinol Enhances the Contractile Response to Dobutamine and Exercise in Dogs With Pacing-Induced Heart Failure Circulation, February 6, 2001; 103(5): 750 - 755. [Abstract] [Full Text] [PDF]

				A. E Belevych and R. D Harvey Muscarinic inhibitory and stimulatory regulation of the L-type Ca2+ current is not altered in cardiac ventricular myocytes from mice lacking endothelial nitric oxide synthase J. Physiol., October 15, 2000; 528(2): 279 - 289. [Abstract] [Full Text] [PDF]

				N. Paolocci, U. E. G. Ekelund, T. Isoda, M. Ozaki, K. Vandegaer, D. Georgakopoulos, R. W. Harrison, D. A. Kass, and J. M. Hare cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1982 - H1988. [Abstract] [Full Text] [PDF]

				P. Kinnunen, I. Szokodi, M. G. Nicholls, and H. Ruskoaho Impact of NO on ET-1- and AM-induced inotropic responses: potentiation by combined administration Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R569 - R575. [Abstract] [Full Text] [PDF]

				J. M. Hare, R. A. Lofthouse, G. J. Juang, L. Colman, K. M. Ricker, B. Kim, H. Senzaki, S. Cao, R. S. Tunin, and D. A. Kass Contribution of Caveolin Protein Abundance to Augmented Nitric Oxide Signaling in Conscious Dogs With Pacing-Induced Heart Failure Circ. Res., May 26, 2000; 86(10): 1085 - 1092. [Abstract] [Full Text] [PDF]

				T. Shinke, H. Takaoka, M. Takeuchi, K. Hata, H. Kawai, H. Okubo, Y. Kijima, T. Murata, and M. Yokoyama Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to {beta}-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy Circulation, April 25, 2000; 101(16): 1925 - 1930. [Abstract] [Full Text] [PDF]

				O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]

				N. Kobayashi, T. Higashi, K. Hara, H. Shirataki, and H. Matsuoka Effects of imidapril on NOS expression and myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats Cardiovasc Res, December 1, 1999; 44(3): 518 - 526. [Abstract] [Full Text] [PDF]

				L. Adam, M. Bouvier, and T. L. Z. Jones Nitric Oxide Modulates beta 2-Adrenergic Receptor Palmitoylation and Signaling J. Biol. Chem., September 10, 1999; 274(37): 26337 - 26343. [Abstract] [Full Text] [PDF]

				J.-L. Balligand Regulation of cardiac {beta}-adrenergic response by nitric oxide Cardiovasc Res, August 15, 1999; 43(3): 607 - 620. [Full Text] [PDF]

				J. Zanzinger Role of nitric oxide in the neural control of cardiovascular function Cardiovasc Res, August 15, 1999; 43(3): 639 - 649. [Abstract] [Full Text] [PDF]

				W Bloch, B.K Fleischmann, D.E Lorke, C Andressen, B Hops, J Hescheler, and K Addicks Nitric oxide synthase expression and role during cardiomyogenesis Cardiovasc Res, August 15, 1999; 43(3): 675 - 684. [Abstract] [Full Text] [PDF]

				S. M. Wildhirt, S. Weismueller, C. Schulze, N. Conrad, A. Kornberg, and B. Reichart Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury Cardiovasc Res, August 15, 1999; 43(3): 698 - 711. [Abstract] [Full Text] [PDF]

				H. Drexler Nitric Oxide Synthases in the Failing Human Heart : A Doubled-Edged Sword? Circulation, June 15, 1999; 99(23): 2972 - 2975. [Full Text] [PDF]

				C. Heymes, M. Vanderheyden, J. G. F. Bronzwaer, A. M. Shah, and W. J. Paulus Endomyocardial Nitric Oxide Synthase and Left Ventricular Preload Reserve in Dilated Cardiomyopathy Circulation, June 15, 1999; 99(23): 3009 - 3016. [Abstract] [Full Text] [PDF]

				G. J. JI, B. K. FLEISCHMANN, W. BLOCH, M. FEELISCH, C. ANDRESSEN, K. ADDICKS, and J. HESCHELER Regulation of the L-type Ca2+ channel during cardiomyogenesis: switch from NO to adenylyl cyclase-mediated inhibition FASEB J, February 1, 1999; 13(2): 313 - 324. [Abstract] [Full Text]

				K. Singh, G. Sirokman, C. Communal, K. G. Robinson, C. H. Conrad, W. W. Brooks, O. H. L. Bing, and W. S. Colucci Myocardial Osteopontin Expression Coincides With the Development of Heart Failure Hypertension, February 1, 1999; 33(2): 663 - 670. [Abstract] [Full Text] [PDF]

				J. Heger, A. Godecke, U. Flogel, M. W. Merx, A. Molojavyi, W. N. Kuhn-Velten, and J. Schrader Cardiac-Specific Overexpression of Inducible Nitric Oxide Synthase Does Not Result in Severe Cardiac Dysfunction Circ. Res., January 11, 2002; 90(1): 93 - 99. [Abstract] [Full Text] [PDF]

				W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hare, J. M. Articles by Colucci, W. S. Search for Related Content PubMed PubMed Citation Articles by Hare, J. M. Articles by Colucci, W. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH