Published online before print November 5, 2007, doi: 10.1161/HYPERTENSIONAHA.107.100032
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2007;50:1009.)
© 2007 American Heart Association, Inc.
Editorial Commentaries |
LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway
NO Donors as a Means of Antiremodeling
From the Department of Pathophysiology (L.P., F.S.), School of Medicine, Comenius University, Bratislava, Slovak Republic; Institute of Normal and Pathological Physiology (L.P.), Slovak Academy of Sciences, Bratislava, Slovak Republic; and the 3rd Clinic of Medicine (F.S.), School of Medicine, Comenius University, Bratislava, Slovak Republic.
Correspondence to Ludovit Paulis, Institute of Pathophysiology, School of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic. E-mail ludo{at}lfuk.sk
The discovery of NO as the endothelium-derived relaxing factor unleashed new horizons. NO is a ubiquitous radical exerting both hemodynamic and tissue growth–modifying effects. The vasodilative and antiproliferative properties of NO produced by endothelial NO synthase are considered to act beneficially within the cardiovascular system. However, under certain circumstances, the inducible NO synthase produces large quantities of NO that may be harmful.1 Most NO effects can be attributed to the activation of soluble guanylate cyclase and the subsequent cascade of events including enhanced cGMP concentration, activation of cGMP-dependent kinase-1, and reduced intracellular calcium levels in target cells. NO acts as a principal regulator of vascular function. Venodilatation and arterial relaxation result in a decrease of left ventricular pressure and chamber size, leading to attenuation of oxygen consumption. NO dilates epicardial coronary arteries, enhances collateral flow, and inhibits platelet aggregation. Moreover, NO was shown to inhibit collagen synthesis and to reduce cardiomyocyte growth. NO, thus, represents an opposing force to vasoconstrictors and growth-promoting substances, such as angiotensin II and endothelin.
The depression of NO signaling, including downregulated expression and attenuated enzymatic activity of NO synthase and scavenging of NO by oxygen-derived free radicals, seems to be a principal disorder in endothelial dysfunction. NO deficiency is, therefore, related to many cardiovascular pathologies, such as coronary atherosclerosis with myocardial ischemia, arterial hypertension with left ventricular hypertrophy, or heart failure. It is obvious that NO plays an important role in the circulatory physiology.
Nevertheless, the impact of therapeutically increased NO bioactivity on cardiovascular morbidity and mortality is unclear. In the Gruppo Italiano per lo Studio della Streptochinasi nell’Inffarto Miocardico 3 and International Study of Infarct Survival 4 trials, nitrates failed to reduce mortality when given after myocardial infarction.2 Although the effect of the combination of isosorbide dinitrate and hydralazine in the Vasodilator-Heart Failure Trial I and African American Heart Failure Trial compared with placebo was encouraging for heart failure treatment, the vasodilators were still inferior in comparison with enalapril.3 Moreover, no trial has been performed to show the effect of the sole use of NO donors on the reduction of cardiovascular events in hypertension or in chronic heart failure. At present, NO donors do not belong to first-line therapy in ischemic heart disease, heart failure, or hypertension, and NO delivery is recommended only when a well-established treatment is contraindicated or has an insufficient effect.4 The explanation for the failure of NO donors to become established in the evidence-based medicine is hard to address. The most prominent problems of NO donors are drug tolerance and NO resistance. An effort has been made to overcome these complications either by direct targeting of the soluble guanylate cyclase, the downstream messenger of NO pathway,5 or by developing novel NO donors with decreased susceptibility to free radicals6 or with enhanced cardioselectivity.7
Recently, LA419, a new organic nitrate containing a thiol group, has been designed to treat clinical conditions associated with NO deficits.8 The thiol group in the molecule of LA419 was expected to protect the formed NO from being degraded by free radicals and, thus, to avoid nitrate tolerance and NO resistance. Experiments have shown that LA419 has anti-ischemic, antithrombotic, and antiatherosclerotic effects at doses that do not influence blood pressure.9
In this issue of Hypertension, Ruiz-Hurtado et al10 report the effect of LA419 on left ventricular hypertrophy and fibrosis induced by aortic stenosis. The use of LA419 in this study yields novel information for hypertension research on 2 major points. First, it directs attention from therapeutic approaches aimed at restoring the neurohumoral balance by attenuating adrenergic and renin-angiotensin-aldosterone system activation back to efforts to restore the balance by the enhancement of the NO vasodilator and antiproliferative activity. Second, the use of NO donors without hypotensive effects could enable the differentiation between effects mediated by hemodynamic load and effects of NO, per se. Ruiz-Hurtado et al10 found that LA419 reversed left ventricular remodeling and restored endothelial NO synthase:heat-shock protein 90 interaction, restored endothelial NO synthase and caveolin-3 expression, and restored cGMP content in the left ventricle but without reducing blood pressure. The authors suggested that LA419 ameliorates cardiac remodeling via the restoration of NO signaling. Thus, NO is again placed in the role of a mighty molecule in the process of heart remodeling.
However, in relation to the antihypertrophic effect of LA419, several questions emerge. The first issue is that LA419 did not reduce blood pressure, either in clipped or in sham-operated rats. The NO release by LA419 may be expected to lead to peripheral vasodilation and blood pressure decrease. Nevertheless, we still do not have unequivocal evidence of the participation of endothelial products, including NO, in the pathogenesis of hypertension.11 Moreover, despite the fact that LA419 seemed to enhance the NO:soluble guanylate cyclase pathway in the left ventricle, NO formation was investigated neither in conduit or in smaller arteries nor in the brain or kidney, major organs participating in blood pressure regulation. We have shown previously that, although L-arginine improved NO synthase activity in the left ventricle, it failed to restore NO synthase activity in the kidney and brain of NG-nitro-L-arginine methyl ester–induced hypertensive rats. Subsequently, L-arginine failed to prevent NG-nitro-L-arginine methyl ester hypertension.12 Similarly, a potential cardioselectivity expected from the new generation of NO donors could be associated with predominant NO delivery in the heart, which may be insufficient to induce systemic effects on blood pressure.
Another major concern is the discrepancy between the success in left ventricular hypertrophy reduction and the failure of blood pressure attenuation. This interesting and almost revolutionary finding questions the role of hemodynamic load as the principal issue in the development of left ventricular hypertrophy and supports the idea that local stimulators of cardiac growth may be decisive in pathologic heart remodeling. The weakness of the experimental design, however, is that blood pressure was not assessed continuously, but rather was assessed from a single measurement under acute conditions. Therefore, this study cannot completely discount the possibility that hemodynamic effects may have contributed to the attenuated left ventricular hypertrophy. Nevertheless, there are several lines of indirect evidence that suggest that NO may be involved in the process of myocardial hypertrophy.13 However, LA419 may not only increase the release of NO but may be expected to interfere with local oxidative status. Because LA419 contains a thiol group, it may improve NO stability by converting NO to nitrosothiols. This cannot only stabilize the NO molecule and prolong its action but also diminish the reaction of NO with superoxide, thus reducing peroxynitrite formation, having 2 important consequences. First, the reduction of oxidative load can reduce the development of tolerance. Second, a decreased level of highly reactive peroxynitrite and prolongation of NO action is thought to have antiproliferative potential (Figure).
|
Finally, an open question remains regarding whether the L-arginine-NO system is the only neurohumoral system targeted by LA419. Ruiz-Hurtado et al10 claim that LA419 is not able to directly activate the soluble guanylate cyclase or to influence circulating levels of angiotensin. However, no data are available regarding whether LA419 is or is not interfering with local renin-angiotensin-aldosterone, sympathetic, or endothelin systems. Furthermore, studies on the potential interaction of LA419 with inflammatory cytokines and local growth factors participating in the process of heart remodeling need to be performed (Figure).
Despite these concerns, the results of Ruiz-Hurtado et al10 are encouraging, and new fields for the experimental hypertension research emerge. Future studies should be designed to disclose how the effect of LA419 is associated with NO bioactivity. If LA419 really attenuates hypertrophy through NO restoration, it would be an encouraging fact for the development and investigation of novel NO donors, which could prove beneficial in the clinical setting. However, irrespective of the outcome of clinical trials designed to find out the therapeutic potential of LA419 and derived agents, these substances are likely to become useful experimental research tools, enabling researchers to design experiments disclosing the different roles of hemodynamic load, NO, and other endothelial factors in cardiovascular pathologies.
 |
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
- Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parrillo JE. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol Regul Integr Comp Physiol. 1999; 276: R265–R276.
[Abstract/Free Full Text] - Rakhit RD, Marber MS. Nitric oxide: an emerging role in cardioprotection? Heart. 2001; 86: 368–372.
[Free Full Text] - Cheng JW. A review of isosorbide dinitrate and hydralazine in the management of heart failure in black patients, with a focus on a new fixed-dose combination. Clin Ther. 2006; 28: 666–678.[CrossRef][Medline] [Order article via Infotrieve]
- Simko F. Is NO the king? Pathophysiological benefit with uncertain clinical impact. Physiol Res. 2007;56(Suppl 2):in press.
- Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch JP, Burnett JC Jr. Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension. 2007; 49: 1128–1133.
[Abstract/Free Full Text] - Miller MR, Megson IL. Recent developments in nitric oxide donor drugs. Br J Pharmacol. 2007; 151: 305–321.[CrossRef][Medline] [Order article via Infotrieve]
- Csont T, Ferdinandy P. Cardioprotective effects of glyceryl trinitrate: beyond vascular nitrate tolerance. Pharmacol Ther. 2005; 105: 57–68.[CrossRef][Medline] [Order article via Infotrieve]
- Lacer. Derivates of isosorbid mononitrate as vasodilator agents with reduced tolerance. WO Patent. 2005; 0020420.
- Vilahur G, Segales E, Casani L, Badimon L. A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters. Thromb Haemost. 2004; 91: 1035–1043.[Medline] [Order article via Infotrieve]
- Ruiz-Hurtado G, Fernandez-Velasco M, Mourelle M, Delgado C. LA419, a novel nitric oxide donor, prevents pathological cardiac remodeling in pressure-overloaded rats via endothelial nitric oxide synthase pathway regulation. Hypertension. 2007; 50: 1049–1056.
[Abstract/Free Full Text] - Schiffrin EL. A critical review of the role of endothelial factors in the pathogenesis of hypertension. J Cardiovasc Pharmacol. 2001; 38 (suppl 2): S3–S6.
- Simko F, Luptak I, Matuskova J, Krajcirovicova K, Sumbalova Z, Kucharska J, Gvozdjakova A, Simko J, Babal P, Pechanova O, Bernatova I. L-arginine fails to protect against myocardial remodelling in L-NAME-induced hypertension. Eur J Clin Invest. 2005; 35: 362–368.[CrossRef][Medline] [Order article via Infotrieve]
- Simko F, Simko J. The potential role of nitric oxide in the hypertrophic growth of the left ventricle. Physiol Res. 2000; 49: 37–46.[Medline] [Order article via Infotrieve]
Related Article:
- LA419, a Novel Nitric Oxide Donor, Prevents Pathological Cardiac Remodeling in Pressure-Overloaded Rats Via Endothelial Nitric Oxide Synthase Pathway Regulation
- Gema Ruiz-Hurtado, María Fernández-Velasco, Marisabel Mourelle, and Carmen Delgado
Hypertension 2007 50: 1049-1056.[Abstract] [Full Text] [PDF]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||