Published online before print March 13, 2003, doi: 10.1161/01.RES.0000066853.09821.98
© 2003 American Heart Association, Inc.
Reports |
Sildenafil Induces Delayed Preconditioning Through Inducible Nitric Oxide Synthase–Dependent Pathway in Mouse Heart
From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Va.
Correspondence to Rakesh C. Kukreja, PhD, Division of Cardiology, Box 980281, Virginia Commonwealth University, Richmond, VA 23298. E-mail rakesh{at}hsc.vcu.edu
Abstract
Sildenafil citrate (Viagra) is the most widely used drug for treating erectile dysfunction in men. We recently demonstrated that it induces potent protective effects against ischemia-reperfusion (I-R) injury in rabbit hearts through the opening of mitochondrial ATP-dependent K+ channels. In the present study, we investigated the role of the NO-dependent signaling pathway in delayed cardioprotection by sildenafil. Adult male ICR mice were treated with saline or sildenafil (0.7 mg/kg IP) 24 hours before global I-R in the Langendorff mode. Infarct size was reduced from 27.6±3.3% in saline-treated control mice to 6.9±1.2% in sildenafil-treated mice (mean±SEM, P<0.05) without compromising cardiac function. Reverse transcription–polymerase chain reaction revealed a transient increase in endothelial and inducible NO synthase (eNOS and iNOS, respectively) mRNA in sildenafil-treated mice, peaking at 45 minutes (eNOS) and 2 hours (iNOS) after sildenafil injection. The magnitude of mRNA increase was more pronounced for iNOS than for eNOS. In addition, a significant increase in both iNOS and eNOS protein was detected 24 hours after sildenafil treatment. A selective inhibitor of iNOS, 1400W (10 mg/kg IP given 30 minutes before I-R), abolished sildenafil-induced protection (23.7±2.8%, P<0.05 versus sildenafil). These data suggest that the induction of NO synthase isoforms is an essential component of the signaling mechanism for sildenafil-induced delayed preconditioning. However, iNOS appears to be the primary isoform that mediates the robust cardioprotection.
Key Words: ischemia • myocardial infarction • nitric oxide synthases • phosphodiesterase inhibitor • late preconditioning
Sildenafil citrate (Viagra) is a selective inhibitor of phosphodiesterase-5, which catalyzes the breakdown of cGMP, one of the primary factors involved in smooth muscle relaxation. It enhances NO-driven cGMP accumulation, which, in turn, causes vasodilatation in the corpus cavernosum. Sildenafil has become the most widely used drug for treating erectile dysfunction in men since its market debut in 1998.1 Interestingly, we recently discovered a powerful preconditioning-like effect of sildenafil in rabbit hearts.2 Both intravenous and oral administration of sildenafil caused significant reduction of infarct size after ischemia-reperfusion (I-R). The protection was abolished by 5-hydroxydecanoate, a selective blocker of mitochondrial ATP-dependent K+ (mitoKATP) channels.2 However, the mechanism by which sildenafil triggers the signaling cascade leading to the opening of mitoKATP remains speculative.2 There is mounting evidence suggesting a role of NO in modulating mitoKATP.3–6 The synthesis of NO is catalyzed by 3 isoforms of NO synthase (NOS), namely, neuronal NOS, inducible NOS (iNOS), and endothelial NOS (eNOS), among which iNOS has been identified as the essential mediator of delayed preconditioning induced by divergent pathophysiological stimuli or pharmacological agents, such as brief episodes of I-R,7 endotoxin derivatives,8,9 G-protein–coupled membrane receptor agonists,10,11 whole-body hyperthermia,12 and systemic hypoxia.13 However, no studies are available showing any link between sildenafil and the activation of a NOS-dependent signaling cascade. The goal of the present report was to determine whether (1) sildenafil induces the synthesis of NOS isoforms in the heart and (2) iNOS mediates the delayed preconditioning effect in the mouse heart.
Materials and Methods
Physiological Studies
Adult male outbred ICR mice were supplied by Harlan Inc (Indianapolis, Ind). Animal experimental protocols were approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University. Viagra pills (Pfizer Inc) were ground into powder and dissolved in saline. The drug solution was filtered (0.45-µm pore size) before intraperitoneal injection. 1400W, an iNOS inhibitor, was obtained from Alexis. We used an isolated perfused mouse heart model subjected to 20 minutes of global ischemia and 30 minutes of reperfusion (Langendorff mode). Myocardial I-R injury was assessed by measuring infarct size, contractile function, and coronary flow as described previously.9
Twenty-eight mice were randomized into the following 4 groups (n=6 to 9 per group): (1) saline (0.15 mL IP), (2) sildenafil (0.7 mg/kg IP, equivalent to 50 mg Viagra pill used for patients with erectile dysfunction, given 24 hours before I-R), (3) sildenafil+1400W (10 mg/kg IP,14 given 30 minutes before I-R), and (4) saline+1400W.
Measurement of NOS Isoforms
Mice were treated with sildenafil (0.7 mg/kg IP), and their hearts were removed at 15, 30, and 45 minutes and 1, 2, 3, 4, and 24 hours after injection (n=3 per group). Three nontreated hearts were used as controls. Tissue samples were ground under liquid nitrogen and homogenized with TRI Reagent (Molecular Research Center) for extracting total RNA, which was reverse-transcribed into cDNA at 50°C for 30 minutes using a OneStep reverse transcription (RT)–polymerase chain reaction (PCR) kit from Qiagen. The oligonucleotide primers were synthesized on the basis of published sequences for murine iNOS, eNOS, and GAPDH15 (Integrated DNA Technology). The RT-PCR products were electrophoresed on 1.5% Tris-acetate-EDTA agarose gel. The target bands were identified on the basis of their specific size using DNA standards.
iNOS and eNOS proteins were measured by Western blots as described previously.13 In brief, triplicate heart samples were collected 24 hours after saline or sildenafil injection and homogenized in ice-cold RIPA buffer (Upstate Biotechnology). The homogenate was centrifuged at 10 000g for 10 minutes at 4°C, and supernatant was recovered as the total cellular protein. Total protein (60 µg) from each sample was separated by SDS-PAGE on 10% acrylamide gels, transferred to a polyvinylidine difluoride membrane, and then blocked with 5% nonfat dry milk in Tris-buffered saline. The membrane was subsequently incubated with a rabbit polyclonal antibody (dilution 1:500, Santa Cruz) reacting specifically to iNOS, eNOS, or actin. The secondary antibody was a horseradish peroxidase–conjugated anti-rabbit IgG (1:1000 dilution, Amersham). The membranes were developed using enhanced chemiluminescence and exposed to x-ray film. The mRNA and protein expression were quantified by scanning each of the RT-PCR or Western blot band using a densitometer (Bioquant 98).
Data Analysis and Statistics
Data are presented as mean±SEM. The difference among the treatment groups or the time points after sildenafil injection was compared by unpaired t test or 1-way ANOVA, followed by the Student-Newman-Keuls post hoc test. A value of P<0.05 was considered significant.
Results and Discussion
Pretreatment of the mice with sildenafil reduced their infarct sizes 24 hours later (6.9±1.2%) compared with saline (control) treatment (27.6±3.3%, P<0.05; Figure 1). The infarct-limiting effect of sildenafil was not associated with compromised ventricular contractile function, ie, stunning (Figure 1, bottom), which is in agreement with the results of Przyklenk and Kloner.16 Sildenafil did not alter preischemic or postischemic coronary flow (data not shown), indicating that its cardioprotective effect may be independent of its vascular response 24 hours later. These results confirmed our previous findings showing a powerful cardioprotective effect of sildenafil in the rabbit heart.2 There was an increase in iNOS and eNOS mRNA and protein expression (Figures 2 and 3). The levels of these transcripts increased transiently, peaking at 45 minutes (eNOS) and 2 hours (iNOS) after sildenafil treatment and returning to baseline levels several hours later (Figure 2). The magnitude of increase was much higher for iNOS compared with eNOS. In addition, sildenafil-induced protection was abolished by the selective iNOS inhibitor 1400W (infarct size 23.7±2.8%, P<0.05 versus sildenafil). 1400W had no significant effect on infarct size compared with the effect of saline (24.5±1.0%, P>0.05 versus saline).
|
|
|
Several studies have shown that NO derived from iNOS plays a major role in the delayed cardioprotection induced by endotoxin derivatives,8,9 agonists of adenosine or adrenergic receptors,10,11 p38 activator,17 and diazoxide, a mitoKATP opener.6 The role of sildenafil in stimulating the release of NO in the heart is unknown. We provide the first evidence indicating that sildenafil is a potent inducer of iNOS mRNA and protein, which lead to delayed cardioprotection. Although eNOS mRNA and protein also increased, their quantitative expression was lower than that of iNOS. The role of eNOS is not clear in the present study. The complete blockade of cardioprotection with 1400W given before ischemia rules out the role of eNOS in the mediator phase of delayed protection. However, eNOS may play a role in the trigger phase, ie, at the time of sildenafil treatment when NO from eNOS may initiate the signaling cascade leading to iNOS expression, as proposed by Bolli.18,19 The iNOS-catalyzed NO generation could potentially activate guanylate cyclase, resulting in an enhanced formation of cGMP. cGMP may activate protein kinase G, which can subsequently open mitoKATP channels, resulting in the cardioprotective effects as recently reported.20
In conclusion, our results show, for the first time, that sildenafil induces delayed preconditioning, which is primarily mediated by NO derived from iNOS. Further studies are needed to understand the signaling mechanism(s) that leads to the transcription and expression of eNOS and iNOS in the heart. The present study in a model of global I-R further expands our knowledge regarding the cardioprotective effect of sildenafil, which may potentially be used in the treatment of patients with ischemic heart diseases.
Acknowledgments
This study was funded by grants from the NIH (HL-51045, HL-59469 to Dr Kukreja) and the American Heart Association (0060289U to Dr Xi). Dr Yin was supported by an NIH postdoctoral training grant (HL-07537).
Footnotes
*Both authors contributed equally to this study. 
Received February 4, 2003; revision received March 5, 2003; accepted March 5, 2003.
References
1. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996; 8: 47–52.[Medline] [Order article via Infotrieve]
2. Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial KATP channels in rabbits. Am J Physiol. 2002; 283: H1263–H1269.
3. Ockaili R, Emani VR, Okubo S, Brown M, Krottapalli K, Kukreja RC. Opening of mitochondrial KATP channel induces early and delayed cardioprotective effects: role of nitric oxide. Am J Physiol. 1999; 277: H2425–H2434.[Medline] [Order article via Infotrieve]
4. Sasaki N, Sato T, Ohler A, O’Rourke B, Marban E. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation. 2000; 101: 439–445.
5. Gross GJ. The role of mitochondrial KATP channels in cardioprotection. Basic Res Cardiol. 2000; 95: 280–284.[CrossRef][Medline] [Order article via Infotrieve]
6. Wang Y, Kudo M, Xu M, Ayub A, Asharf M. Mitochondrial KATP channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. J Mol Cell Cardiol. 2001; 33: 2037–2046.[CrossRef][Medline] [Order article via Infotrieve]
7. Guo Y, Jones WK, Xuan YT, Tang XL, Bao W, Wu WJ, Han H, Laubach VE, Ping P, Yang Z, Qiu Y, Bolli R. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci U S A. 1999; 96: 11507–11512.
8. Zhao L, Weber PA, Smith JR, Comerford ML, Elliott GT. Role of inducible nitric oxide synthase in pharmacological "preconditioning" with monophosphoryl lipid A. J Mol Cell Cardiol. 1997; 29: 1567–1576.[CrossRef][Medline] [Order article via Infotrieve]
9. Xi L, Jarrett NC, Hess ML, Kukreja RC. Essential role of inducible nitric oxide synthase in monophosphoryl lipid A–induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation. 1999; 99: 2157–2163.
10. Zhao T, Xi L, Chelliah J, Levasseur JE, Kukreja RC. Inducible nitric oxide synthase mediates delayed myocardial protection induced by activation of adenosine A1 receptors: evidence from gene-knockout mice. Circulation. 2000; 102: 902–907.
11. Tejero-Taldo MI, Gursoy E, Zhao TC, Kukreja RC. 
-Adrenergic receptor stimulation produces late preconditioning through inducible nitric oxide synthase in mouse heart. J Mol Cell Cardiol. 2002; 34: 185–195.[CrossRef][Medline]
[Order article via Infotrieve]
12. Arnaud C, Laubriet A, Joyeux M, Godin-Ribuot D, Rochette L, Demenge P, Ribuot C. Role of nitric oxide synthases in the infarct size-reducing effect conferred by heat stress in isolated rat hearts. Br J Pharmacol. 2001; 132: 1845–1851.[CrossRef][Medline] [Order article via Infotrieve]
13. Xi L, Tekin D, Gursoy E, Salloum F, Levasseur JE, Kukreja RC. Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. Am J Physiol. 2002; 283: H5–H12.
14. Sharp BR, Jones SP, Rimmer DM, Lefer DJ. Differential response to myocardial reperfusion injury in eNOS-deficient mice. Am J Physiol. 2002; 282: H2422–H2426.
15. Wang Y, Guo Y, Zhang SX, Wu W-J, Wang J, Bao W, Bolli R. Ischemic preconditioning upregulates inducible nitric oxide synthase in cardiac myocyte. J Mol Cell Cardiol. 2002; 34: 5–15.[CrossRef][Medline] [Order article via Infotrieve]
16. Przyklenk K, Kloner RA. Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis. J Am Coll Cardiol. 2001; 37: 286–292.
17. Zhao TC, Taher MM, Valerie KC, Kukreja RC. p38 triggers late preconditioning elicited by anisomycin in heart: involvement of NF-
B and iNOS. Circ Res. 2001; 89: 915–922.
18. Bolli R. The late phase of preconditioning. Circ Res. 2000; 87: 972–983.
19. Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol. 2001; 33: 1897–1918.[CrossRef][Medline] [Order article via Infotrieve]
20. Han J, Kim N, Joo H, Kim E, Earm YE. ATP-sensitive K+ channel activation by nitric oxide and protein kinase G in rabbit ventricular myocytes. Am J Physiol. 2002; 283: H1545–H1554.
This article has been cited by other articles:
 |
|
 |
|
  G. Szabo, T. Radovits, G. Veres, N. Krieger, S. Loganathan, P. Sandner, and M. Karck Vardenafil protects against myocardial and endothelial injuries after cardiopulmonary bypass Eur. J. Cardiothorac. Surg., October 1, 2009; 36(4): 657 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. N. Salloum, V. Q. Chau, N. N. Hoke, A. Abbate, A. Varma, R. A. Ockaili, S. Toldo, and R. C. Kukreja Phosphodiesterase-5 Inhibitor, Tadalafil, Protects Against Myocardial Ischemia/Reperfusion Through Protein-Kinase G-Dependent Generation of Hydrogen Sulfide Circulation, September 15, 2009; 120(11_suppl_1): S31 - S36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Vandeput, J. Krall, R. Ockaili, F. N. Salloum, V. Florio, J. D. Corbin, S. H. Francis, R. C. Kukreja, and M. A. Movsesian cGMP-Hydrolytic Activity and Its Inhibition by Sildenafil in Normal and Failing Human and Mouse Myocardium J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 884 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Choi, J. Y. Jeong, B. J. Lim, S. Chung, Y. K. Chang, S. J. Lee, K. R. Na, S. Y. Kim, Y. T. Shin, and K. W. Lee Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats Am J Physiol Renal Physiol, August 1, 2009; 297(2): F362 - F370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Reffelmann and R. A. Kloner Phosphodiesterase 5 inhibitors: are they cardioprotective? Cardiovasc Res, July 15, 2009; 83(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ahmad, Y. Wang, A. K. Ali, and M. Ashraf Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H387 - H391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wolk, W. B. Smith, J. M. Neutel, J. Rubino, D. Xuan, J. Mancuso, J. Gilbert, and M. L. Pressler Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension Hypertension, June 1, 2009; 53(6): 1091 - 1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Das, F. N. Salloum, L. Xi, Y. J. Rao, and R. C. Kukreja ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1236 - H1243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Yin, F. N. Salloum, and R. C. Kukreja A Novel Role of MicroRNA in Late Preconditioning: Upregulation of Endothelial Nitric Oxide Synthase and Heat Shock Protein 70 Circ. Res., March 13, 2009; 104(5): 572 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Das, L. Xi, and R. C. Kukreja Protein Kinase G-dependent Cardioprotective Mechanism of Phosphodiesterase-5 Inhibition Involves Phosphorylation of ERK and GSK3{beta} J. Biol. Chem., October 24, 2008; 283(43): 29572 - 29585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Caretti, P. Bianciardi, R. Ronchi, M. Fantacci, M. Guazzi, and M. Samaja Phosphodiesterase-5 Inhibition Abolishes Neuron Apoptosis Induced by Chronic Hypoxia Independently of Hypoxia-Inducible Factor-1{alpha} Signaling Experimental Biology and Medicine, October 1, 2008; 233(10): 1222 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Khairallah, R. J. Khairallah, M. E. Young, B. G. Allen, M. A. Gillis, G. Danialou, C. F. Deschepper, B. J. Petrof, and C. Des Rosiers Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency PNAS, May 13, 2008; 105(19): 7028 - 7033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. N. Salloum, A. Abbate, A. Das, J.-E. Houser, C. A. Mudrick, I. Z. Qureshi, N. N. Hoke, S. K. Roy, W. R. Brown, S. Prabhakar, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1398 - H1406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, Z.-y. Liu, and Q. Guan Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats Interactive CardioVascular and Thoracic Surgery, October 1, 2007; 6(5): 608 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Senthilkumar, R. D. Smith, J. Khitha, N. Arora, S. Veerareddy, W. Langston, J. H. Chidlow Jr, S. C. Barlow, X. Teng, R. P. Patel, et al. Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1947 - 1954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lucchinetti, J. Aguirre, J. Feng, M. Zhu, M. Suter, D. R. Spahn, L. Harter, and M. Zaugg Molecular Evidence of Late Preconditioning After Sevoflurane Inhalation in Healthy Volunteers Anesth. Analg., September 1, 2007; 105(3): 629 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Natarajan, F. N. Salloum, B. J. Fisher, E. D. Ownby, R. C. Kukreja, and A. A. Fowler 3rd Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1571 - H1580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zaccolo and M. A. Movsesian cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology Circ. Res., June 8, 2007; 100(11): 1569 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.G. Ferrini, I. Kovanecz, S. Sanchez, D. Vernet, H.H. Davila, J. Rajfer, and N.F. Gonzalez-Cadavid Long-Term Continuous Treatment with Sildenafil Ameliorates Aging-Related Erectile Dysfunction and the Underlying Corporal Fibrosis in the Rat Biol Reprod, May 1, 2007; 76(5): 915 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Elrod, J. J. M. Greer, and D. J. Lefer Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H342 - H347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Das, A. Smolenski, S. M. Lohmann, and R. C. Kukreja Cyclic GMP-dependent Protein Kinase I{alpha} Attenuates Necrosis and Apoptosis Following Ischemia/Reoxygenation in Adult Cardiomyocyte J. Biol. Chem., December 15, 2006; 281(50): 38644 - 38652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Kudej, Y.-T. Shen, A. P. Peppas, C.-H. Huang, W. Chen, L. Yan, D. E. Vatner, and S. F. Vatner Obligatory Role of Cardiac Nerves and {alpha}1-Adrenergic Receptors for the Second Window of Ischemic Preconditioning in Conscious Pigs Circ. Res., November 24, 2006; 99(11): 1270 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Kukreja Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channels Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2041 - H2043. [Full Text] [PDF]
|
|
|
|
 |
|
 B.-N. Wu, C.-W. Chen, S.-F. Liou, J.-L. Yeh, H.-H. Chung, and I.-J. Chen Inhibition of Proinflammatory Tumor Necrosis Factor-{alpha}-Induced Inducible Nitric-Oxide Synthase by Xanthine-Based 7-[2-[4-(2-Chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-Nitrobenzene)piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) in Rat Trachea: The Involvement of Soluble Guanylate Cyclase and Protein Kinase G Mol. Pharmacol., September 1, 2006; 70(3): 977 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-K. Dai, M.-S. Tan, C.-Y. Chai, S.-H. Chou, P.-C. Lin, J.-L. Yeh, A. Y. Jeng, C.-I Chang, I.-J. Chen, and J.-R. Wu Effects of Sildenafil on Pulmonary Hypertension and Levels of ET-1, eNOS, and cGMP in Aorta-Banded Rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 942 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Atar, Y. Ye, Y. Lin, S. Y. Freeberg, S. P. Nishi, S. Rosanio, M.-H. Huang, B. F. Uretsky, J. R. Perez-Polo, and Y. Birnbaum Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1960 - H1968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Cohen, X.-M. Yang, and J. M. Downey Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies Cardiovasc Res, May 1, 2006; 70(2): 231 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Korom, S. Hillinger, M. Cardell, W. Zhai, Q. Tan, A. Dutly, B. Leskosek, and W. Weder Sildenafil extends survival and graft function in a large animal lung transplantation model Eur. J. Cardiothorac. Surg., March 1, 2006; 29(3): 288 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Natarajan, F. N. Salloum, B. J. Fisher, R. C. Kukreja, and A. A. Fowler III Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury Circ. Res., January 6, 2006; 98(1): 133 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Borlaug, V. Melenovsky, T. Marhin, P. Fitzgerald, and D. A. Kass Sildenafil Inhibits {beta}-Adrenergic-Stimulated Cardiac Contractility in Humans Circulation, October 25, 2005; 112(17): 2642 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fung, R. R. Fiscus, A. P. C. Yim, G. D. Angelini, and A. A. Arifi The Potential Use of Type-5 Phosphodiesterase Inhibitors in Coronary Artery Bypass Graft Surgery Chest, October 1, 2005; 128(4): 3065 - 3073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ockaili, R. Natarajan, F. Salloum, B. J. Fisher, D. Jones, A. A. Fowler III, and R. C. Kukreja HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H542 - H548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhao, G. He, Y.-R. Chen, R. P. Pandian, P. Kuppusamy, and J. L. Zweier Endothelium-Derived Nitric Oxide Regulates Postischemic Myocardial Oxygenation and Oxygen Consumption by Modulation of Mitochondrial Electron Transport Circulation, June 7, 2005; 111(22): 2966 - 2972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Fisher, F. Salloum, A. Das, H. Hyder, and R. C. Kukreja Phosphodiesterase-5 Inhibition With Sildenafil Attenuates Cardiomyocyte Apoptosis and Left Ventricular Dysfunction in a Chronic Model of Doxorubicin Cardiotoxicity Circulation, April 5, 2005; 111(13): 1601 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Das, L. Xi, and R. C. Kukreja Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis: ESSENTIAL ROLE OF NITRIC OXIDE SIGNALING J. Biol. Chem., April 1, 2005; 280(13): 12944 - 12955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Gross Sildenafil and Endothelial Dysfunction in Humans Circulation, February 15, 2005; 111(6): 721 - 723. [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, C. Yin, L. Xi, and R. C. Kukreja Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2070 - H2077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C Kukreja, R. Ockaili, F. Salloum, and L. Xi Sildenafil-induced cardioprotection in rabbits Cardiovasc Res, December 1, 2003; 60(3): 700 - 701. [Full Text] [PDF]
|
|
|
|
|
|
T. Reffelmann and R. A Kloner Cardiovascular effects of sildenafil in experimental ischemia-reperfusion (reply to "Sildenafil-induced cardioprotection in rabbits, by Kukreja, R.C., Ockaili, R., Salloum, F., Xi, L.") Cardiovasc Res, December 1, 2003; 60(3): 702 - 703. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||