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Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial KATP channels when administered at reperfusion following ischemia in rabbits

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Abstract

Phosphodiesterase-5 (PDE-5) inhibitors including sildenafil and vardenafil induce powerful preconditioning-like cardioprotective effect against ischemia/reperfusion injury through opening of mitochondrial KATP channels in the heart. The goal of these studies was to demonstrate the protective effect of sildenafil and vardenafil on reperfusion injury and to compare it with the antianginal vasodilator nitroglycerin (NTG). In addition, we determined the role of mitochondrial KATP channels in protection. Adult male New Zealand white rabbits were anesthetized and subjected to ischemia by 30 min of coronary artery occlusion followed by 3 h of reperfusion. Seven groups were studied. 1—Controls; 2—Sildenafil (total dose: 0.71 mg/kg; iv) infused for 65 min starting 5 min before reperfusion; 3—Sildenafil + 5-hydroxydecanoate (5-HD, blocker of mitochondrial KATP channel, total dose: 5 mg/kg) administered as 2 bolus injections; 4—Vardenafil (total dose: 0.014 mg/kg; iv) administered as in group 2; 5—Vardenafil + 5-HD administered as in group 3; 6—5-HD administered as two bolus injections and 7—Nitroglycerin (NTG, total dose: 2 μg kg 1 min 1) administered as in group 2. Infarct size was reduced in sildenafil (19.19 ± 1.3%) as well as vardenafil (17.0 ± 2.0%) treated groups as compared to controls (33.8 ± 1.7%). However, NTG failed to confer similar cardioprotection (31.5 ± 0.8%). 5-HD blocked the cardioprotective effects of sildenafil and vardenafil as shown by an increase in infarct size (34.0 ± 1.1% and 28.3 ± 1.9%, respectively). Both sildenafil and vardenafil protect the ischemic myocardium against reperfusion injury through a mechanism dependent on mitochondrial KATP channel opening.

Introduction

Phosphodiesterase-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a class of drugs that have been developed for treatment of erectile dysfunction (ED) [1] and more recently for pulmonary artery hypertension [2]. A number of recent studies from our laboratory demonstrated powerful preconditioning-like cardioprotection with PDE-5 inhibitors against ischemia/reperfusion (I/R) injury in several animal models [3], [4], [5], [6], [7] that extends beyond their therapeutic capacity for treatment of ED. We showed that PDE-5 inhibition caused significant reduction of infarct size [3], [4], [7], inhibition of necrosis and apoptosis in adult cardiomyocytes [5] and attenuation of doxorubicin-induced cardiomyopathy in mice [8]. We also demonstrated that the cardioprotective effect of PDE-5 inhibition is mediated through opening of mitochondrial KATP (mitoKATP) channel [1], [6] and activation of KCa channel [9]. In addition, we showed that nitric oxide (NO) generated from endothelial (eNOS) and inducible (iNOS) nitric oxide synthase [4] as well as activation of protein kinase C (PKC) [10] played a role in the cardioprotective effect of sildenafil. All of these studies were performed under experimental conditions where the animals or cardiomyocytes were treated with PDE-5 inhibitors prior to ischemia. However, it is not known whether these drugs would cause infarct size reduction when administered at reperfusion.

Nitroglycerin (glyceryl trinitrate, NTG) has been used to treat angina and heart failure for over 130 years. It is assumed that NTG is converted in vascular smooth muscle cells to NO or an NO congener (S-nitrosothiol, SNO), which activates guanylate cyclase and thus relaxes vascular smooth muscle [11], [12]. Studies have shown that pretreatment with NTG produces a delayed cardioprotective effect that improves tolerance to ischemia during coronary angioplasty [13]. Also, there is ample evidence which suggests that exogenous nitric oxide (NO) that results from administration of a NO donor is cardioprotective [14], [15], [16]. In the current study, we hypothesized that a similar protection against I/R would be possible if PDE-5 inhibitors or NTG were administered at the time of reperfusion. Our data suggest that both sildenafil and vardenafil, but not NTG, reduce infarct size in the rabbit heart following I/R when infused at reperfusion. The protective effect of PDE-5 inhibitors was blunted by treatment with 5-hydroxydecanoate (5-HD), a putative blocker of the mitoKATP channel [17].

Section snippets

Animals

Male New Zealand White rabbits (2.8–3.3 kg) were used for the studies. The care and use of the animals were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of Virginia Commonwealth University and the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 80-23; Office of Science and Health Reports, Bethesda, MD 20205].

Myocardial infarction protocol

The rabbit model of I/R has been described previously [2]. After the

Infarct size

The infarct size (% of risk area, mean ± SE, P < 0.05) decreased from 33.8 ± 1.7 in the saline-treated control group to 19.2 ± 1.3 and 17.0 ± 2.0 in the sildenafil and vardenafil-treated rabbits, respectively (Fig. 1B). The infarct-limiting effect of sildenafil and vardenafil was abolished in animals treated with 5-HD as shown by significant increase in infarct size to 34.0 ± 1.1 and 28.3 ± 1.9, respectively. In contrast, NTG failed to mimic the protective effect of PDE-5 inhibitors as indicated by an

Discussion

Our results show that intravenous administration of sildenafil or vardenafil at reperfusion induced a significant cardioprotective effect as demonstrated by a reduction in infarct size when compared to the saline-treated controls. The cardioprotective effect of PDE-5 inhibitors at reperfusion was similar to their preconditioning-like effect [3], [7], whereas NTG failed to express similar infarct-limiting effects. The protection was blocked by 5-HD suggesting that it was mediated by opening of

Acknowledgements

This study was supported in part by grants from National Institutes of Health (HL51045, HL59469, and HL79424), Pfizer Inc. and Bayer Healthcare AG to RCK.

References (43)

  • L.B. Kane et al.

    Present and future treatment strategies for pulmonary arterial hypertension: focus on phosphodiesterase-5 inhibitors

    Treat. Respir. Med.

    (2006)
  • R. Ockaili et al.

    Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial KATP channels in rabbits

    Am. J. Physiol.: Heart Circ. Physiol.

    (2002)
  • F. Salloum et al.

    Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart

    Circ. Res.

    (2003)
  • S. Das et al.

    Cardioprotection with sildenafil, a selective inhibitor of cyclic 3′,5′-monophosphate-specific phosphodiesterase 5

    Drugs Exp. Clin. Res.

    (2002)
  • P.W. Fisher et al.

    Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity

    Circulation

    (2005)
  • X. Wang et al.

    Essential role of Ca2+-activated K+ channels in triggering and mediating sildenafil-induced delayed cardioprotection: evidence from pharmacological inhibition and in vivo gene knockdown with small interfering RNA

    Circulation

    (2005)
  • A. Das et al.

    Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

    Am. J. Physiol.: Heart Circ. Physiol.

    (2004)
  • F. Murad et al.

    Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin

    Adv. Cyclic Nucleotide Res.

    (1978)
  • L.J. Ignarro et al.

    Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates

    J. Pharmacol. Exp. Ther.

    (1981)
  • M.A. Leesar et al.

    Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty

    Circulation

    (2001)
  • D.J. Lefer et al.

    Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion in dogs

    Circulation

    (1993)
  • Cited by (0)

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