We have read with great interest the recent article by Sesti et al.,1 which reports the protective effect of Cialis (tadalafil) against myocardial infarction in rats. This study led by Dr Kloner is the newest addition to the growing list of published studies on cardioprotective effects of phosphodiesterase type-5 (PDE-5) inhibitors, the class of drugs used to treat erectile dysfunction in men. The authors show that oral administration of tadalafil (10 mg/kg) 2 h before 30 min-coronary artery occlusion resulted in a smaller infarct size (42±2%) as compared with the vehicle-treated animals (54±3%; P<0.01). This infarct-limiting protection by tadalafil was associated with only a mild decline in mean arterial blood pressure.1 The study is particularly interesting because it extends further support to our original hypothesis that the class of PDE-5 inhibitors has anti-infarct effect against ischemia–reperfusion injury (I–R).2
In 2002, we first reported a powerful protective effect of sildenafil against myocardial infarction in a rabbit model of I–R in vivo.3 Since then, several laboratories across the world reproduced these findings in various animal models of I–R injury as summarized in Table 1. Moreover, a recent study from our laboratory showed that vardenafil (Levitra), another potent PDE-5 inhibitor, was equally effective as sildenafil in reducing infarct size following I–R injury in rabbits.4 The present study demonstrates the protective effect of a longer acting PDE-5 inhibitor suggesting that the differences in half-life of the three PDE-5 inhibitors has little, if any impact on the cardioprotective effect, at least during the acute time-window of treatment 30 min before I--R. The degree of infarct size reduction was, however, lower with tadalafil (∼22%)1 as opposed to sildenafil (68%)3 or vardenafil (58%)4 in rabbits as reported previously from our laboratory. These differences may be attributed to the animal species studied (rat versus rabbit) or lower potency of tadalafil (IC50 6.74 nM) as compared to sildenafil (IC50 3.5 nM) and vardenafil (IC50 0.14 nM). Nevertheless, the current study reconciles a previous discrepancy between Kloner's group and ours concerning sildenafil-induced acute infarct size reduction in rabbits.5 Another important aspect of this study is that it was conducted in an investigator-blinded manner. The drug manufacturer labeled the bottles of tadalafil and vehicle with a secret code, which eliminated any possible bias in infarct size assessment.1
Ischemic heart disease (IHD) remains a leading cause of morbidity and mortality in the global community, particularly those of age 65 years and older. Over the past 30 years, a large number of studies have been performed aiming at developing novel cardioprotective therapies for treatment of IHD. Unfortunately, none has produced any notable clinical applications. Considering the safety of PDE-5 inhibitors and their overwhelmingly reproducible protective effects in the heart and their potential benefits in other organ systems,6 it is logical to expect that this class of drugs may be promising therapeutic agents to treat IHD, similar to the recently approved use of sildenafil for treating pulmonary hypertension. Clearly, future clinical trials are required to fully exploit the cardioprotective potential of PDE-5 inhibitors in patients.
Sesti C, Florio V, Johnson EG, Kloner RA . The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. Int J Impot Res 2007; 19: 55–61.
Kukreja RC, Ockaili R, Salloum F, Yin C, Hawkins J, Das A et al. Cardioprotection with phosphodiesterase-5 inhibition – a novel preconditioning strategy. J Mol Cell Cardiol 2004; 36: 165–173.
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 Heart Circ Physiol 2002; 283: H1263–H1269.
Salloum FN, Ockaili RA, Wittkamp M, Marwaha VR, Kukreja RC . Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial KATP channels in rabbits. J Mol Cell Cardiol 2006; 40: 405–411.
Kukreja RC, Ockaili R, Salloum F, Xi L . Sildenafil-induced cardioprotection in rabbits. Cardiovasc Res 2003; 60: 700–701.
Schwarz ER, Kapur V, Rodriguez J, Rastogi S, Rosanio S . The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res 2007; 19: 139–148.
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Kukreja, R., Salloum, F. & Xi, L. Anti-ischemic effects of sildenafil, vardenafil and tadalafil in heart. Int J Impot Res 19, 226–227 (2007) doi:10.1038/sj.ijir.3901533
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