Tadalafil in pulmonary hypertension: May be more than seen?

I read an interesting article about the superiority of tadalafil over tempol via its antioxidant capacity on acute hypoxia-induced pulmonary hypertension (PH) model. ¹ Rashid et al. investigated and compared the antioxidant capacity of specific phosphodiesterase type-5 (PDE5) inhibitor, tadalafil, with superoxide dismutase mimetic and an efficient free radical scavenging agent tempol in acute hypoxia-induced PH model. They demonstrated that tadalafil was superior to tempol in inhibiting hypoxia-induced rise in right ventricular systolic pressure (RVSP) without producing any fall in mean arterial pressure. Also, tadalafil was shown to partially prevent oxidative stress. In conclusion, Rashid et al. highlighted the superiority of tadalafil especially in the settings of chronic hypoxia-induced PH.

Monocrotaline (MCT)-induced PH is the other widely accepted animal model in PH studies. ² MCT is a member of the pyrrolizidine alkaloid family of plant toxins, which induces a delayed, yet progressive vascular injury resulting in PH in rats, dogs and monkeys. ^3,4 It is recognized that the initial reaction to MCT-induced PH is injury to the endothelial cells that precedes media hypertrophy in small size pulmonary arteries, and leads to an increase in pulmonary artery disease. These alterations in morphology largely mimic the primary PH in humans.

We have recently compared the effects of three commercially available PDE5 inhibitors: sildenafil, vardenafil and tadalafil in rat MCT-induced PH model. ⁵ It has been briefly demonstrated that vardenafil was more effective than sildenafil and tadalafil in this model. Vardenafil relaxes pulmonary artery rings in pulmonary hypertensive group through nitric oxide (NO)-cyclic guanosine monophosphate (NO-cGMP)-independent pathway. Neither sildenafil nor tadalafil achieves to induce relaxation response in pulmonary artery rings when NO-cGMP pathway inhibitor (NO synthase inhibitor, l-NAME and soluble guanylyl cyclase inhibitor, ODQ) incubations were used. This superiority potentially results from the differences in the heterocyclic ring system of vardenafil. ⁶ Biochemical potencies (affinities) of these compounds for PDE5 have been determined by half maximal inhibitory concentration (IC₅₀) and dissociation rate (K _D), respectively, were the following: sildenafil (3.7 ± 1.4, 3.7 ± 0.29 nM), tadalafil (1.8 ± 0.40, 1.9 ± 0.37 nM), vardenafil (0.091 ± 0.031, 0.27 ± 0.01 nM), and it has been clearly demonstrated that vardenafil was the most potent inhibitor of PDE-5 because of its slow dissociation rate. ⁷ Although tadalafil has an advantage over sildenafil and vardenafil because of its longer duration of action, tadalafil did not significantly alter the time to exercise treadmill test-induced ischemia compared with placebo in subjects with coronary artery disease. ⁸ It is well-known that PH and coronary artery disease share similar risk factors, including endothelial dysfunction, diminishing of NO production and increased oxidative stress. This study is also in agreement with the others demonstrating that tadalafil was less effective than sildenafil and vardenafil in reducing the infarct size. ⁹ In other preparations such as rat aorta-penile arteries and rabbit isolated pulmonary artery–corpus cavernosum tissue, vardenafil was shown to be more potent than other PDE5 inhibitors in relaxing the vascular tissues and preparations. ^{10 –12} These discrepancies may be attributed to experimental model, protocols or preparations difference employed in these studies. Also, these studies demonstrated that vardenafil has some beneficial effects in addition to its PDE5 inhibitory activity (e.g. activation of some ion channels or blocking of calcium influx).

For the past three decades, two rodent models have been central to the investigation of human PH: the hypoxia exposure model and the MCT lung injury model. Although the increase in pulmonary arterial pressure and right ventricular hypertrophy were comparable in the rat hypoxia and MCT models, structural analysis of muscular pulmonary arteries reveals major differences between the two models. ¹³ It has been shown that chronic hypoxia and MCT induce different patterns of pulmonary vascular remodeling. Muscularization of arterioles is seen in both the models; however, medial hypertrophy of muscular pulmonary arteries is more extensive in MCT-treated rats. ^14,15 Although the pathophysiological mechanisms of hypoxic pulmonary vasoconstriction are still under discussion, Rashid et al. should also focus on pulmonary artery responsiveness in vitro and clarify the related mechanisms on the effect of tadalafil in this model. They try to explain the reason for the inhibitory effect of tadalafil on RVSP without changing cardiac output. Reduction in pulmonary vascular resistance was given as an answer for this situation by the authors. To confirm this hypothesis, the next approach would be to investigate the tadalafil-induced alterations in pulmonary tone.

Although I agree with the concept that tadalafil also showed a partial antioxidant action, we should always think and reveal the other possible responsible mechanisms associated with this protective effect.