Lipoxin A4 as a possible mediator of the beneficial actions of phosphodiesterase-5 enzyme inhibitors

Lipoxin A4 as a possible mediator of the beneficial actions of phosphodiesterase-5 enzyme inhibitors Undurti N. Das Phosphodiesterase-5 enzyme inhibitors (PDE-5-Is) such as sildenafil, vardenafil and tadalafil are used in the treatment of male erectile dys-function (ED). Their beneficial action can be attributed to an increase in the intracellular cGMP level due to inhibition of PDE-5 and consequent increase of the levels of nitric oxide (NO), a potent vasodilator, anti-in-flammatory agent and platelet anti-aggregator. In addition to their useful action in ED, PDE-5-Is have also been suggested to be of significant benefit in pulmonary hypertension, bronchial asthma, ischemic acute stroke, chronic obstructive pulmonary disease, pre-eclampsia and other diseases. In a recent study, El-Sayed and Amin [1] showed that administration of the PDE-5-Is sildenafil, vardenafil and tadalafil intravenously three times weekly for 4 weeks significantly increased PGF1α, calcium levels, prothrombin time (PT) and thrombin time (TT), and decreased TXB2 and fibrinogen levels compared to the control. Based on these results, the authors concluded that PDE-5-Is bring about their endothelial cyto-protective , thrombo-resistance anti-inflammatory and antinociception effects via activation of endothelial NOS (eNOS), increase of PGI2 synthesis and decrease of fibrinogen with significant increases in PT and TT. The results described by the authors El-Sayed and Amin are as expected, since PDE-5-Is are expected to enhance NO generation. The changes in the amount of generation of NO and differences shown by sildenafil, vardenafil and tadalafil with regard to their endothelial cyto-protective, thrombo-resistance anti-inflammatory and antinociception effects are not unexpected due to differences in their structure, half-life, pharmacodynamics and pharmacokinetics and their ability to enhance prostacyclin (PGI2) and/or decrease thromboxane A2 (TXA2) synthesis and action. In this context, I would like to suggest an alternative mechanism of action of PDE-5-Is that could explain both their beneficial effects and differences in their endothelial cyto-protective, thrombo-resistance anti-inflammatory and antinociception effects. I propose that the PDE-5-Is sildenafil, vardenafil and tadalafil either directly or by their ability to inhibit PDE are able to enhance formation of the anti-inflammatory, cytoprotective and antino-ciceptive molecule lipoxin A4 (LXA4). Cis-linoleic acid (LA, 18:2 w-6) and α-linolenic acid (ALA, 18:3 w-3) are called " essential fatty acids " (EFAs) since they are not formed in the body. Cis-linoleic acid is converted to g-linolenic acid (GLA, 18:3, w-6) by the enzyme D 6 desaturase, and GLA, in turn, is elongated to form di-homo-GLA (DGLA, 20:3, w-6), the precursor of the 1 series of …