Phosphodiesterase-5 enzyme inhibitors (PDE-5-Is) such as sildenafil, vardenafil and
tadalafil are used in the treatment of male erectile dysfunction (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-inflammatory 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 antinociceptive molecule lipoxin A4 (LXA4).
Cis-linoleic acid (LA, 18:2 ω-6) and α-linolenic acid (ALA, 18:3 ω-3) are called “essential
fatty acids” (EFAs) since they are not formed in the body. Cis-linoleic acid is converted
to γ-linolenic acid (GLA, 18:3, ω-6) by the enzyme Δ6 desaturase, and GLA, in turn,
is elongated to form di-homo-GLA (DGLA, 20:3, ω-6), the precursor of the 1 series
of prostaglandins. DGLA can be converted to arachidonic acid (AA, 20:4, ω-6) by the
enzyme Δ5 desaturase, the precursor of the 2 series of prostaglandins, thromboxanes
and the 4 series leukotrienes (LTs). Arachidonic acid is also converted into non-enzymatic
lipid mediators – 4-hydroxynonenal, isoprostanes, isoketals and isofurans – in tissues
by free radicals in vivo and are useful as markers for oxidative stress.
Similar to ω-6 LA, ω-3 ALA is converted to eicosapentaenoic acid (EPA, 20:5, ω-3)
by Δ6 and Δ5 desaturases, the precursor of the 3 series of prostaglandins and the
5 series of LTs. Eicosapentaenoic acid can be elongated to form docosahexaenoic acid
(DHA, 22:6, ω-3). The AA, EPA and DHA also give rise to anti-inflammatory lipoxins:
resolvins, protectins and maresins [2–11] (see Figure 1 for metabolism of EFAs and
the formation of lipoxins and resolvins). Eicosanoids bind to G protein-coupled receptors
and mediate many steps of inflammation [7–10]. Non-steroidal anti-inflammatory drugs
(NSAIDs) such as aspirin inhibit cyclo-oxygenase (COX) activity and thus bring about
their anti-inflammatory action.
Figure 1
Schematic diagram showing metabolism of essential fatty acids, their role in inflammation
and cytoprotection of endothelial cells
The general purpose of lipoxins and similar compounds generated from AA, EPA and DHA
is not only to suppress the production of pro-inflammatory prostaglandins, thromboxanes,
leukotrienes and isoprostanes but also to limit inflammation, enhance wound healing
and resolve inflammation and thus restore cell function to normal. Hence, when the
formation of lipoxins, resolvins, protectins and maresins is defective or subnormal,
it could lead to persistent inflammation and tissue injury [6]. This implies that
increased formation of lipoxins, resolvins, protectins and maresins protects various
cells including endothelial cells against the cytotoxic action of interleukin-6 (IL-6),
tumor necrosis factor-α (TNF-α) and free radicals.
In this context, it is interesting to note that the beneficial effects of aspirin
can be related to its inhibitory action on the enzyme cyclooxygenase (COX-2) and consequently
a decrease in the production of pro-inflammatory prostaglandins (PGs), thromboxanes
(TXs) and leukotrienes (LTs). It is noteworthy that aspirin does not interfere with
the production of PGI2 but decreases the production of TXA2. In addition to inhibiting
COX-2 activity, aspirin can also inhibit pro-inflammatory signaling pathways, gene
expression and other factors distinct from eicosanoid biosynthesis that drive inflammation
as well as enhance the synthesis of endogenous protective anti-inflammatory factors.
Recent studies showed that aspirin induces the production of NO, which inhibits leukocyte/endothelium
interaction during acute inflammation. Aspirin has the unique ability to acetylate
the active site of inducible cyclooxygenase (COX-2), a property not shared with other
NSAIDs, and generate the anti-inflammatory lipid mediators lipoxins (so-called aspirin-triggered
epi-lipoxins), compounds that have profound roles in a range of host defense responses
[12]. It was reported that a single anti-inflammatory dose of aspirin caused high
levels of nitrite/nitrate to appear in the peripheral blood of the treated animals
after a few hours. It was noted that a reduction in local inflammation correlated
inversely with a dose-dependent and significant increase in plasma NO levels [13].
Further studies revealed that inhibiting aspirin-elicited NO nullified the anti-inflammatory
effects of aspirin. Moreover, aspirin was not anti-inflammatory in either constitutive
(eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1β-induced peritonitis.
It was found that aspirin generated NO through its unique ability to trigger the synthesis
of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 inhibited leukocyte trafficking
in an NO-dependent manner. Both aspirin and 15-epi-lipoxin A4 markedly reduced effects
on leukocyte-endothelial cell adherence in eNOS- and iNOS-deficient mice compared
with wild type. This evidence led to the conclusion that aspirin acetylates COX 2
within the endothelium or circulating leukocytes to trigger 15-epi-lipoxin A4, which,
in turn, elicits NO synthesis from both eNOS and iNOS. It is this aspirin-triggered
NO that mediates the anti-inflammatory effects of aspirin in the microcirculation
[13]. These results imply that one of the factors that regulate the production of
NO is LXA4.
This is supported by the observation that the phosphodiesterase-III inhibitor cilostazol
augments the infarct size (IS)-limiting effects of MK0626 (MK), a dipeptidyl-peptidase-4
(DPP4) inhibitor, by increasing intracellular cAMP in mice with type-2 diabetes. MK
and cilostazol additive IS-limiting effects in diabetic mice were found to be associated
with an increase in myocardial cAMP levels and protein kinase A (PKA) activity with
downstream phosphorylation of Akt, eNOS, 5-lipoxygenase and CREB and downregulation
of PTEN expression. It was shown that PKA phosphorylates 5-lipoxygenase at ser523,
leading to increased production of 15-epi-lipoxin A4 [14–16].
Based on these results [12–16], I suggest that the beneficial actions of PDE-5-Is
shown by El-Sayed and Amin [1] are, at least in part, due to increased formation of
LXA4 and, possibly, resolvins, protectins and maresins. This proposal could be verified
by measuring plasma and tissue levels of LXA4 in those experimental animals and humans
treated with sildenafil, vardenafil and tadalafil. This also implies that deficiency
of AA, EPA and DHA (as would occur in EFA-deficient states) could interfere with the
beneficial actions of sildenafil, vardenafil and tadalafil due to reduced formation
of LXA4, resolvins, protectins and maresins. In addition, it is known that LXA4 has
potent anti-nociceptive action similar to PDE-5-Is [17–19]. Based on the preceding
discussion, it is concluded that further research is needed to confirm the role of
LXA4, resolvins, protectins and maresins as one of the mechanisms of action of PDE-5-Is
under different (patho)physiological conditions.