Abstract
Although phosphodiesterase type 5 inhibitors are widely used and well-studied drugs, the potential benefits of their application in the treatment of various diseases and new drug delivery systems, including liposome forms, are still being discussed. In this regard, the role of the lipid matrix of cell membranes in the pharmacological action of the inhibitors is of special interest. It was shown that sildenafil, vardenafil, and tadalafil caused a significant decrease in the boundary potential of model membranes composed of palmitoyloleoylphosphatidylcholine or its mixture with cholesterol, by 70–80 mV. The reduction in the membrane dipole potential induced by inhibitors led to a 20–25% increase in the conductance of cation-selective pores formed by the antimicrobial peptide gramicidin A. The addition of sildenafil or vardenafil also led to a significant decrease in the temperature of the main phase transition of dipalmytoylphosphatidylcholine, by about 1.5 °C, while tadalafil did not change the melting temperature. Sildenafil, vardenafil, and tadalafil enhanced the pore-forming activity of the antifungal polyene antibiotic nystatin by 11, 13, and 2 times, respectively. This fact might indicate the induction of membrane curvature stress by the inhibitors. The data obtained might be of special interest for the development of lipid-mediated forms of drugs.
Highlights
For decades, sildenafil, vardenafil, and tadalafil have been used to treat erectile dysfunction through the selective inhibition of cGMP-specific phosphodiesterase type 5 (PDE-5), which is responsible for cGMP degradation in the corpus cavernosum
Tadalafil is characterized by a different structure compared with structurally related sildenafil and vardenafil and has a logPo/w value of about 2.4 [23]
Summarizing the data presented, we conclude that: (i) sildenafil, vardenafil, and tadalafil affect the membrane dipole potential due to the incorporation of their dipoles into the lipid bilayer; (ii) the greater efficiency of sildenafil and vardenafil in affecting lipid phase behavior compared with tadalafil might be related to a deeper insertion of their molecules into the hydrophobic region of the membrane; (iii) sildenafil, vardenafil, and tadalafil might influence ion channels induced by the antimicrobial peptide gramicidin A via alterations in the membrane dipole potential; (iv) the changes in the pore-forming activity of nystatin are in agreement with the assumption about the modulation of the membrane curvature stress by sildenafil, vardenafil, and tadalafil
Summary
Sildenafil, vardenafil, and tadalafil have been used to treat erectile dysfunction through the selective inhibition of cGMP-specific phosphodiesterase type 5 (PDE-5), which is responsible for cGMP degradation in the corpus cavernosum. The vasodilating and protective properties of PDE-5 inhibitors allow these drugs to be used as first-line treatment for a number of serious diseases, including pulmonary and renal hypertension, prostatitis, ischemic lesions of various organs, and in vitro fertilization. Oral administration of the drug is characterized by a significant reduction in the bioavailability and pharmacological activity due to the hepatic first-pass metabolism [7]. A delayed onset of the pharmacological effect, which usually started within 45 min after dosing, was reported [9]. Treatment with PDE-5 inhibitors requires repeated doses to sustain drug plasma levels and is concomitant with numerous side effects such as blood pressure reduction, headaches, flushing, and nasal congestion [7,8,11]
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