phosphodiesterase type
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2022 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Sajad Moradi ◽  
Dinyar Khazaeli ◽  
Mohammadreza Dadfar ◽  
Nima Bakhtiari

Background: We aimed to evaluate the safety and efficacy of 50-unit dose against 100-unit dose of intracavernosal injection (ICI) of AbobotulinumtoxinA (BTX-A) (Masport®) in patients with vascular erectile dysfunction (ED) resistant to first-line therapies, including phosphodiesterase type 5 inhibitors (PDE5I). Methods: In this double-blind randomized controlled trial (RCT), 40 patients with ED resistant to PDE5I were randomly divided into two groups: ICI of a single dose of Masport® 50 units and single dose of 100 units. Peak systolic velocity (PSV) confirmed arterial insufficiency vascular disorder. For all patients, IIEF (International Index of Erectile Function), SHIM (Sexual Health Inventory for Men), and EHS (Erection Hardness Score) questionnaires were completed. Six weeks after the treatment, the subjects were re-examined. Results: Our results showed an acceptable clinical efficacy and safety of ICI of Masport® six weeks after injection. No systemic complications in patients were seen. Three patients complained of brief penile pain shortly after injection, but there were no other local complications. The increase in mean PSV in the 100-unit group due to treatment was significant (P-value < 0.0001). Also, there was a significant difference between the two groups of 50- and 100-unit (P-value < 0.0001). In addition, the increase in mean IIEF-EF, SHIM score, and EHS due to treatment was significant between the two groups. For the 100-unit group, P-value < 0.0001 and the difference between the two groups was also significant (P-value < 0.0001), which indicated a better response to treatment in the 100-unit group. The mean increase of IIEF score (EF domain) was 4.3 (mean IIEF: 9.4 and 13.7 after and before, respectively) in the 100-unit group and (mean IIEF: 8.1 and 9.1 after and before, respectively) in the 50-unit group. Conclusions: The results of this study showed that ICI of AbobotulinumtoxinA, especially at a dose of 100 units, in patients with refractory vasculogenic ED is safe and effective in improving sexual function and ultrasound indices.


Author(s):  
Chongyang Zhang ◽  
Amy Mohan ◽  
Hangchuan Shi ◽  
Chen Yan

Background cGMP‐hydrolyzing phosphodiesterase type 5 (PDE5) regulates vascular smooth muscle cell (SMC) contraction by antagonizing cGMP‐dependent protein kinase I (PKGI)–dependent SMC relaxation. SMC contractile dysfunction is implicated in the pathogenesis of aortic aneurysm. PDE5 inhibitors have been used for treating erectile dysfunction, such as drug Viagra (sildenafil). However, a few clinical cases have reported the association of Viagra usage with aortic dissection, and reduced PDE5A expression was found in human aortic aneurysm tissues. Therefore, we aimed to investigate the effect of sildenafil on experimental abdominal aortic aneurysm (AAA), the most common form of aortic aneurysm in elderly men. Methods and Results AAA was induced in C57BL/6J male mice by periaortic elastase in combination with blocking elastin/collagen formation via 3‐aminopropionitrile fumarate salt for 35 days. PDE5A protein levels detected by immunostaining were significantly reduced in mouse AAA. Sildenafil application in drinking water significantly aggravated aortic wall dilation and elastin degradation with pre‐existing moderate AAA. The phosphorylation level of myosin light chain 2 at Ser19, a biochemical marker of SMC contraction, was significantly reduced by sildenafil in AAA. Proximity ligation assay further revealed that the interaction between cGMP and PKGI was significantly increased by sildenafil in AAA, suggesting an elevation of PKGI activation in AAA. Conclusions Sildenafil treatment aggravated the degradation of elastin fibers and progression of experimental AAA by dysregulating cGMP and contractile signaling in SMCs. Our findings may raise the caution of clinical usage of Viagra in aneurysmal patients.


Author(s):  
Amy J. Tibbo ◽  
Delphine Mika ◽  
Sara Dobi ◽  
Jiayue Ling ◽  
Aisling McFall ◽  
...  

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 893
Author(s):  
Anastasiia A. Zakharova ◽  
Svetlana S. Efimova ◽  
Olga S. Ostroumova

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.


2021 ◽  
Author(s):  
◽  
Manvi Yadav

<p>Bidirectional communication between mammalian oocytes and their surrounding somatic cells is essential for oocyte maturation. Gap junctions promote the transfer of essential metabolites, nucleotides, amino acids and ions from cumulus cells to the oocyte that are crucial for oocyte growth and development. However, the range of factors present in the microenvironment of the developing antral follicle, which modulate gap junction activity of the cumulus-oocyte complexes (COCs), is largely unknown. The primary objective of this study was to determine the effects of various steroids, growth factors and cAMP stimulators on the gap junction activity in rat COCs. The gap junction activity was measured in presence or absence of different treatments using a fluorescence dye and in the presence of milrinone, a phosphodiesterase type 3 inhibitor. The major findings of this study were that cAMP stimulators increased the rate of dye transfer from cumulus cells to the oocyte. Under in vitro conditions it was established that neither steroids nor IGF1 by themselves were able to modulate gap junction activity in rat COCs. Furthermore, forskolin, a potent cAMP stimulator; caused a relative increase in Cx37 gene expression levels following a four hours incubation period. The outcomes from the present study may help to provide new insights into developing suitable in vitro conditions, for the in vitro maturation of mammalian oocytes.</p>


2021 ◽  
Author(s):  
◽  
Manvi Yadav

<p>Bidirectional communication between mammalian oocytes and their surrounding somatic cells is essential for oocyte maturation. Gap junctions promote the transfer of essential metabolites, nucleotides, amino acids and ions from cumulus cells to the oocyte that are crucial for oocyte growth and development. However, the range of factors present in the microenvironment of the developing antral follicle, which modulate gap junction activity of the cumulus-oocyte complexes (COCs), is largely unknown. The primary objective of this study was to determine the effects of various steroids, growth factors and cAMP stimulators on the gap junction activity in rat COCs. The gap junction activity was measured in presence or absence of different treatments using a fluorescence dye and in the presence of milrinone, a phosphodiesterase type 3 inhibitor. The major findings of this study were that cAMP stimulators increased the rate of dye transfer from cumulus cells to the oocyte. Under in vitro conditions it was established that neither steroids nor IGF1 by themselves were able to modulate gap junction activity in rat COCs. Furthermore, forskolin, a potent cAMP stimulator; caused a relative increase in Cx37 gene expression levels following a four hours incubation period. The outcomes from the present study may help to provide new insights into developing suitable in vitro conditions, for the in vitro maturation of mammalian oocytes.</p>


Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1658
Author(s):  
Yasuyoshi Miyata ◽  
Tomohiro Matsuo ◽  
Yuichiro Nakamura ◽  
Kensuke Mitsunari ◽  
Kojiro Ohba ◽  
...  

Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many factors, such as fibrosis, lipid metabolism abnormalities, the immune system, and stem cells, play crucial roles in the etiology and development of ED. Although phosphodiesterase type 5 (PDE5) inhibitors are currently the standard treatment agents for patients with ED, they are effective only in a subgroup of patients. Therefore, further insight into the pathological mechanism underlying ED is needed to discuss ED treatment strategies. In this review, we focused on the biological and pathological significance of macrophages in ED because the interaction of macrophages with ED-related mechanisms have not been well explored, despite their important roles in vasculogenic and neurogenic diseases. Furthermore, we examined the pathological significance of macrophages in Peyronie’s disease (PD), a cause of ED characterized by penile deformation (visible curvature) during erection and pain. Although microinjury and the subsequent abnormal healing process of the tunica albuginea are known to be important processes in this disease, the detailed etiology and pathophysiology of PD are not fully understood. This is the first review on the pathological role of macrophages in PD.


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