JAHA: "Viagra" also has shortcomings!

Sildenafil became the first oral anti-impotence drug to be marketed in the United States in April 1998 , which made Pfizer famous .
Many studies have proved that: Sildenafil is a selective inhibitor of phosphodiesterase ( PDE ) V , which can enhance the release of nitric oxide ( NO ) under sexual stimulation , thereby causing the physiological response of penile erection, wherein NO is the cause of spongy Main mediator of smooth muscle relaxation and erection .

Sildenafil became the first oral anti-impotence drug to be marketed in the United States in April 1998 , which made Pfizer famous .

Many studies have proved that: Sildenafil is a selective inhibitor of phosphodiesterase ( PDE ) V , which can enhance the release of nitric oxide ( NO ) under sexual stimulation , thereby causing the physiological response of penile erection, wherein NO is the cause of spongy Main mediator of smooth muscle relaxation and erection .

However, some clinical cases have reported the use of sildenafil to be associated with aortic dissection, and decreased expression of PDE5A was found in human aortic aneurysm tissue .

Abdominal aortic aneurysms are more common in older men, especially those with emphysema, family history of abdominal aortic aneurysm, high blood pressure , high cholesterol , smoking, and obesity .
The study, titled "Sildenafil ( Viagra ) Aggravates the Development of Experimental Abdominal Aortic Aneurysm," published in the journal JAHA , revealed the effect of sildenafil on the worsening of abdominal aortic aneurysms .

However, some clinical cases have reported the use of sildenafil to be associated with aortic dissection, and decreased expression of PDE5A was found in human aortic aneurysm tissue .
Abdominal aortic aneurysms are more common in older men, especially those with emphysema, family history of abdominal aortic aneurysm, high blood pressure , high cholesterol , smoking, and obesity .
The study titled "Sildenafil ( Viagra ) Aggravates the Development of Experimental Abdominal Aortic Aneurysm," published in the JAHA Journal of Hypertensive Cholesterol , reveals the effect of sildenafil on the worsening of abdominal aortic aneurysms .

Research results (Image source: JAHA )

Research results (Image source: JAHA )

In a healthy aortic wall, the medial layer is composed of contractile smooth muscle cells ( SMCs ) and elastin fibers, which maintain the viscoelasticity of the aorta
.

In contrast, aortic aneurysm ( AA ) is caused by progressive wall degeneration through depletion of the medial SMC and degradation of the elastic matrix, resulting in permanent dilation of the aorta, which eventually leads to aortic rupture .

In a healthy aortic wall, the medial layer is composed of contractile smooth muscle cells ( SMCs ) and elastin fibers, which maintain the viscoelasticity of the aorta

Smooth muscle contraction mainly depends on the phosphorylation status of myosin light chain ( MLC ), which is regulated by the activities of myosin light chain kinase ( MLCK ) and myosin light chain phosphatase ( MLCP )

cGMP hydrolyzing phosphodiesterase type V ( PDE5 ) is a cGMP - specific PDE that is highly expressed in vascular SMCs .
PDE5 acts as an important regulator of SMC contraction by hydrolyzing cGMP and antagonizing PKGI -mediated vasodilation , and sildenafil is one of the PDE5 inhibitors .

The research team investigated the effect of sildenafil on the development of abdominal aortic aneurysm ( AAA )
in experimental mice .

First, abdominal aortic aneurysms were induced in mice 7 days after surgery by blocking elastin / collagen cross-linking by applying peri-aortic elastase-conjugated 3 -aminopropionitrile fumarate ( BAPN ) in male mice .
The mice were then randomized into two groups, one receiving sildenafil dissolved in water daily at a dose of 60-100 mg/kg/ day; one group drinking water without sildenafil .
Compared with mice not receiving sildenafil, mice receiving sildenafil for 4 consecutive weeks had larger abdominal aortic aneurysms, with a mean increase in width of 37% ; and degeneration or weakening of elastic fibers in abdominal aortic aneurysms degree increased by 50% .

The research team investigated the effect of sildenafil on the development of abdominal aortic aneurysm ( AAA )

Next, the researchers used immunofluorescence staining to detect the immune PDE5A protein

 Decreased expression of cGMP hydrolyzed PDE5A in medial smooth muscle cell SMCs from mouse AAA tissue (Credit: JAHA )

 Decreased expression of cGMP hydrolyzed PDE5A in medial smooth muscle cell SMCs from mouse AAA tissue (Credit: JAHA )

We examined the effect of sildenafil on SMC contractile function by immunostaining pMLC and total MLC in aortic tissue, often used as a biochemical indicator of vascular SMC contraction .

Finally, compared with the blank control group, the pMLC staining signal in the medial lesion area of ​​the AAA group was significantly reduced, indicating that sildenafil can reduce aortic SMC contractility by inhibiting MLC phosphorylation .

We examined the effect of sildenafil on SMC contractile function by immunostaining pMLC and total MLC in aortic tissue, often used as a biochemical indicator of vascular SMC contraction .
Finally, compared with the blank control group, the pMLC staining signal in the medial lesion area of ​​the AAA group was significantly reduced, indicating that sildenafil can reduce aortic SMC contractility by inhibiting MLC phosphorylation .

The effect of sildenafil on SMC type 2 MLC phosphorylation in AAA ( Credit : JAHA )

The effect of sildenafil on SMC type 2 MLC phosphorylation in AAA ( Credit : JAHA )

 Finally, we hypothesized that sildenafil reduces MLC phosphorylation through PKGI -mediated MLC dephosphorylation .

To determine the activation of PKGI by sildenafil, the binding of cGMP and PKGI was determined by proximity ligation assay ( PLA ) .
The results showed that the PLA signal was further increased in the sildenafil-treated AAA group , indicating increased cGMP and PKGI binding after sildenafil treatment; whereas immunofluorescence staining showed that PKGI expression in AAA was not significantly altered by sildenafil .
Taken together , sildenafil treatment upregulated the activation of PKG in aortic SMCs of AAA .

 Finally, we hypothesized that sildenafil reduces MLC phosphorylation through PKGI -mediated MLC dephosphorylation .
To determine the activation of PKGI by sildenafil, the binding of cGMP and PKGI was determined by proximity ligation assay ( PLA ) .
The results showed that the PLA signal was further increased in the sildenafil-treated AAA group , indicating increased cGMP and PKGI binding after sildenafil treatment; whereas immunofluorescence staining showed that PKGI expression in AAA was not significantly altered by sildenafil .
Taken together , sildenafil treatment upregulated the activation of PKG in aortic SMCs of AAA .

Effects of sildenafil on cGMP -dependent PKGI activation in AAA medial SMCs ( Credit: JAHA ) 

Effects of sildenafil on cGMP -dependent PKGI activation in AAA medial SMCs ( Credit: JAHA ) 

Taken together, sildenafil exacerbates the exacerbation of abdominal aortic aneurysm
.

PDE5 inhibitors have been used clinically in patients with erectile dysfunction or pulmonary hypertension, often with cardiovascular disease

Taken together, sildenafil exacerbates the exacerbation of abdominal aortic aneurysm

References:

[1] Zhang C, Mohan A, Shi H, et al.

Sildenafil ( Viagra ) Aggravates the Development of Experimental Abdominal Aortic Aneurysm.
JAm Heart Assoc.
2022 Jan 5:e023053.
doi: 10.

[1] Zhang C, Mohan A, Shi H, et al.
Sildenafil ( Viagra ) Aggravates the Development of Experimental Abdominal Aortic Aneurysm.
JAm Heart Assoc.
2022 Jan 5:e023053.
doi: 10.
1161/JAHA.
121.
023053.
Epub ahead ofprint.
PMID: 34984916.

[2] JAHA : " Viagra " has been found to have potentially fatal side effects and promote the worsening of abdominal aneurysms
.
http://med.
china.
com.
cn/content/pid/313270/tid/1026

[2] JAHA : " Viagra " has been found to have potentially fatal side effects and promote the worsening of abdominal aneurysms
.
http://med.
china.
com.
cn/content/pid/313270/tid/1026Leave a message here