PDE5 inhibitor efficacy is estrogen dependent in female heart disease.

Abstract

Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

• Authors: Hideyuki Sasaki, Takahiro Nagayama, Robert M Blanton, Kinya Seo, Manling Zhang, Guangshuo Zhu, Dong I Lee, Djahida Bedja, Steven Hsu, Osamu Tsukamoto, Seiji Takashima, Masafumi Kitakaze, Michael E Mendelsohn, Richard H Karas, David A Kass, Eiki Takimoto
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 6 Pg. 2464-71 (Jun 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24837433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Estrogens
• Phosphodiesterase 5 Inhibitors
• Piperazines
• Purines
• Sulfones
• Estradiol
• Sildenafil Citrate
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Cyclic GMP-Dependent Protein Kinase Type I
• GTP-Binding Protein alpha Subunits, Gq-G11
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• Cyclic GMP

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Cyclic GMP (biosynthesis)
• Cyclic GMP-Dependent Protein Kinase Type I (metabolism)
• Disease Models, Animal
• Estradiol (administration & dosage)
• Estrogens (metabolism)
• Female
• GTP-Binding Protein alpha Subunits, Gq-G11 (metabolism)
• Guanylate Cyclase (metabolism)
• Heart Diseases (drug therapy, metabolism)
• Heart Failure (drug therapy, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type III (deficiency, genetics, metabolism)
• Ovariectomy
• Phosphodiesterase 5 Inhibitors (pharmacology)
• Piperazines (pharmacology)
• Purines (pharmacology)
• Receptors, Atrial Natriuretic Factor (deficiency, genetics, metabolism)
• Sex Characteristics
• Sildenafil Citrate
• Sulfones (pharmacology)
• Treatment Outcome