[HTML][HTML] Sex, drugs, and trial design: sex influences the heart and drug responses

E Murphy, C Steenbergen - The Journal of clinical …, 2014 - Am Soc Clin Investig
E Murphy, C Steenbergen
The Journal of clinical investigation, 2014Am Soc Clin Investig
Preclinical studies indicate that the phosphodiesterase 5 (PDE5) inhibitor sildenafil is
protective against hypertrophy-induced cardiac remodeling. Despite an initial clinical study
demonstrating sildenafil-dependent amelioration of pathological remodeling, the
cardioprotective effect of this drug was not significant in a large placebo-controlled clinical
trail. In this issue, Sasaki and colleagues reveal that the efficacy of PDE5 inhibition in female
mice requires estrogen. Induction of cardiac stress in male and intact female mice resulted in …
Preclinical studies indicate that the phosphodiesterase 5 (PDE5) inhibitor sildenafil is protective against hypertrophy-induced cardiac remodeling. Despite an initial clinical study demonstrating sildenafil-dependent amelioration of pathological remodeling, the cardioprotective effect of this drug was not significant in a large placebo-controlled clinical trail. In this issue, Sasaki and colleagues reveal that the efficacy of PDE5 inhibition in female mice requires estrogen. Induction of cardiac stress in male and intact female mice resulted in increased activation of protein kinase G (PKG) signaling, which was further enhanced by sildenafil. PKG activity was not enhanced in ovariectomized (OVX) female mice as a result of cardiac stress, but administration of estrogen restored PKG activation and enhancement by sildenafil. These data highlight the importance of considering sex-specific differences and drug responses in clinical trial design.
The Journal of Clinical Investigation