Sex, drugs, and trial design: sex influences the heart and drug responses
Elizabeth Murphy, Charles Steenbergen
Elizabeth Murphy, Charles Steenbergen
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2375-2377. https://doi.org/10.1172/JCI76262.
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Commentary

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

Abstract

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.

Authors

Elizabeth Murphy, Charles Steenbergen

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Figure 1

The cardioprotective effect of sildenafil in females is estrogen dependent.

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The cardioprotective effect of sildenafil in females is estrogen depende...
(A) In males, hypertrophic Gq stress activates sGC to promote the generation of cGMP, much of which is degraded by PDE5. Degradation of cGMP prevents the beneficial effects of PKG activation on pathological cardiac remodeling. Treatment of males with sildenafil inhibits PDE5, thus enhancing cGMP levels, which increases PKG activation. PKG phosphorylation of downstream targets blocks the pathogenic response to Gq stress. (B) In intact females, Gq stress promotes cardiac remodeling; however, Gq stress does not directly stimulate the generation of cGMP. Instead, estrogen is required to increases NO signaling, which leads to increased cGMP and activation of PKG. The protective effect of sildenafil in females requires the presence of estrogen to enhance cGMP and attenuate pathological remodeling.