Rafael Fais
◽
Rafael Menezes da Costa
◽
Allan Carvalho Mendes
◽
Fabiola Antunes Cardoso Mestriner
◽
Simon Comerma-Steffensen
◽
...
Background and Purpose: Endothelin-1 (ET-1) and Nucleotide
Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3
(NLRP3) play an essential role in erectile dysfunction. ET-1 and NLRP3
activate inflammatory processes by increasing calcium
(Ca) and reactive oxygen species (ROS). In the
present study, we hypothesized that endothelin receptors
(ET and ET) stimulation, through
increased calcium and ROS formation, leads to NLRP3 activation.
Experimental approach: Intracavernosal pressure (ICP/MAP) was
measured in C57BL/6 (WT) mice. Functional and immunoblotting assays were
performed in corpora cavernosa (CC) strips from WT,
NLRP3 and caspase mice after
ET-1 (100 nM) stimulation in the presence of vehicle, MCC950, tiron,
BAPTA AM, BQ123, or BQ788. Key Results: ET-1 gradually reduced
the ICP/MAP in WT mice, and MCC950 administration prevented the effect
of ET-1. ET-1 decreased CC relaxation to ACh and sodium nitroprusside
(SNP) and increased caspase-1 protein expression, effects reversed by
the ET receptor antagonist BQ123. The
ET receptor antagonist BQ788 also reversed the effect
of ET-1 on ACh and SNP relaxation. Additionally, tiron, BAPTA AM, and
NLRP3 genetic deletion prevented the ET-1-induced loss of ACh and SNP
relaxation. Moreover, BQ123 diminished CC caspase-1 expression, while
BQ788 increased caspase-1 and IL-1β levels in a concentration-dependent
manner (100 nM to 10 µM). Furthermore, tiron and BAPTA AM prevented
ET-1-induced increase in caspase-1. In addition, BAPTA AM blocked
ET-1-induced ROS generation. Conclusion and Implications: NLRP3
activation contributes to acute ET-1-induced erectile dysfunction by
mechanisms that depend on ET- and
ET-induced Ca influx and ROS
generation.