Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions.

Autor:	Pereira DA; Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)., Calmasini FB; Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)., Costa FF; Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)., Burnett AL; Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.)., Silva FH; Laboratory of Pharmacology, São Francisco University Medical School, Bragança Paulista, SP, Brazil (D.A.P., F.H.S.); Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Pharmacology, São Paulo, SP, Brazil (F.B.C.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.F.C.); and The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, Maryland (A.L.B.) fabio.hsilva@usf.edu.br fabiohsilva87@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jul 18; Vol. 390 (2), pp. 203-212. Date of Electronic Publication: 2024 Jul 18.
DOI:	10.1124/jpet.123.001962
Abstrakt:	Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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