title: Cystathionine β-synthase-derived hydrogen sulfide is involved in human malignant hyperthermia.
abstract: Hydrogen sulfide is an endogenous gasotransmitter and its mechanism of action involves activation of ATP-sensitive K(+) channels and phosphodiesterase inhibition. As both mechanisms are potentially involved in malignant hyperthermia (MH), in the present study we addressed the involvement of the L-cysteine/hydrogen sulfide pathway in MH. Skeletal muscle biopsies obtained from 25 MH-susceptible (MHS) and 56 MH-negative (MHN) individuals have been used to perform the in vitro contracture test (IVCT). Quantitative real-time PCR (qPCR) and Western blotting studies have also been performed. Hydrogen sulfide levels are measured in both tissue samples and plasma. In MHS biopsies an increase in cystathionine β-synthase (CBS) occurs, as both mRNA and protein expression compared with MHN biopsies. Hydrogen sulfide biosynthesis is increased in MHS biopsies (0.128±0.12 compared with 0.943±0.13 nmol/mg of protein per min for MHN and MHS biopsies, respectively; P<0.01). Addition of sodium hydrosulfide (NaHS) to MHS samples evokes a response similar, in the IVCT, to that elicited by either caffeine or halothane. Incubation of MHN biopsies with NaHS, before caffeine or halothane challenge, switches an MHN to an MHS response. In conclusion we demonstrate the involvement of the L-cysteine/hydrogen sulfide pathway in MH, giving new insight into MH molecular mechanisms. This finding has potential implications for clinical care and could help to define less invasive diagnostic procedures.
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.affiliation: Centre of Biotechnology, Cardarelli Hospital, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Centre for Advanced Biomaterials for Health Care (CRIB), Italian Institute of Technology, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Attanasio
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy Weill Cornell University Medical College, New York City, NY 10065, U.S.A.
authors.forename: Anna
authors.initials: A
authors.lastname: Cantalupo
authors.affiliation: Centre of Biotechnology, Cardarelli Hospital, Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Andria
authors.affiliation: Unit of Anaesthesiology and Resuscitation IV, Cardarelli Hospital, Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Savoia
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Panza
authors.affiliation: Centre of Biotechnology, Cardarelli Hospital, Naples, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Di Martino
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy cirino@unina.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
mesh_terms: D001706:Biopsy; D002110:Caffeine / Q000494:pharmacology; D016022:Case-Control Studies; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D064426:Gasotransmitters / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005905:Glyburide / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008305:Malignant Hyperthermia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D064426:Gasotransmitters; D054086:KATP Channels; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D013440:Sulfides; D002110:Caffeine; D003541:Cystathionine beta-Synthase; C025451:sodium bisulfide; D005905:Glyburide; D006221:Halothane; D006862:Hydrogen Sulfide
keywords: L-cysteine; cystathionine β-synthase; gasotransmitter; hydrogen sulfide; malignant hyperthermia; skeletal muscle