The novel H2S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoKATPchannels and reduction of oxidative stress.
The endogenous gasotransmitter hydrogen sulphide (H2S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H2S-donors, i.e. pro-drugs able to generate exogenous H2S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H2S-donor 4-carboxy phenyl-isothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R. In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoKATPchannels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H2S-producing enzymes to be present in myocardial tissue: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE. In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells. In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of KATPchannels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix. Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/R-induced tissue injury. In conclusion, H2S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.
Department of Pharmacy, University of Pisa, Pisa, Italy.
Lara
L
Testai
Department of Pharmacology, Weill Cornell Medicine, New York, USA.
Alice
A
Marino
Department of Pharmacy, University of Pisa, Pisa, Italy.
Ilaria
I
Piano
Department of Science, University of Basilicata, Potenza, Italy.
Vincenzo
V
Brancaleone
Department of Pharmacology, Weill Cornell Medicine, New York, USA.
Kengo
K
Tomita
Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, Florence, Italy.
Lorenzo
L
Di Cesare Mannelli
Department of Pharmacy, University of Pisa, Pisa, Italy.
Alma
A
Martelli
Department of Pharmacy, University of Pisa, Pisa, Italy.
Valentina
V
Citi
Department of Pharmacy, University of Pisa, Pisa, Italy.
Maria C
MC
Breschi
Department of Pharmacology, Weill Cornell Medicine, New York, USA.
Roberto
R
Levi
Department of Pharmacy, University of Pisa, Pisa, Italy.
Claudia
C
Gargini
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Mariarosaria
M
Bucci
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Giuseppe
G
Cirino
Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, Florence, Italy.
Carla
C
Ghelardini
Department of Pharmacy, University of Pisa, Pisa, Italy. Electronic address: calderone@farm.unipi.it.
Vincenzo
V
Calderone
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000378:metabolism / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006880:Hydroxy Acids / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D017879:Isothiocyanates; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; C005441:phenylisothiocyanate; C008366:3-mercaptopyruvic acid; C052853:5-hydroxydecanoic acid; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006862:Hydrogen Sulfide
4-hydroxyphenylisothiocyanate (PubChem CID: 121230993); Cardioprotection; H(2)S-donors; Hydrogen sulphide; Isothiocyanate; Mitochondrial potassium channels; Myocardial ischemia/reperfusion