The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

• Published in: Pharmacological research 2016-11, Vol.113 (Pt A), p.290-299
• Main Authors: Testai, Lara, Marino, Alice, Piano, Ilaria, Brancaleone, Vincenzo, Tomita, Kengo, Di Cesare Mannelli, Lorenzo, Martelli, Alma, Citi, Valentina, Breschi, Maria C, Levi, Roberto, Gargini, Claudia, Bucci, Mariarosaria, Cirino, Giuseppe, Ghelardini, Carla, Calderone, Vincenzo
• Format: Article
• Language: English
• Subjects: Animals; Cardiotonic Agents - pharmacology; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - metabolism; Cystathionine beta-Synthase - metabolism; Cystathionine beta-Synthase - pharmacology; Cystathionine gamma-Lyase - metabolism; Cysteine - analogs & derivatives; Cysteine - pharmacology; Decanoic Acids - pharmacology; Heart - drug effects; Hydrogen Sulfide - metabolism; Hydroxy Acids - pharmacology; Isothiocyanates - pharmacology; Male; Mast Cells - drug effects; Mast Cells - metabolism; Mice; Mice, Inbred C57BL; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Ischemia - drug therapy; Myocardial Ischemia - metabolism; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Oxidative Stress - drug effects; Potassium Channels - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2016.09.006

The endogenous gasotransmitter hydrogen sulphide (H S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H S 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, H S-donors, i.e. pro-drugs able to generate exogenous H S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H S-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 mitoK channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H S-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 K channels). 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, H S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.