Pharmacological characterization of the vascular effects of aryl isothiocyanates: Is hydrogen sulfide the real player?

Martelli, Alma; Testai, Lara; Citi, Valentina; Marino, Alice; Bellagambi, Francesca G.; Ghimenti, Silvia; Breschi, Maria Cristina; Calderone, Vincenzo

doi:10.1016/j.vph.2013.11.003

Cited by 89 publications

(102 citation statements)

References 35 publications

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“…The H 2 S-releasing properties of 4CPI were clearly characterized in previous studies by usual amperometric and spectrometric measurements, and further confirmed by gas chromatography, coupled with mass spectrophotometry [23].…”

Section: Discussionmentioning

confidence: 56%

“…4-carboxy phenyl-isothiocyanate (4CPI, Fig. 1) is a H 2 S-releasing compound, known to evoke vasorelaxing responses in isolated rat aorta and to increase coronary flow in isolated rat hearts [23]. Moreover, 4CPI was shown to cause membrane hyperpolarization in human aortic smooth muscle cells through the activation of Kv7 potassium channels, which play a role in H 2 Sinduced vasodilation [24].…”

Section: Introductionmentioning

confidence: 99%

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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

Testai

Marino

Piano

et al. 2016

Pharmacological Research

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a b s t r a c tThe endogenous gasotransmitter hydrogen sulphide (H 2 S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H 2 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 2 S-donors, i.e. pro-drugs able to generate exogenous H 2 S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H 2 S-donor 4-carboxy phenylisothiocyanate (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 ATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H 2 S-producing enzymes to be present in myocardial tissue: cystathionine ␥-lyase (CSE), cystathionine ␤-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 ATP 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/Rinduced tissue injury.In conclusion, H 2 S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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

Testai

Marino

Piano

et al. 2016

Pharmacological Research

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“…Endogenously presented biothiols seemed to be sufficient to promote H 2 S release from the donors. Very recently, the same group reported that aryl isothiocyanate derivatives were another type of slow-release H 2 S donors (Scheme 12) (Martelli et al 2014). Thiol activation for these donors was also necessary.…”

Section: Thioamide-and Aryl Isothiocyanate-based Donorsmentioning

confidence: 99%

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Zhao

Pacheco

Xian

2015

Handbook of Experimental Pharmacology

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Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.

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“…8 To address this issue, small molecule H 2 S donors that release H 2 S at controlled rates comparable to enzymatic H 2 S production have been prepared and investigated. 9 Current common motifs found in H 2 S donation include aryl isothiocyanates, 10 phosphinodithioates, 11 thioacids 12 /amides, 13 dithiolethiones, 14 thiolysis of trisulfides 15 and protected persulfides, 16 and stimulated release of carbonyl sulfide (COS) from thiocarbamates, which is subsequently converted to H 2 S by carbonic anhydrase. 17 Of these methods, one of the simplest and most commonly-used for H 2 S donation is the allium-derived diallyl trisulfide (DATS), which releases H 2 S upon reaction with thiols (Figure 1a).…”

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confidence: 99%

Applications of Synthetic Organic Tetrasulfides as H₂S Donors

et al. 2017

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Pharmacological characterization of the vascular effects of aryl isothiocyanates: Is hydrogen sulfide the real player?

Cited by 89 publications

References 35 publications

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

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

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Applications of Synthetic Organic Tetrasulfides as H₂S Donors

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Pharmacological characterization of the vascular effects of aryl isothiocyanates: Is hydrogen sulfide the real player?

Cited by 89 publications

References 35 publications

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

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

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Applications of Synthetic Organic Tetrasulfides as H2S Donors

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Applications of Synthetic Organic Tetrasulfides as H₂S Donors