Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel

Calderone, Vincenzo; Testai, Lara; Martelli, Alma; Rapposelli, Simona; Digiacomo, Maria; Balsamo, Aldo; Breschi, Maria Cristina

doi:10.1016/j.bcp.2009.07.017

Cited by 36 publications

(41 citation statements)

References 44 publications

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“…To solidify this hypothesis, we investigated the effects of 4CPI on isolated rat heart mitochondria. As previously observed with activators of mitochondrial potassium channels, 4CPI caused a partial depolarization of the mitochondrial membrane potential [28]. This effect was inhibited by ATP, thus suggesting the involvement of ATP-sensitive channels.…”

Section: Discussionsupporting

confidence: 82%

“…The final mitochondrial pellet was resuspended in a minimal volume of 400 l of the isolation buffer (without EGTA) and stored on ice throughout the experiments, which were performed within 2 h. Mitochondrial protein concentrations were determined using the Bradford reaction. Previous experiments (data not shown) confirmed the reliability of the isolation procedures by measurement of the mitochondrial respiratory function with an ATP bioluminescence assay, in agreement with the method of Drew and Leeuwenburgh, as previously described [28].…”

Section: Isolated Cardiac Mitochondriasupporting

confidence: 83%

“…Mitochondrial membrane potential ( m) was measured potentiometrically with tetraphenylphosphonium (TPP + )-sensitive mini-electrodes, coupled with a reference electrode (WPI, FL, USA), using a data acquisition software (Biopac Inc. California, USA), as previously described [28]. Briefly, electrodes were calibrated before each experiment using known concentrations of TPP + Cl − .…”

Section: Mitochondrial Membrane Potentialmentioning

confidence: 99%

“…Mitochondrial calcium uptake was measured by potentiometric technique, as described [28]. In particular, the changes of calcium concentration in the medium (i.e.…”

Section: Mitochondrial Calcium Uptakementioning

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: Discussionsupporting

confidence: 82%

Section: Isolated Cardiac Mitochondriasupporting

confidence: 83%

Section: Mitochondrial Membrane Potentialmentioning

confidence: 99%

“…Mitochondrial calcium uptake was measured by potentiometric technique, as described [28]. In particular, the changes of calcium concentration in the medium (i.e.…”

Section: Mitochondrial Calcium Uptakementioning

confidence: 99%

See 2 more Smart Citations

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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“…Liver tissue was used to obtain the mitochondrial pellet by differential centrifugations (Calderone et al, 2010). Rat liver mitochondria were used for these studies, because purified healthy mitochondria from intestinal tissues could not be obtained in sufficient yields.…”

Section: Methodsmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E 2 (PGE 2 ) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE 2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

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Synthesis and Biological Evaluation of 2′‐Oxo‐2,3‐dihydro‐3′H‐ spiro[chromene‐4,5′‐[1,3]oxazolidin]‐3′yl]acetic Acid Derivatives as Aldose Reductase Inhibitors

Rapposelli

Settimo

Digiacomo

et al. 2011

Archiv der Pharmazie

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Aldose reductase (ARL2) is the first enzyme in the polyol pathway which catalyzes the NADPH-dependent reduction of glucose to sorbitol. Its involvement on diabetic complications makes this enzyme a challenge therapeutic target widely investigated to limit and/or prevent them. On this basis, a limited series of 4-spiro-oxazolidinone-benzopyran derivatives (1-7) were synthesized to evaluate them as potential ARL2 inhibitors. The activity was determined spectrophotometrically by monitoring the oxidation of NADPH catalyzed by ALR2. Within the series of compounds, the 4-methoxy derivative 1b showed to be the most active compound, exhibiting inhibitory levels in the submicromolar range. In addition, the activity against the aldehyde reductase isoform (ARL1) was also evaluated. Unlike sorbinil (reference drug) that lack of selectivity towards the two enzyme all the tested compounds resulted to be devoid of ARL1 inhibitory activity (IC(50) > 10 µM), thus proving to be selective.

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Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel

Cited by 36 publications

References 44 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

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Synthesis and Biological Evaluation of 2′‐Oxo‐2,3‐dihydro‐3′H‐ spiro[chromene‐4,5′‐[1,3]oxazolidin]‐3′yl]acetic Acid Derivatives as Aldose Reductase Inhibitors

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