Phlorizin Prevents Electrically-Induced Ventricular Tachyarrhythmia during Ischemia in Langendorff-Perfused Guinea-Pig Hearts

Hirose, Masao; Shibazaki, Toshihide; Nakada, Tsutomu; Kashihara, Toshihide; Yano, Shiharu; Okamoto, Yoshie; Isaji, Masayuki; Matsushita, Naoko; Taira, Eiichi; Yamada, Mitsuhiko

doi:10.1248/bpb.b14-00046

Cited by 15 publications

(7 citation statements)

References 23 publications

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“…To date, various actions of phlorizin have been reported, and some effects may be mediated through SGLT1-independent mechanisms (including the potential direct effects on mitochondria, as described above). The possible cardioprotective role of phlorizin as an anti-arrhythmic agent, as well as a free radical scavenger, cannot be excluded as reported by others [ 45 ], although a variety of important differences between the experimental animal species used (the study by Hirose et al [ 43 ] used guinea pig hearts, in which SGLT1 expression has not yet been detected), the experimental conditions and the time course of phlorizin perfusion may have contributed to the differences in the observations. In addition, considering that the aglycone of phlorizin is actually a GLUTs inhibitor [ 46 – 48 ], and also that 2-DG, used for the glucose uptake measurement ( Fig 6C ), is thought to be a relatively poor substrate for SGLT1 (although 2-DG has been used for the glucose uptake assay of SGLTs in prior studies [ 49 ]), non-specific inhibitory effects of phlorizin on other glucose transporters might be at least partly involved in the findings observed in the current study.…”

Section: Discussionmentioning

confidence: 94%

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

et al. 2015

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ObjectiveSodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.Methods and ResultsWe determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.ConclusionsCardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

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Section: Discussionmentioning

confidence: 94%

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

et al. 2015

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“…Cai et al [91] identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function and cardiomyopathy by isobaric tags for relative and absolute quantitation (iTRAQ) proteomics, which implied that phloridzin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. Hirose et al [92] indicated that phloridzin prevented ischemiainduced ventricular tachyarrhythmia through the improvement of impulse conduction slowing during ischemia in Langendorff-perfused guinea pig hearts.…”

Section: Cardioprotective Effectsmentioning

confidence: 99%

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin

Tian

Cao

Zhao

et al. 2021

IJMS

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Phloridzin is an important phytochemical which was first isolated from the bark of apple trees. It is a member of the dihydrochalcones and mainly distributed in the plants of the Malus genus, therefore, the extraction method of phloridzin was similar to those of other phenolic substances. High-speed countercurrent chromatography (HSCCC), resin adsorption technology and preparative high-performance liquid chromatography (HPLC) were used to separate and purify phloridzin. Many studies showed that phloridzin had multiple pharmacological effects, such as antidiabetic, anti-inflammatory, antihyperglycaemic, anticancer and antibacterial activities. Besides, the physiological activities of phloridzin are cardioprotective, neuroprotective, hepatoprotective, immunomodulatory, antiobesity, antioxidant and so on. The present review summarizes the biosynthesis, distribution, extraction and bioavailability of the natural compound phloridzin and discusses its applications in food and medicine.

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“…In vivo treatment of PHLOR prevented diabetic cardiomyopathy in db/db mice by changing the expression of some cardiac damaging proteins, and adjusting cardiac energy metabolism and lipids (Cai et al 2013). PHLOR has also been shown to exert partial cardioprotection against isoproterenol-induced myocardial necrosis (Gupta et al 2013) and to prevent electrically-induced ventricular tachyarrhythmia in guinea pig hearts during ischemia (Hirose et al 2014). Previous studies have reported the effects of PHLOR on healthy ventricular myocyte shortening and intracellular Ca 2+ (Olson et al 2007); however, the effects of PHLOR on myocytes from diabetic heart remain to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Reduction in the Amplitude of Shortening and Ca2+ Transient by Phlorizin and Quercetin-3-O-Glucoside in Ventricular Myocytes From Streptozotocin-Induced Diabetic Rats

Hamouda

Qureshi²,

Alkaabi³

et al. 2016

Physiol Res

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Diabetes mellitus is the leading cause of cardiovascular morbidity and mortality. Phlorizin (PHLOR) and quercetin-3-O-glucoside (QUER-3-G) are two natural compounds reported to have antidiabetic properties by inhibiting sodium/glucose transporters. Their effects on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin (STZ)-induced diabetic rats were investigated. Video edge detection and fluorescence photometry were used to measure ventricular myocyte shortening and intracellular Ca2+, respectively. Blood glucose in STZ rats was 4-fold higher (469.64±22.23 mg/dl, n=14) than in Controls (104.06±3.36 mg/dl, n=16). The amplitude of shortening was reduced by PHLOR in STZ (84.76±2.91 %, n=20) and Control (83.72±2.65 %, n=23) myocytes, and by QUER-3-G in STZ (79.12±2.28 %, n=20) and Control (76.69±1.92 %, n=30) myocytes. The amplitude of intracellular Ca2+ was also reduced by PHLOR in STZ (82.37±3.16 %, n=16) and Control (73.94±5.22 %, n=21) myocytes, and by QUER-3-G in STZ (73.62±5.83 %, n=18) and Control (78.32±3.54 %, n=41) myocytes. Myofilament sensitivity to Ca2+ was not significantly altered by PHLOR; however, it was reduced by QUER-3-G modestly in STZ myocytes and significantly in Controls. PHLOR and QUER-3-G did not significantly alter sarcoplasmic reticulum Ca2+ in STZ or Control myocytes. Altered mechanisms of Ca2+ transport partly underlie PHLOR and QUER-3-G negative inotropic effects in ventricular myocytes from STZ and Control rats.

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Phlorizin Prevents Electrically-Induced Ventricular Tachyarrhythmia during Ischemia in Langendorff-Perfused Guinea-Pig Hearts

Cited by 15 publications

References 23 publications

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin

Reduction in the Amplitude of Shortening and Ca2+ Transient by Phlorizin and Quercetin-3-O-Glucoside in Ventricular Myocytes From Streptozotocin-Induced Diabetic Rats

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