Biochemische Grundlagen der Diazoxid-Hyperglyk�mie

Schultz, Günter; Senft, G.; Losert, Wolfgang; Sitt, R.

doi:10.1007/bf00245976

Cited by 61 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The latter observation can only be substantiated by direct measurement of [Ca 2ϩ ] i transient. However, the participation of Ca 2ϩ in the diazoxide-induced protection may have some relevance because diazoxide is also a known inhibitor of phosphodiesterase, 37,38 and this enzyme degrades cAMP. 39 Therefore, an increase in cAMP influences cellular functions.…”

Section: Role Of Pkc On the Activation Of The Mitok Atp Channel By DImentioning

confidence: 99%

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium

Wang

Ashraf

1999

Circulation Research

158

View full text Add to dashboard Cite

Growing evidence exists that ATP-sensitive mitochondrial potassium channels (MitoK ATP channel) are a major contributor to the cardiac protection against ischemia. Given the importance of mitochondria in the cardiac cell, we tested whether the potent and specific opener of the MitoK ATP channel diazoxide attenuates the lethal injury associated with Ca 2 overload. The specific aims of this study were to test whether protection by diazoxide is mediated by MitoK ATP channels; whether diazoxide mimics the effects of Ca 2 preconditioning; and whether diazoxide reduces Ca 2 paradox (PD) injury via protein kinase C (PKC) signaling pathways. Langendorff-perfused rat hearts were subjected to the Ca 2 PD (10 minutes of Ca 2 depletion followed by 10 minutes of Ca 2 repletion). The effects of the MitoK ATP channel and other interventions on functional, biochemical, and pathological changes in hearts subjected to Ca 2 PD were assessed. In hearts treated with 80 mol/L diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca 2 PD; peak lactate dehydrogenase release was also significantly decreased, although ATP content was less depleted. The cellular structures were well preserved, including mitochondria and intercalated disks in diazoxide-treated hearts compared with nontreated Ca 2 PD hearts. The salutary effects of diazoxide on the Ca 2 PD injury were similar to those in hearts that underwent Ca 2 preconditioning or pretreatment with phorbol 12-myristate 13-acetate before Ca 2 PD. The addition of sodium 5-hydroxydecanoate, a specific MitoK ATP channel inhibitor, or chelerythrine chloride, a PKC inhibitor, during diazoxide pretreatment completely abolished the beneficial effects of diazoxide on the Ca 2 PD. Blockade of Ca 2 entry during diazoxide treatment by inhibiting L-type Ca 2 channel with verapamil or nifedipine also completely reversed the beneficial effects of diazoxide on the Ca 2 PD. PKC-was translocated to the mitochondria, intercalated disks, and nuclei of myocytes in diazoxide-pretreated hearts, and PKC-and PKC-were translocated to sarcolemma and intercalated disks, respectively. This study suggests that the effect of the MitoK ATP channel is mediated by PKC-mediated signaling pathway. (Circ Res. 1999;84:1156-1165.) Key Words: K channel Ca 2 paradox Ca 2 preconditioning protein kinase C diazoxide M assive cell damage occurs in the heart within seconds when it is perfused with perfusate devoid of Ca 2 followed by perfusion with a solution that contains Ca 2. This phenomenon has been called the Ca 2 paradox (Ca 2 PD). The common features of the Ca 2 PD are Ca 2 overload, sarcolemmal destruction, necrosis of the cell, depletion of high-energy phosphates, and loss of intracellular contents. 1,2 Mechanisms by which Ca 2 PD induces cell injury include altered Ca 2 channels, damaged cell membranes, disrupted intercalated disks, impaired Na-Ca 2 exchange, disruptive mechanical forces, and oxidative stress. 3-6 To understand these mechanisms, we plan to use the reverse st...

show abstract

Section: Role Of Pkc On the Activation Of The Mitok Atp Channel By DImentioning

confidence: 99%

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium

Wang

Ashraf

1999

Circulation Research

158

View full text Add to dashboard Cite

show abstract

“…2). Very recently, Schultz et al [11] demonstrated that diazoxide also inhibits significantly phospho diesterase in the liver, consequently increasing the cellular con centration of cyclic AMP. Hitherto, no study has been made to substantiate the direct inhibitory action of diazoxide on phospho diesterase activity in adipose tissues.…”

Section: Discussionmentioning

confidence: 99%

Effect of Diazoxide on Lipolysis in Isolated Rat Fat Cells

Nakano¹,

Ishii²,

Gin³

1968

Pharmacology

View full text Add to dashboard Cite

“…Volume contraction secondary to diuresis may stimulate proximal renal tubular reabsorption of urate leading to elevated serum uric acid levels [ 2,3 ] . Both furosemide and diazoxide induce hyperlacticacidemia which reduces renal tubular excretion of urate resulting in an elevation of serum urate levels [ 4,5 ] . Furosemide and its congeners are bound to plasma proteins and are not fi ltered to a signi fi cant degree at the glomerulus.…”

Section: Management Of Asymptomatic Hyperuricemiamentioning

confidence: 99%

Management of Hyperuricemia and Gout

Newcombe¹

2012

Gout

View full text Add to dashboard Cite

Biochemische Grundlagen der Diazoxid-Hyperglyk�mie

Cited by 61 publications

References 33 publications

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium

Effect of Diazoxide on Lipolysis in Isolated Rat Fat Cells

Management of Hyperuricemia and Gout

Contact Info

Product

Resources

About

Biochemische Grundlagen der Diazoxid-Hyperglyk�mie

Cited by 61 publications

References 33 publications

Role of Protein Kinase C in Mitochondrial K ATP Channel–Mediated Protection Against Ca 2+ Overload Injury in Rat Myocardium

Role of Protein Kinase C in Mitochondrial K ATP Channel–Mediated Protection Against Ca 2+ Overload Injury in Rat Myocardium

Effect of Diazoxide on Lipolysis in Isolated Rat Fat Cells

Management of Hyperuricemia and Gout

Contact Info

Product

Resources

About

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium

Role of Protein Kinase C in Mitochondrial K _ATP Channel–Mediated Protection Against Ca ²⁺ Overload Injury in Rat Myocardium