Mechanism for the Cardioprotective Effects of the Calcium Channel Blocker Clentiazem During Ischemia and Reperfusion

Kusuoka, Hideo; Corretti, Mary C.; Koretsune, Yukihiro; Marbán, Eduardo

doi:10.1253/jcj.62.611

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…In support of this is our finding that concomitant inhibition of intracellular Ca 2ϩ stores attenuated hypoxia-reoxygenation induced Ca 2ϩ loading. The significance of both extracellular and intracellular Ca 2ϩ stores in hypoxiareoxygenation injury is further underscored by the absence of protection afforded by calcium channel blockers when applied during reoxygenation (30,31) and by the efficacy of pre-and postischemic administration of Na/H exchange inhibitors to diminish cytosolic Ca 2ϩ overload (32). Thus, an effective mean to maintain Ca 2ϩ homeostasis under different stages of hypoxia-reoxygenation should be able to target both sources of Ca 2ϩ .…”

Section: Discussionmentioning

confidence: 99%

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Jovanović

et al. 1999

FASEB j.

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Metabolic injury is a complex process affecting various tissues, with intracellular Ca2+ loading recognized as a common precipitating event leading to cell death. We have recently observed that cells overexpressing recombinant ATP-sensitive K+ (KATP) channel subunits may acquire resistance against metabolic stress. To examine whether, under metabolic challenge, intracellular Ca2+ homeostasis can be maintained by an activator of channel proteins, we delivered Kir6.2 and SUR2A genes, which encode KATP channel subunits, into a somatic cell line lacking native KATP channels. Hypoxia-reoxygenation was simulated by application and removal of the mitochondrial poison 2,4 dinitrophenol. Under such metabolic stress, Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. Delivery of Kir6.2/SUR2A genes, in conjunction with the KATP channel activator pinacidil, prevented intracellular Ca2+ loading irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. In all stages of injury, the effect of pinacidil was inhibited by the selective antagonist of KATP channel, 5-hydroxydecanoate. The present study provides evidence that combined use of gene delivery and pharmacological targeting of recombinant proteins can handle intracellular Ca2+ homeostasis under hypoxia-reoxygenation irrespective of the stage of the metabolic insult.

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Section: Discussionmentioning

confidence: 99%

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Jovanović

et al. 1999

FASEB j.

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“…[12][13][14]17,18 Nuclear magnetic resonance detected an increase in [Ca 2+ ]i after 15-20 min of ischemia, 28 so the time to the onset of increase in [Ca 2+ ]i might depend on the method of investigation. In our previous studies, 21,25 hypoxia caused inhibition of the exchanger in a few minutes.…”

Section: Effects Of the Ncx Inhibitor On [Ca 2+ ]I During Ischemia Anmentioning

confidence: 99%

Inhibition by KB-R7943 of the Reverse Mode of the Na+/Ca2+ Exchanger Reduces Ca2+ Overload in Ischemic-Reperfused Rat Hearts.

Seki

Taniguchi

Takeda

et al. 2002

Circ J

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Publication No. 85-23, revised 1996). Adult male Sprague-Dawley rats weighing 300-350 g were anesthetized with pentobarbital Na (30 mg/kg, ip). The heart was quickly isolated and the aorta was cannulated for retrograde Langendorff perfusion. N-2-hydroxy-ethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered Tyrode solution (140 mmol/L NaCl, 6 mmol/L KCl, 1 mmol/L MgCl2, 2 mmol/L CaCl2, 10 mmol/L HEPES, 10 mmol/L J 2002; 66: 390 -396 (Received September 28, 2001; revised manuscript received January 9, 2002; accepted January 11, 2002 ]i dynamics and left ventricular pressure were monitored in perfused beating hearts. The effects of KB-R7943 (KBR), a selective inhibitor of the NCX in the reverse mode, were analyzed during low-Na + exposure and ischemia -reperfusion. Hearts from Sprague-Dawley rats were retrogradely perfused and loaded with 4 mol/L fura-2 to measure the fluorescence ratio as an index of [Ca 2+ ]i. To evaluate KBR effects on the reverse mode exchanger, the increase in [Ca 2+ ]i induced by low-Na + exposure (Na + : 30 mmol/L, 10 mmol/L caffeine pre-treatment) was measured with and without 10 mol/L KBR (n=5). In another series, the hearts were subjected to 10 min of low-flow ischemia with pacing, followed by reperfusion in the absence (n=6) or in the presence of 10 mol/L KBR (n=6). Background autofluorescence was subtracted to estimate the ratio in the ischemia -reperfusion protocol. KBR significantly suppressed the increase in [Ca 2+ ]i induced by low-Na + (40.2±11.2% of control condition, p=0.014), as well as on increase in diastolic [Ca 2+ ]i during ischemia (% increase from pre-ischemia in [Ca 2+ ]i at 10 min: KBR, 17.9±6.4%; no KBR, 44.4±7.7%; p=0.024). After reperfusion, diastolic [Ca 2+ ]i normalized more rapidly in KBR-treated hearts (% increase at 1 min: KBR, 4.5±7.0%; no KBR, 39.8±12.2%; p=0.03). Treatment with KBR also accelerated recovery of the rate -pressure product on reperfusion (1 min: KBR, 8,944±1,554 min -1 ·mmHg; no KBR, 4,970±1,325; p<0.05). Thus, inhibition of the reverse mode exchanger by KBR reduced ischemic Ca 2+ overload and possibly improved functional myocardial recovery during reperfusion in a whole heart model. (Circ J 2002; 66: 390 -396) Circ

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Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

Kochegarov¹

2003

Cell Calcium

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Mechanism for the Cardioprotective Effects of the Calcium Channel Blocker Clentiazem During Ischemia and Reperfusion

Cited by 4 publications

References 22 publications

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Inhibition by KB-R7943 of the Reverse Mode of the Na+/Ca2+ Exchanger Reduces Ca2+ Overload in Ischemic-Reperfused Rat Hearts.

Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

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Mechanism for the Cardioprotective Effects of the Calcium Channel Blocker Clentiazem During Ischemia and Reperfusion

Cited by 4 publications

References 22 publications

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+homeostasis under metabolic stress

Inhibition by KB-R7943 of the Reverse Mode of the Na+/Ca2+ Exchanger Reduces Ca2+ Overload in Ischemic-Reperfused Rat Hearts.

Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

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Product

Resources

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Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺homeostasis under metabolic stress