Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists

Higgins, Alan J.; Blackburn, K J

doi:10.1016/s0022-2828(84)80614-8

Cited by 80 publications

(29 citation statements)

References 34 publications

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“…This finding is in agreement with various other studies showing dissociation between depletion-repletion of high energy phosphates and postischaemic ventricular recovery under various experimental conditions (Higgins & Blackburn, 1984;Neely & Grotyohann, 1984;Karmazyn & Neely, 1989;Currie & Karmazyn, 1990;Murphy et al, 1991). Not unexpectedly therefore, the only significant metabolic consequence of lactate pretreatment that was measured in this study was the significantly elevated lactate content at the end of ischaemia in the absence or presence of Na+/H+ exchange inhibitors.…”

Section: Discussionsupporting

confidence: 94%

Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Karmazyn

1993

British J Pharmacology

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1 By use of pharmacological approaches, the present study examined the hypothesis that the deleterious effect of lactate on postischaemic ventricular recovery may be mediated, at least in part, by enhanced activation of the Na+/H+ exchanger at the time of reperfusion. 2 Spontaneously beating isolated hearts of the rat were subjected to 15 min zero-flow global ischaemia followed by 30min reperfusion. The effects of lactate (10, 20 or 40mM) were studied by adding it 20min before ischaemia whereas reperfusion was carried out with lactate-free buffer. 3 Pretreatment with 20 or 40mM lactate significantly reduced postischaemic recovery of developed force to 17 ± 3% and 16 ± 4% of preischaemic values (P<0.05) compared to a 78 ± 4% recovery in control hearts. Similarly, recovery in ventricular rate was significantly reduced to 34 ± 7.6% and 38 ± 12% with 20 and 40 mM lactate, respectively compared to 97.5 ± 6.4% recovery in control hearts. At a concentration of 10mM, lactate was without effect on either force or ventricular rate recovery. 4 Coadministration of either of two Na+/H+ exchange inhibitors, amiloride (174JAM) or 5-N,Nhexamethylene amiloride (HMA, 1 gM) with lactate and inclusion of the two drugs during the first 5 min of reperfusion resulted in reversal of lactate-induced inhibition of force recovery with observed recoveries of 69 ± 6.7% and 64 ± 5% with amiloride and HMA, respectively. Similarly, recovery in ventricular rate was significantly enhanced to 92 ± 10% and 89 ± 6% with amiloride and HMA, respectively compared to 38 ± 12% recovery in control hearts. (Neely & Grotyohann, 1984) suggested that enhanced accumulation of glycolytic products, particularly lactate, at the end of the ischaemic period can contribute significantly to diminished recovery of ventricular function after reperfusion. The evidence for lactate involvement originated primarily from two observations; (1) prevention of lactate accumulation during ischaemia by glycogen depletion resulted in enhanced postischaemic recovery whereas, (2) exogenous lactate administration to isolated hearts significantly attenuated recovery (Neely & Grotyohann, 1984).The mechanisms underlying lactate-induced depression in postischaemic recovery are unknown, nonetheless its inclusion in ischaemiamimetic solutions is required for the production of manifestations of tissue dysfunction in various experimental models (Ferrier et al., 1985;Northover, 1987;1989). One possibility is that lactate directly depresses contractility and thus recovery following reperfusion or inhibits energy substrate utilization (Tennant, 1935;Armiger et al., 1974;Neely & Grotyohann, 1984). Alternatively, enhanced intracellular lactate accumulation and subsequent cellular acidification may contribute to diminished recovery. In this regard, it has been suggested that Na+/H+ exchange activation at the time of reflow would result in enhanced tissue injury as stimulation of this exchanger would elevate intracellular Na' concentrations and, subsequently, cellular Ca2" content via the Na+/...

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Section: Discussionsupporting

confidence: 94%

Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Karmazyn

1993

British J Pharmacology

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“…The values for cromakalim were generated in a study done previously in our laboratory [20], The potency of EMD 56431 in relaxing methoxamine-contracted rat aortas also seems to be similar to that of cromakalim [pers. Anti-ischemic compounds such as vera pamil and diltiazem [25], which block calcium channels and W-7, which blocks calmodulin [26] cause cardiodepression in nonischemic tissue, at doses required for cardioprotection. This is an undesirable effect in a compromised myocardium.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Potassium Channel Opener EMD 56431 on Globally Ischemic Rat Hearts

Sargent¹,

Dzwonczyk²,

Grover³

1992

Pharmacology

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The effect of the ATP-sensitive potassium channel opener EMD 56431 on coronary vasodilation and cardioprotection in isolated rat hearts was investigated. EMD 56431 caused a significant increase in pre-ischemic coronary flow. Time to contracture and reperfusion function were significantly increased at 3, 10 and 30 μM concentrations. LDH release was significantly reduced at 10 and 30 μM concentrations. 1 μM glyburide completely abolished the protective effects found with 10 μM EMD 56431. When given during reperfusion only, 10 μM EMD 56431 showed no cardioprotection. Thus, EMD 56431 appeared to reduce the severity of ischemia/reperfusion injury. The vasorelaxant versus cardioprotective effects for EMD 56431 are similar to other potassium channel openers, such as cromakalim.

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“…Several other calcium blocking agents have also been found to have such protective effects (Nayler et al, 1980;Bourdillon & Poole-Wilson, 1982;Watts et al, 1986). This is presumably due to the reduction of the calcium load imposed upon the cardiac cells, although direct protective actions by some of the drugs have also been considered (Higgins & Blackburn, 1984).…”

Section: Discussionmentioning

confidence: 99%

The effects of prenylamine on single ventricular myocytes of guinea‐pig

Shimoni

Posner²,

Spindler³

et al. 1988

British J Pharmacology

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1 The action of prenylamine, an antianginal drug, was studied in single ventricular guinea-pig myocytes. In concentrations of 10-50 pm, prenylamine significantly (P <0.01) shortened action potentials, and significantly (P < 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor-blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action. 2 Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time-dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time-independent potassium conductance. 3 It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.

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Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists

Cited by 80 publications

References 34 publications

Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Effect of the Potassium Channel Opener EMD 56431 on Globally Ischemic Rat Hearts

The effects of prenylamine on single ventricular myocytes of guinea‐pig

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Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists

Cited by 80 publications

References 34 publications

Na+/H+ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Na+/H+ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Effect of the Potassium Channel Opener EMD 56431 on Globally Ischemic Rat Hearts

The effects of prenylamine on single ventricular myocytes of guinea‐pig

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Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery

Na⁺/H⁺ exchange inhibitors reverse lactate‐induced depression in postischaemic ventricular recovery