The dissociation of cardiodepression and cardioprotection with calcium antagonists: Diltiazem protects ischemic rat myocardium with a lower functional cost compared to verapamil or nifedipine

Grover, G J

doi:10.1016/0022-2828(89)91515-0

Cited by 10 publications

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“…Surgical intervention is the most commonly employed treatment because of its efficacy, along with agents such as aspirin, which are efficacious in secondary prevention of myocardial infarction. Many types of agents are efficacious in reducing infarct size or showing cardioprotection in animal models such as in dog and rat infarct size models and isolated rat hearts [1][2][3][4][5][6]. These agents include calcium antagonists, β-adrenoceptor blockers, preconditioning, and ATPsensitive potassium channel (K ATP ) openers.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Grover¹,

Malm²

2008

Cardiovascular Therapeutics

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The mitochondrial F 1 F 0 ATP synthase is responsible for the majority of ATP production in mammals and does this through a rotary catalytic mechanism. Studies show that the F 1 F 0 ATP synthase can switch to an ATP hydrolase, and this occurs under conditions seen during myocardial ischemia. This ATP hydrolysis causes wasting of ATP that does not produce work. The degree of ATP inefficiently hydrolyzed during ischemia may be as high as 50-90% of the total. A naturally occurring, reversible inhibitor (IF-1) of the hydrolase activity is in the mitochondria, and it has a pH optimum of 6.8. Based on studies with the nonselective (inhibit both synthase and hydrolase activity) inhibitors aurovertin B and oligomycin B reduce the rate of ATP depletion during ischemia, showing that IF-1 does not completely block hydrolase activity. Oligmycin and aurovertin cannot be used for treating myocardial ischemia as they will reduce ATP production in healthy tissue. We generated a focused structureactivity relationship, and several compounds were identified that selectively inhibited the F 1 F 0 ATP hydrolase activity while having no effect on synthase function. One compound, BMS-199264 had no effect on F 1 F 0 ATP synthase function in submitochondrial particles while inhibiting hydrolase function, unlike oligomycin that inhibits both. BMS-199264 selectively inhibited ATP decline during ischemia while not affecting ATP production in normoxic and reperfused hearts. BMS-191264 also reduced cardiac necrosis and enhanced the recovery of contractile function following reperfusion. These data also suggest that the reversal of the synthase and hydrolase activities is not merely a chemical reaction run in reverse. IntroductionMyocardial ischemia is caused by an oxygen supply/demand imbalance. The degree of coronary occlusion will give differential clinical presentations and different therapeutic modes of treatment. Chronic stable angina is myocardial ischemia seen only upon increased oxygen demand (increased exertion) as the coronary stenosis alone will not cause pain or ST-segment abnormalities at rest. Resolution of symptoms often occurs after cessation of the increased exertion. Numerous therapeutics can resolve the symptoms of stable angina pectoris and these include nitrates, calcium antagonists, and β-adrenoceptor blockers [1][2][3].Severe myocardial ischemia causing necrosis or infarction has been difficult to effectively treat pharmacologically. Surgical intervention is the most commonly employed treatment because of its efficacy, along with agents such as aspirin, which are efficacious in secondary prevention of myocardial infarction. Many types of agents are efficacious in reducing infarct size or showing cardioprotection in animal models such as in dog and rat infarct size models and isolated rat hearts [1][2][3][4][5][6]. These agents include calcium antagonists, β-adrenoceptor blockers, preconditioning, and ATPsensitive potassium channel (K ATP ) openers. These agents are associated with preservation of ATP in ischemic myocyt...

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Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Grover¹,

Malm²

2008

Cardiovascular Therapeutics

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“…This is an undesirable effect in a compromised myocardium. Experiments have shown that cardiodepression is not required for cardio protection in diltiazem [25]. ATP-sensitive potassium channels do not cause cardiode pression in non-ischemic tissue except at very high concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…Such damage is only partially recovered even if the coronary perfusion is recovered. Many agents have been reported to show protective effects against myocardial ischemiareperfusion damage (33). In most cases, the protection appeared to be accompanied by drug-induced reduction of myocardial performance.…”

Section: Effects Of Ischemiamentioning

confidence: 99%

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

et al. 2009

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Abstract. The waveform of the myocardial action potential (AP) triggering contraction differs among the species, developmental stage, and pathological state. The species difference in heart rate, which inversely correlates with body size, originates in the ion-channel mechanisms responsible for diastolic depolarization of the sinoatrial node. In some cases, such as the chronically AV-blocked dog and 11-to 13-day chick embryo, the repolarization reserve is decreased making the heart useful for drug evaluation. The degree of dependence of contraction on sarcoplasmic reticulum (SR) function increases during development. The large SR dependence and short AP of the adult mouse and rat support their rapid contraction under high heart rate. The function of the Na + /Ca 2+ exchanger is affected by AP waveform and ion concentrations; its major role is Ca 2+ extrusion, but under pathological conditions such as ischemia-reperfusion, it allows Ca 2+ influx and leads to myocardial injury, including loss of mitochondrial function. The role of mitochondria in ATP supply is less in the fetus where glycolysis plays a greater role. The pharmacological properties of the myocardium are affected by all of these factors and also by autonomic innervation and the hormonal status. Such comprehensive understanding is indispensable for the development of novel therapeutic strategies.

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The dissociation of cardiodepression and cardioprotection with calcium antagonists: Diltiazem protects ischemic rat myocardium with a lower functional cost compared to verapamil or nifedipine

Cited by 10 publications

References 0 publications

Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

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

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

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The dissociation of cardiodepression and cardioprotection with calcium antagonists: Diltiazem protects ischemic rat myocardium with a lower functional cost compared to verapamil or nifedipine

Cited by 10 publications

References 0 publications

Pharmacological Profile of the Selective Mitochondrial F1F0 ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Pharmacological Profile of the Selective Mitochondrial F1F0 ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

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

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

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Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia