The antianginal agent ranolazine is a weak inhibitor of the respiratory Complex I, but with greater potency in broken or uncoupled than in coupled mitochondria

Wyatt, Katrina; Skene, Caroline D.; Veitch, Keith; Hue, Louis; McCormack, James G.

doi:10.1016/0006-2952(95)02042-x

Cited by 36 publications

(26 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a previous study [38] using a similar experimental protocol, we showed that blocking complex I of the ETC with amobarbital, a reversible complex I blocker, decreased electron flow to complex III and subsequently reduced ROS generation and protected mitochondria against ischemic injury. Like amobarbital, ranolazine is reported to block complex I [20], albeit as a weaker inhibitor compared to amobarbital or rotenone, especially in energetically coupled mitochondria. However, in uncoupled mitochondria, ranolazine had a greater effect to inhibit complex I [20].…”

Section: Discussionmentioning

confidence: 99%

“…Another proposal is that ranolazine selectively blocks a ROS-induced late sarcolemmal Na + channel current [19], which may reduce the rise in c[Na + ] and c[Ca 2+ ] during IR. It has also been suggested that ranolazine inhibits complex I of the electron transport chain (ETC) to afford protection [20]. Together, these studies clearly show that ranolazine protects against cardiac IR injury and suggest that mitochondrial mechanisms may underlie this protection.…”

Section: Introductionmentioning

confidence: 85%

See 1 more Smart Citation

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Aldakkak

Camara

Heisner

et al. 2011

Pharmacological Research

102

100

View full text Add to dashboard Cite

Ranolazine is a clinically approved drug for treating cardiac ventricular dysrhythmias and angina. Its mechanism(s) of protection is not clearly understood but evidence points to blocking the late Na+ current that arises during ischemia, blocking mitochondrial complex I activity, or modulating mitochondrial metabolism. Here we tested the effect of ranolazine treatment before ischemia at the mitochondrial level in intact isolated hearts and in mitochondria isolated from hearts at different times of reperfusion. Left ventricular (LV) pressure (LVP), coronary flow (CF), and O2 metabolism were measured in guinea pig isolated hearts perfused with Krebs-Ringer’s solution; mitochondrial (m) O2•−, Ca2+, NADH/FAD (redox state), and cytosolic (c) Ca2+ were assessed on-line in the LV free wall by fluorescence spectrophotometry. Ranolazine (5 µM), infused for 1 min just before 30 min of global ischemia, itself did not change O2•−, cCa2+, mCa2+ or redox state. During late ischemia and reperfusion (IR) O2•− emission and m[Ca2+] increased less in the ranolazine group vs. the control group. Ranolazine decreased c[Ca2+] only during ischemia while NADH and FAD were not different during IR in the ranolazine vs. control groups. Throughout reperfusion LVP and CF were higher, and ventricular fibrillation was less frequent. Infarct size was smaller in the ranolazine group than the control group. Mitochondria isolated from ranolazine-treated hearts had mild resistance to permeability transition pore (mPTP) opening and less cytochrome c release than control hearts. Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Subsequently it indirectly reduces O2•− emission, preserves bioenergetics, delays mPTP opening, and restricts loss of cytochrome c, thereby reducing necrosis and apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Aldakkak

Camara

Heisner

et al. 2011

Pharmacological Research

102

100

View full text Add to dashboard Cite

show abstract

“…However, it has recently been shown that complex I inhibition may underlie the cardioprotective effects of agents such as amobarbital [29,30], volatile anesthetics [60], and ranolazine [61]. Complex II inhibitors such as diazoxide [60] and 3-nitropropionic acid [62,63] are also cardioprotective, as are complex IV inhibitors such as hydrogen sulfide [64,65] and carbon monoxide [66].…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Nadtochiy

Burwell

Brookes

2007

Journal of Molecular and Cellular Cardiology

132

118

View full text Add to dashboard Cite

Mitochondrial dysfunction is a key pathologic event in cardiac ischemia-reperfusion (IR) injury, and protection of mitochondrial function is a potential mechanism underlying ischemic preconditioning (IPC). Acknowledging the role of nitric oxide (NO • ) in IPC, it was hypothesized that mitochondrial protein S-nitrosation may be a cardioprotective mechanism. The reagent S-nitroso-2-mercaptopropionyl-glycine (SNO-MPG) was therefore developed to enhance mitochondrial Snitrosation and elicit cardioprotection. Within cardiomyocytes, mitochondrial proteins were effectively S-nitrosated by SNO-MPG. Consistent with the recent discovery of mitochondrial complex I as an S-nitrosation target, SNO-MPG inhibited complex I activity and cardiomyocyte respiration. The latter effect was insensitive to the NO • scavenger c-PTIO, indicating no role for NO • -mediated complex IV inhibition. A cardioprotective role for reversible complex I inhibition has been proposed, and consistent with this SNO-MPG protected cardiomyocytes from simulated IR injury. Further supporting a cardioprotective role for endogenous mitochondrial S-nitrosothiols, patterns of protein S-nitrosation were similar in mitochondria isolated from Langendorff perfused hearts subjected to IPC, and mitochondria or cells treated with SNO-MPG. The functional recovery of perfused hearts from IR injury was also improved under conditions which stabilized endogenous S-nitrosothiols (i.e. dark), or by pre-ischemic administration of SNO-MPG. Mitochondria isolated from SNO-MPG-treated hearts at the end of ischemia exhibited improved Ca 2+ handling and lower ROS generation. Overall these data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation.

show abstract

“…With octanoate, observed increases in C 8 , C 6 and C 4 CoA esters suggested inhibition of fatty acid β-oxidation as the site of action [4] and indeed the term 'partial fatty acid oxidation', or pFOX, inhibitors was coined, with ranolazine as the prototypical agent of this new drug class [7,8]. With ranolazine, there is good evidence linking this mechanism to its anti-ischaemic efficacy; however, another mechanism(s) may also play a role (see [8]), including the finding that it is a weak inhibitor of the respiratory complex I, but with much greater potency in broken or uncoupled mitochondria than in coupled mitochondria [9].…”

Section: A Metabolic Aspect To the Action Of The Anti-anginal Agent Rmentioning

confidence: 98%

Applying science to drug discovery

McCormack¹

2006

Biochemical Society Transactions

View full text Add to dashboard Cite

Scientists and science in the pharmaceutical industry rely heavily on the more academically orientated basic research carried out at Universities, for first of all training, but also as a source of new ideas and approaches to drug discovery. Progress in the discovery and development of novel therapeutics benefits from a healthy alliance with, and the output from, more basic research institutions, and the reverse is also true, with many advances in understanding of physiological and pathological processes being as the result of the application of novel targeted molecules. To illustrate this, some examples related to the themes of this meeting from my experiences in three different companies will be described. The first involves a metabolic angle in the unravelling of the mechanism of the novel anti-anginal agent ranolazine. The second describes the application of detailed knowledge of insulin structure and action to then use recombinant approaches to design novel molecules to be able to offer the Type I (insulin-dependent) diabetic patient therapies allowing a more physiological treatment regime, and also the further application of learned technology to then discover a means of harnessing the potential of GLP-1 (glucagon-like polypeptide 1) for treating Type II (non-insulin-dependent) diabetes. The last illustrates how findings of novel binding sites on glycogen phosphorylase and glucokinase as the result of drug discovery programmes have led to increased understanding of these key metabolic enzymes and also potential new therapies for Type II diabetes.

show abstract

The antianginal agent ranolazine is a weak inhibitor of the respiratory Complex I, but with greater potency in broken or uncoupled than in coupled mitochondria

Cited by 36 publications

References 27 publications

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Applying science to drug discovery

Contact Info

Product

Resources

About