Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

Maslov, L. N.; Khaliulin, Igor; Oeltgen, Peter R.; Naryzhnaya, N. V.; Pei, Jian Ming; Brown, Stephen; Lishmanov, Yu. B.; Downey, James M.

doi:10.1002/med.21395

Cited by 46 publications

(33 citation statements)

References 294 publications

(506 reference statements)

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“…Results from several studies generally support the role of PKCε activation in preconditioning, for example, agents that mimic preconditioning also activate PKCε such as adenosine, volatile anesthetics, and exogenously applied PKCε agonists [16,[25][26][27][28]. …”

Section: Discussionmentioning

confidence: 99%

“…The resulting ROS then activates a second PKCε mitochondrial pool that prevents the opening of the mitochondrial permeability transition pore (MPTP). The MPTP is a large conductance channel in the inner mitochondrial membrane whose extended opening leads to the dissipation of the inner mitochondrial membrane potential, matrix swelling and rupture of the outer mitochondrial membrane, ultimately leading to necrosis [20][21][22][23][24].Results from several studies generally support the role of PKCε activation in preconditioning, for example, agents that mimic preconditioning also activate PKCε such as adenosine, volatile anesthetics, and exogenously applied PKCε agonists [16,[25][26][27][28]. …”

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confidence: 99%

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Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

2017

J Cardiobiol

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Background: The generation of reactive oxygen species (ROS) during myocardial ischemia (I)/reperfusion (R) contributes to postreperfusion cardiac injury. The increase in ROS is attributed in part to the uncoupling of endothelial nitric oxide synthase (eNOS) that produces ROS instead of nitric oxide (NO) and mitochondrial derived ROS which in part is derived from opening of mitochondrial ATPsensitive K + channels (mK ATP ). Both the activity of uncoupled eNOS and the opening of mK ATP channels in mitochondria are stimulated by protein kinase C epsilon (PKCε) that is activated during reperfusion. We hypothesize that a cell permeable PKCε peptide inhibitor, (N-myristic acid-EAVSLKPT, Myr-PKCε-) given at reperfusion will improve postreperfused cardiac function and attenuate infarct size compared to untreated isolated perfused rat hearts subjected to ischemic reperfusion injury. Methods:Male Sprague-Dawley rats (275-325 g) were anesthetized with sodium pentobarbital (60 mg/kg) and anticoagulated with heparin 1000 units given intraperitoneally. The hearts were excised and attached to a Langendorff perfusion system. All hearts were subjected to 30 min of global ischemia, followed by 90 min of reperfusion. Myr-PKCε-was dissolved in Krebs' buffer and infused during the first 10 min of reperfusion at final concentrations of 5, 10 and 20 µM.Results: Myr-PKCε-treated hearts (10 and 20 μM) exhibited significant improvement in post-reperfused cardiac function at 90 min compared to untreated controls. The maximal rate of left ventricular developed pressure generation (+dP/dt max ) of Myr-PKCε-treated hearts showed significant recovery to 56±4% (10 μM, p<0.05, n=8) and 50±3%; (20 μM, p<0.05, n=8) of initial baseline values. By contrast, the +dP/ dt max of both untreated control hearts (n=9) and those treated with the lowest concentration of Myr-PKCε-(5 μM, n=8) recovered to only 30±4% and 33±4% of initial baseline values, respectively. Interestingly, all Myr-PKCε-treated hearts (5-20 μM) showed significant reduction in infarct size to 28±2% compared to untreated control hearts, which averaged 38±3% (p<0.05, n=9). Conclusion:The results suggest that Myr-PKCε-given at reperfusion effectively reduces infarct size, improves cardiac function and is a putative treatment that could aid in clinical myocardial infarction/ organ transplantation patient recovery. [3][4][5][6][7]. The necessity for effective pharmacological intervention still exists, despite numerous basic studies firmly establishing that I/R injury can be delayed or even reduced by the introduction of cardioprotective agents or strategies prior to a prolonged ischemic insult (preconditioning) or at the start of reperfusion [1,8]. Such interventions have been shown to reduce infarct size, attenuate the frequency and severity of reperfusion-induced arrhythmias, and prevent endothelial dysfunction [9][10][11][12][13].Preconditioning of the myocardium can be induced by several rounds of brief ischemia (i.e. less than 4 min) followed by several rounds of brief reperfus...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

2017

J Cardiobiol

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“…This indicates that the cardioprotection by S. coccinea is mediated via the opioid pathway. Agonist binding to the opioid receptor usually inhibits adenylyl cyclase and activates phospholipase C signaling (26). Previous studies have shown that PLC signaling leads to the activation of the PKC and RISK kinases which are activated by salvianolic acid A and B which are phenolic compounds commonly found in salvia species (27).…”

Section: Discussionmentioning

confidence: 99%

The freeze-dried extracts of Salvia coccinea Juss. Ex Murray attenuate myocardial ischemia reperfusion injury in a global ischemia Rat model

Nyaga

Mwangi

Bukachi

2018

Preprint

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21Background: Ischemia reperfusion injury is the leading cause of myocardial cell death in Ischemic 22 Heart Disease. Thus intensive research efforts are geared at discovering pharmacological 23 approaches that prevent it. Over twenty species from the genus Salvia are widely applied in 24 traditional Chinese medicine in the management of heart diseases with Salvia miltiorrhiza 25 (Danshen) being a canonical example. Our study aimed to investigate the cardio-protective effects 26 of the freeze-dried extracts of salvia coccinea against ischemia reperfusion injury in a rodent in-27 vitro model of global ischemia. 28 Methods: Forty two (42) Sprague Dawley rats were randomly assigned into five groups: positive 29 control (Glucosamine 1000mg/kg), negative control group (Krebs Henseleit buffer), low dose test 30 (50 mg/100ml), medium dose test (100 mg/100ml), and high dose test (200 mg/100ml). 31The cardio-protective effects of the different treatments were evaluated in a global ischemia model 32 using isolated rat hearts mounted on a Langendorff system. 33Naloxone 2.2 µmol/L (µ opioid receptor blocker), and theophylline 1000 µmol/L (non-specific 34 adenosine receptor blocker) were co-administered with 50 mg of S.coccinea in the mechanism of 35 action experiments. 36The following indices of cardiac function were recorded pre-and post-ischemia: left ventricular 37 developed pressure (LVDP), heart rate, and maximum rate of contraction and relaxation. All data 38 were expressed as Mean ± Standard Error of Mean and analyzed using one-way ANOVA and 39 Tukey post-hoc tests. Significance was set at p < 0.05. 40 Results: The freeze-dried extracts of S. coccinea had significant effects on post-ischemic 41 contractile function recovery in the early [51.4 ± 9.7% (low dose test) vs. 14.9 ± 3.3% (medium 3 42 dose test) vs. 12.7 ± 2.6% (high dose test) vs. 13.7 ± 5.7% (negative control): p<0.05] and late 43 [38.6 ± 8.9% (low dose test) vs. 22.0± 7.1% (medium dose test) vs. 14.6 ± 5.8 (high dose test) vs. 44 12.5 ± 4.2% (negative control): p< 0.05]. Reperfusion phases with the highest LVDP recovery 45were observed at the 50 mg dosage level. 46The freeze-dried extracts of S. coccinea had significant negative chronotropic effects on heart rate 47 [234.0 ± 2.4 beats/min to 90.0 ± 7.0 beats/min, 50 mg vs. 102.0 ± 13.9 beats/min to 135.0 ± 25.9 48 beats/min, control P<0.05]. 49 The cardioprotective effects of S. coccinea displayed an inverted U-shaped dose-response curve 50 with low dose stimulation and high dose inhibition. 51 Naloxone completely abolished the LVDP recovery afforded by the freeze-dried extracts of S. 52 coccinea at the 50 mg dosage level while adenosine only partly abolished the LVDP recovery (9.5 53 ± 3.2% (naloxone) vs. 15.5 ± 5.8% (adenosine): P˃0.05). 54 Conclusion: The freeze-dried extracts of S. coccinea possessed significant cardioprotective effects 55 which appear to be mediated by activation of the opioidergic pathway in the heart.56 57

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“…31 Selective mu-opioid receptor agonists, such as fentanyl and morphine, increase the ventricular fibrillation threshold in dogs with coronary artery occlusion. 32 A meta-analysis including 1295 patients in 9 studies concluded that dexmedetomidine is associated with a lower incidence of ventricular arrhythmia after elective cardiac surgery. 33 Methohexital minimizes the possibility of potentially life-threatening cardiac arrhythmias during electroconvulsive therapy compared with thiamylal or thiopental.…”

Section: Antiarrhythmic Effects Of Anesthesia Agentsmentioning

confidence: 99%

Effects of anesthetic and sedative agents on sympathetic nerve activity

et al. 2019

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BACKGROUND The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. OBJECTIVE The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. METHODS We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 mg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 6 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 6 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. RESULTS SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P 5 .000 and P 5 .000, respectively), morphine (P 5 .011 and P 5 .014, respectively), and hydromorphone (P 5 .000 and P 5 .012, respectively), along with decreased BP and heart rate (HR) (P ,.001 for each). Midazolam had no significant effect on SGNA and ScNA (P 5 .248 and P 5 .149, respectively) but increased HR (P 5 .015) and decreased BP (P 5 .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 6 0.25 mV to 0.77 6 0.15 mV; P 5 .001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 6 0.45 mV to 1.22 6 0.58 mV (P 5 .000) and arm SKNA from 0.76 6 0.43 mV to 0.55 6 0.07 mV (P 5 .001). The effects lasted for at least 10 minutes after the cardioversion shock. CONCLUSION Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.

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Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

Cited by 46 publications

References 294 publications

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

The freeze-dried extracts of Salvia coccinea Juss. Ex Murray attenuate myocardial ischemia reperfusion injury in a global ischemia Rat model

Effects of anesthetic and sedative agents on sympathetic nerve activity

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