Role of δ1 Opiate Receptors in Regulation of Contractility in Isolated Rat Heart during Normal Oxygenation and Ischemia/Reperfusion

The experiments with the isolated rat heart demonstrated a significant decrease in reperfusion-induced damage of cardiomyocytes upon adding the selective ₁ receptor agonist DPDPE (0.1 mg/l) to the perfusion solution. On the contrary, no cardioprotective effect was observed for 0.5 mg/l concentration of the peptide or after its intravenous injection. Stimulation of the cardiac ₁ opioid receptors by intravenous injection of 0.5 mg/kg DPDPE or its addition to the perfusion solution decreased myocardial contractility both under conditions of normal oxygenation and during reperfusion. Thus, the cardioprotective and negative inotropic effect of DPDPE is mediated by activation of the cardiac ₁ opioid receptors.     

Long non‐coding RNAs in melanoma

Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma development, the involvement of regulatory non‐coding RNAs remain unclear. Long non‐coding RNAs (lncRNAs) are a group of endogenous non‐protein‐coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY‐IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.     

Role of cannabinoid receptors in regulation of cardiac tolerance to ischemia and reperfusion

Coronary artery occlusion (45 min) and reperfusion (2 h) were modeled in vivo in anesthetized artificially ventilated Wistar rats. Total ischemia (45 min) and reperfusion (30 min) of the isolated rat heart were performed in vitro. The selective agonist of cannabinoid (CB) receptors HU-210 was injected intravenously at a dose of 0.1 mg/kg 15 min prior to the coronary artery ligation. The selective CB1 antagonist SR141716A and the selective CB2 antagonist SR144528 were injected intravenously 25 min prior to ischemia. In vitro, HU-210 and SR141716A were added to the perfusion solution at the final concentrations of 0.1 μM prior to total ischemia. Preliminary injection of HU-210 reduced the infarct size-to-area at risk (IS/AAR) ratio in vivo. This cardioprotective effect was completely abolished by SR141716A but remained after SR144528 injection. Both antagonists had no effect on the IS/AAR ratio. Preliminary injection of the K_ATP channel blocker glibenclamide did not abolish the cardioprotective effect of HU-210. The addition of HU-210 prior to ischemia reduced the creatine phosphokinase (CPK) level in the coronary effluent and decreased left ventricular developed pressure. SR141716A alone had no effect on cardiac contractility and CPK levels. These results suggest that cardiac CB1 receptor activation increases cardiac tolerance to ischemia-reperfusion and has a negative effect on the cardiac pump function. Endogenous cannabinoids are not involved in the regulation of cardiac contractility and tolerance to ischemia and reperfusion. ATP-sensitive k_ATP-channels are not involved in the mechanism of the cardioprotective effect of HU-210.     

Protective effect of bixin on carbon tetrachloride-induced hepatotoxicity in rats

Background

The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl₄) in rats.

Results

The animals were divided into four groups with six rats in each group. CCl₄ (0.125 mL kg^-1 body wt.) was injected intraperitoneally, and bixin (5.0 mg kg^-1 body wt.) was given by gavage 7 days before the CCl₄ injection. Bixin prevented the liver damage caused by CCl₄, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl₄ by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment.

Conclusion

Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl₄ is related to the antioxidant activity of the compound.     

Effect of stimulation of mu-opiate receptors on contractility of the isolated heart in normal oxygenation and during ischemia-reperfusion]

Activation of mu-opioid receptor (OR) in rats prevented development of reperfusion-induced myocardial cell damage. In contrast, direct cardiac mu-OR stimulation with the opioid receptor agonist DAMGO decreased cardiac contractility in normal oxygenation and aggravated the reperfusion-induced myocardial cell damage. The findings suggest that the cardioprotective effect of mu-OR stimulation is not mediated via cardiac mu-OR activation.     

Activation of δ-opioid receptors increases resistance of isolated heart to ischemia/reperfusion: The role of cAMP and intracellular calcium

Activation of cardiac -opioid receptors (ORs) by their selective agonist DPDPE (154 nM) increased the resistance of perfused rat heart to ischemia/reperfusion injury. Decreased release of creatine phosphokinase to the perfusate and decreased incidence of arrhythmias were observed during reoxygenation. At the same time, opioidergic decrease in left ventricular developed pressure took place both during the preischemic period and after restoring the coronary circulation. All these effects could be prevented by blocking -ORs by naltrindole or inhibition of Ca²⁺-ATPase of sarcoplasmic reticulum by cyclopiazonic acid. -OR agonist DPDPE had no effect on cAMP levels in myocardial tissue during the whole experiment. The obtained data suggest that the antiarrhythmic and cytoprotective effects observed after -OR stimulation can be realized through the changes in Ca²⁺ transport at the level of the sarcoplasmic reticulumTranslated from Izvestiya Akademii Nauk, Seriya Biologicheskaya, No. 1, 2005, pp. 55–62.Original Russian Text Copyright © 2005 by Lishmanov, Maslov, Lasukova, Platonov, Oeltgen.     

Significance of cardiac cannabinoid receptors in regulation of cardiac rhythm,myocardial contractility,and electrophysiologic processes in heart

Intravenous administration of cannabinoid (CB) receptor agonists (HU-210, 0.1 mg/kg; ACPA, 0.125 mg/kg; methanandamide, 2.5 mg/kg; and anandamide, 2.5 mg/kg) induced bradycardia in chloralose-anesthetized rats irrespective of the solubilization method. Methanandamide, HU-210, and ACPA had no effect on the electrophysiological activity of the heart, while anandamide increased the duration of the QRS complex. The negative chronotropic effect of HU-210 was due to CB1 receptor activation since it was not observed after CB1 receptor blockade by SR141716A (1 mg/kg intravenously) but was present after pretreatment with CB2 receptor antagonist SR144528 (1 mg/kg intravenously). CB receptor antagonists SR141716A and SR144528 had no effect on cardiac rhythm or ECG indices. Hence, in the intact heart, endogenous CB receptor agonists are not involved in the regulation of cardiac rhythm and electrophysiological processes. The chronotropic effect of CBs was independent of the autonomic nervous system because it remained significant after autonomic ganglion blockade by hexamethonium (1 mg/kg intravenously). CB receptor activation by HU-210 (0.1 and 1 μM) in vitro decreased the rate and force of isolated heart contractions, the rates of contraction and relaxation, and end diastolic pressure. The negative chronotropic effect of HU-210 was less pronounced in vitro than in vivo. The maximum inotropic effect of HU-210 was reached at the concentration of 0.1 μM.     

Role of κ1 opioid receptors and cAMP in regulation of cardiac tolerance to ischemia and reperfusion

Cardioprotective, inotropic, and antiarrhythmic effects of the selective agonist of κ₁ opioid receptors (κ₁-ORs) U-50.488H have been studied after 45-min global ischemia and 30-min reperfusion of isolated perfused rat hearts. The heart κ₁-ORs were stimulated by adding 0.1 or 1 μmol/l U-50.488H to the perfusion solution. The opioid did not affect the frequency of reperfusion arrhythmias. At a concentration of 0.1 μmol/l, it induced a twofold decrease in the reperfusion release of creatine phosphokinase (CPK), which positively correlated with a decrease in the myocardial cAMP level (r = 0.89, p < 0.01). Application of U-50.488H at a final concentration of 1 μmol/l did not change the cAMP level and CPK release. These results suggest that the cardioprotective effect of U-50.488H is due to a decrease in the level of cAMP in cardiomyocytes. Activation of κ₁-ORs decreased the frequency and force of myocardial contractions. It has been shown that the negative inotropic and chronotropic effects of U-50.488H are independent of changes in the myocardial cAMP level. A hypothesis is proposed that the absence of cardioprotective effect of 1μM U-50.488H is a result of activation of nonopioid receptors in cardiomyocytes.     

Enkephalins and hormonal-metabolic reactions in experimental stress of differing severity

Experiments on rats were made to study the effects of enkephalins on blood cortisol, insulin and glucose and excretion of catecholamines with urine during stress. In mild stress, enkephalins were demonstrated to be able to increase the catabolic processes, thereby accelerating the transition of the reaction to the phase of resistance. In severe stress, parenteral administration of enkephalins was discovered to promote the reduction in alterations of the parameters under study characteristic of stress.     

Contribution of delta1-opioid receptors in regulation of cardiac resistance to ischemia-reperfusion

It has been found that pretreatment with a delta 1-opioid receptor agonist, DPDPE, in dose of 0.1 mg/kg intravenously 15 min before heart isolation, prevents appearance of reperfusion, ventricular arrhythmias during total global ischemia (45 min) and reperfusion (10 min) of isolated rat heart. This effect was dose-dependent. Addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/L and/or 0.5 mg/L 15 min before ischemia also decreased the incidence of reperfusion arrhythmias in a concentration-dependent manner. Addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/L also decreased creatine kinase levels in the coronary sinus. However DPDPE had no cardio-protective effect in concentration of 0.5 mg/L or after intravenous administration. A previous intravenous injection of DPDPE in dose of 0.5 mg/kg exacerbated reperfusion-induced contractile dysfunction of isolated heart but exerted no effect in dose of 0.1 mg/kg. Previous perfusion of the rat isolated heart by DPDPE in concentration of 0.1 mg/L and 0.5 mg/L 15 min before ischemia also exacerbated myocardial contractile dysfunction during reperfusion. It is proposed that the antiarrhythmic, cardio-protective and negative inotropic effect of DPDPE during reperfusion may be due to stimulation of cardiac delta-1 receptors.