Biomedical subjects
Publications and source records attributed to L N Maslov.
It has been shown that the stable analog of leu-enkephalin diminishes to a great extent the stress-induced changes in the blood content of ACTH, cortisol, hypophyseal-thyroid hormones, the CAMP level in the adrenal and thymic tissues of white rats. It is assumed that this circumstance may interfere with depletion of the adrenal cortex and suppression of the lymphoid-macrophagal system.
Acute cold exposure of organism (4 hours at -20 degrees C) inhibits myocardial protein synthesis and increases cortisol/insulin index in rat blood. Preliminary repeated administration in [D-Ala2, Leu5, Arg6]-enkephalin (dalargin) prevents the decrease of myocardial protein synthesis rate after cold stress and decreases cortisol/insulin ratio. Pretreatment with naloxone at dose of 0.2 mg/kg or 2 mg/kg doesn't eliminate "anabolic" effect of dalargin. "Anabolic" effect of dalargin is suggested to be connected with -opioid receptor stimulation and change in insulin and cortisol secretion.
It was shown that the agonists of peripheral mu-receptors DALBA and PLO17 increase the resistance of the heart to adrenaline, aconitine, ischemic, reperfusion, and CaCl2-induced arrhythmias and also raise the threshold of ventricular fibrillation in postinfarction cardiosclerosis. The antagonists of mu-receptors naloxon and STAR removed these effects. The ganglion-blocking agent hexamethonium had no influence on the antiarrhythmic effect of DALBA. It is supposed that the autonomic nervous system does not play any essential role in the mechanism of the antiarrhythmic effect of agonists of peripheral mu-receptors.
It was shown that the agonist of peripheral ORL1 receptors nociceptine raises heart resistance to the antiarrhythmic effect of aconitine. The antiarrhythmic effect of nociceptine is not connected with a change in the tonus of the autonomous nervous system or with an effect on opiate receptors. It is assumed that the antiarrhythmic properties of nociceptine are realized through inhibition of Na+/Ca2+ metabolism or blockade of rapid Na(+) channels of the cardiomyocytes.
It has been found that the sigma 1- and sigma 3-receptor antagonists, DuP 734 intraperitoneally and XJ 448 intravenously, had antiarrhythmic effects against epinephrine-induced arrhythmias in rats. The ED50 for antiarrhythmic effect of DuP 734 was 0.157 mg/kg after intraperitoneal administration. Other sigma-receptor antagonists (rimcazole, BMY 14802, haloperidol) did not affect the incidence of epinephrine-induced arrhythmias. sigma 1-Receptor agonists (DTG, N-allyl-normetazocine, (+)-3-PPP, (-)-3-PPP) had proarrhythmic effect after systemic administration. The sigma-agonist N-allyl-normetazocine and sigma-antagonist XJ 488 had no effect on the incidence of epinephrine-induced arrhythmias after intracerebroventricular administration. Therefore, it appears that the central nervous system does not play a significant role in the antiarrhythmic or proarrhythmic effects of sigma ligands. We hypothesize that these effects of sigma ligands might be dependent on their action on cardiac sigma receptors.
Immobilization stress leads to the increase of 99mTc-pyrophosphate accumulation in the heart that points to the cardiomyocyte damage. The stress-reaction was accompanied by a decrease of protein synthesis rate in the heart muscle and immunoreactive insulin level in blood plasma and increase of blood plasma cortisol and aldosteron. Pretreatment with agonists mu-opioid receptors DALDA and DAGO (0.1 mg/kg intraperitonealy (i.p.) twice during stress) completely prevented the stress-induction decrease of myocardial protein synthesis rate, heart damage and hormonal imbalance. Cycloheximide administration (0.3 mg/kg i.p.) increased rats myocardial membrane injury during immobilization and reduced cardioprotective effect of DALDA.
Upon intravenous injection of the delta-opioid receptor agonists, the isolated perfused rat heart became resistant to free radical damage. The cardioprotector activity of the delta-receptor agonists is more pronounced than that of the antioxidant dibunol. Both dibunol and the delta-receptor agonists favored a decrease in the level of diene conjugates in myocardium. Stimulation of the mu-opioid receptors did not change the resistance of rat heart to the oxidative stress.
Repeated prophylactic administration of plant adaptogen preparations based on extracts from rhodiola, eleutherococcus, leuzea, and ginseng, produced a pronounced antiarrhythmic effect on the model of adrenal arrhythmia in animals. Preliminary opioid receptor block by naloxone reduced the protective effect of phytopreparations in the adapted animals. Intravenous and intracerebroventricular administration of naloxone (opioid receptor antagonist) showed that the anti-arrhythmic effect of rhodiola extract proceeds through the activation of both central and peripheral opioid receptors.
Intraperitoneal administration of the sigma-receptor antagonist DuP 734 (1 mg/kg) 15 min before heart excision produces a decrease in the reperfusion heart contractility and prevented from the reperfusion induced cardiac cell lesion upon global ischemia of the isolated perfused rat heart. At the same time, a preliminary treatment with DuP 734 potentiated the reperfusion induced suppression of the cardiac pump function, while affecting neither the cardiac contractility dysfunction nor the cardiac cell injury during the oxidative stress. It is concluded that DuP 734 is not effective in preventing the myocardial stunning. The cardio-protector effect of DuP 734 during reperfusion is not related to inhibition of the free radical cell damage.
It has been found that in vivo pretreatment of rats with the sigma receptor antagonist DuP 734 (1 mg/kg) resulted in an increase in the heart tolerance to ischemic and reperfusion arrhythmias both in vivo and ex vivo. Administration of DuP 734 (1 mg/liter) directly in the perfusion solution of isolated rat heart 10 min before total ischemia also promoted a decrease in the incidence of reperfusion arrhythmias. The normoxic perfusion of isolated rat heart at a dose of 1 mg/liter had no effect on the action potential. It was concluded that antiarrhythmic effect of DuP 734 might depend on the decrease in the Ca2+ overload but not on K+ and Na+ channel blockade.
Peripheral administration of the mu- or kappa-receptor agonists or sigma-receptor antagonists produced a significant receptor-dependent increase in the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis. The effect was not observed upon administration of the epsilon-receptor agonist beta-endorphin. The receptor and molecular mechanisms of the observed effects are discussed.
The cardioselective KATP channel activator BMS 180448 (3 mg/kg) administered intravenously 15 min before the coronary artery occlusion (10 min) decreased the incidence of ischemic and reperfusion arrhythmias in rats. A similar antiarrhythmic effect was observed when BMS 180448 was infused 2 min before reperfusion. Pretreatment with BMS 180448 also prevented the occurrence of CsCl induced arrhythmias, but but did not affect the incidence of epinephrine induced arrhythmias. On the contrary, BMS 180448 potentiated the arrhythmogenic action of CaCl2. The mechanism of the antiarrhythmic activity of BMS 180448 is discussed.
Activation of peripheral mu-opioid receptors contributes to an increase in stability of cardiomyocytes to stress damage manifesting with decreased accumulation of Tc-99m pyrophosphate in the heart muscle and contractures of the myocardium. As a principal mechanism of mu-receptor-dependent increase in resistance of the heart to stress damage, modulated influence of opioids on adrenergic pathogenetic links of heart stress damage is considered. In realization of the discovered cardioprotective effect associated with mu-receptor activation, opioidergic limitation of histamine release from mast cells in the myocardium and also mu-receptor-dependent intensification of coronary bloodstream in stressed animals may play a definite role.
Intravenous administration of peptide delta 2-opioid receptor agonists increased cardiac sarcolemma resistance to subsequent oxidative stress in the isolated perfused rat heart in vitro. delta-Opioid receptor stimulation prevented oxidative stress-induced accumulation of lipid peroxides in myocardium and inhibition of superoxide dismutase. The cardioprotective and "antioxidant" effects of delta-agonists were completely abolished by in vivo pretreatment with the delta-receptor antagonist ICI 174,864. mu-Opioid receptor activation in vivo did not protect the isolated myocardium from cardiotoxic action of activated oxygen species.
The cannabinoid (CB1) receptor agonist HU-210 (0.5 mg/kg, i.v.) exhibited a pronounced antiarrhythmic effect in rats with the adrenaline (epinephrine) and aconitine induced arrhythmia models. At the same time, the intracerebrovascular introduction of HU-210 (500 or 5000 ng) did not affect the adrenaline-induced arrhythmia. The CB1 receptor pretreatment (blocking) with the SR 141716 antagonist (3 mg/kg) and the introduction of a ganglion blocker (hexamethonium, 10 mg/kg) did not inhibit the antiarrhythmic effect of HU-210. It is concluded that the antiarrhythmic effect of intravenously injected HU-210 is neither related to the CB 1 receptor activation nor mediated by the autonomous (vegetative) nervous system.
It is demonstrated that intravenous administration of the kappa 1-opioid receptor (OR) agonists (-)-trans-(1S,S)-U-50,488 and (+)-trans-(1R,2R)-U-50,488 increases heart tolerance to the arrhythmogenic effect of epinephrine in rats. This antiarrhythmic effect was completely abolished by preliminary kappa-OR blocking with norbinaltorphimine. Preliminary administration of of a high-affinity kappa 1-OR agonist (-)-trans-(1S,S)-U-50,488 significantly reduced the incidence of ventricular arrhythmias upon coronary artery occlusion and reperfusion in vivo. The low-affinity (+)-trans-(1R,2R)-U-50,488 does not show antiarrhythmic activity under ischemia and reperfusion of myocardium. It is concluded that the antiarrhythmic action of kappa 1-OR agonists in the adrenal, ischemic, and reperfusion arrhythmia models has a receptor-specific character.
Preliminary administration of the mu-opioid receptor (mu-OR) agonist DAMGO (0.1 mg/kg) 15 min before heart isolation led to attenuation of the postischemic systolic and diastolic contractility dysfunction in isolated perfused rat heart. In addition, the mu-OR decreased creatine kinase (CK) release from the heart during the postischemic period, which was indicative of an increase in the sarcolemma tolerance to reperfusion injury. This protective effects are mediated by KATP channel activation. These data show that the mu-OR stimulation in vivo increases, by means of the KATP channel activation, the cardiac tolerance to the ischemia and reperfusion injury in vitro. Pretreatment with mu-OR agonists DAMGO or DALDA in vitro (0.5 mg/liter, 15 min prior to ischemia) exacerbated the postischemic contractility dysfunction of myocardium and did not affect the CK release. It is concluded that the protective effect of mu-OR simulation in vivo is mediated by the activation of these receptors localized outside the heart, probably with an unknown circulating humoral factor.
The intravenous pretreatment with enkephalinase inhibitors KB 101 and acetorphan increased the heart resistance to the arrhythmogenic action of adrenaline (epinephrine), is related to activation of the delta-opioid receptors by endogenous enkephalins. At the same time, the mu-receptors and their endogenous agonists play an insignificant role in development of the antiarrhythmic effect of acetorphan. The enkephalinase inhibitors are a promising group of compounds for the development of new antiarrhythmic drugs, because these agents, in contrast to opiates, do not lead to narcotic addiction.