Chronotropic effect of D-Ala<Superscript>2</Superscript>,Leu<Superscript>5</Superscript>,Arg<Superscript>6</Superscript>-enkephalin (dalargin) is associated with activation of peripheral κ-opioid receptors

Intravenous infusion of D-Ala²,Leu⁵,Arg⁶-enkephalin (dalargin) caused bradycardia in narcotized rats. This effect was not observed during opioid receptor blockade with naloxone, naloxone methiodide, and norbinaltorphimine. Dalargin and (-)-U-50,488 added to Krebs—Henseleit perfusion solution for isolated rat heart decreased heart rate. Ganglionic blocker hexamethonium potentiated the negative chronotropic effect of dalargin. The negative chronotropic effect of dalargin is probably associated with activation of cardiac κ-opioid receptors. It should be noted that dalargin caused tachycardia in some animals. This reaction was not observed after treatment with hexamethonium. The positive chronotropic effect of dalargin is probably related to modulation of the parasympathetic autonomic nervous system. Agonists and antagonists of δ-opioid receptors caused persistent bradycardia. We hypothesized that selective δ-opioid antagonists exhibit properties of partial δ-receptor agonists. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 140, No. 12, pp. 633–638, December, 2005     

Effect of dalargin on energy metabolism of heart contractile function in acute blood loss

The authors studied the mechanisms of disorders of energy provision of myocardial contractility in rabbits in hemorrhagic shock and appraised the efficacy of a new Soviet-produced agent dalargin possessing an antiadrenergic property. It is shown that dalargin exerts a significant effect on the condition of the cardiovascular system and the function of the myocardial mitochondria (MC). The effect differed depending on the time of the injection and the condition of the organism. Increase of the heart contractive function, improvement of MC function, and prolonged survival of the animals were encountered only in rabbits who received dalargin 30 minutes after blood loss. The mechanisms of the effects of dalargin in acute blood loss are discussed.     

Activation of μ-opiate receptors as a factor of regulation of heart resistance to ischemia-reperfusion and oxidative stress

Intravenous injection of the selective μ-opiate receptor agonist DAMGO (0.1 mg/kg, 15 min before isolation of the heart) improved resistance of isolated perfused rat heart to ischemia (45 min) and reperfusion (60 min) damages.In vivo administration of DAMGO prevented reperfusion-induced damages to cardiomyocytes and decreased the content of conjugated dienes in the myocardium during ischemia-reperfusionin vitro. Furthermore, stimulation of μ-opiate receptors promoted recovery of myocardial contractility during reoxygenation, but had no effect on heart resistance to free radical-induced damages during perfusion of isolated heart with a solution containing Fe²⁺ and ascorbic acid.     

Effects of central opiate and serotoninergic structures on heart rhythm during acute myocardial ischemia

Electrostimulation of the central gray matter in the sylvian aqueduct and nucleus raphe magnus produced an antiarrhythmic effect during acute myocardial ischemia. Stimulation and blockade of opiate receptors in the central amygdaloid nucleus and lateral hypothalamus with dalargin and naloxone induced the same effect. Destruction of the central gray matter in the sylvian aqueduct and nucleus raphe magnus decreased electrical stability of ischemic myocardium.     

Activation of μ-opiate receptors as a factor of regulation of heart resistance to ischemia-reperfusion and oxidative stress

Intravenous injection of the selective μ-opiate receptor agonist DAMGO (0.1 mg/kg, 15 min before isolation of the heart) improved resistance of isolated perfused rat heart to ischemia (45 min) and reperfusion (60 min) damages.In vivo administration of DAMGO prevented reperfusion-induced damages to cardiomyocytes and decreased the content of conjugated dienes in the myocardium during ischemia-reperfusionin vitro. Furthermore, stimulation of μ-opiate receptors promoted recovery of myocardial contractility during reoxygenation, but had no effect on heart resistance to free radical-induced damages during perfusion of isolated heart with a solution containing Fe²⁺ and ascorbic acid. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 163–167, August, 2000     

Increased contribution of alpha 1- vs. beta-adrenoceptor-mediated inotropic response in rats with congestive heart failure

AIM: In failing myocardium the mechanical response to beta-adrenoceptor stimulation is attenuated. Alternative signalling systems might provide inotropic support when the beta-adrenoceptor system is dysfunctioning. Accordingly, the inotropic responses to alpha 1- and beta-adrenoceptor stimulation by the endogenous adrenoceptor agonist noradrenaline in non-failing and failing rat hearts were compared. METHODS: Chronic heart failure was induced in male Wistar rats by coronary artery ligation. Corresponding sham groups were prepared. After 6 weeks, papillary muscles from non-failing and failing hearts were isolated. Receptor binding studies were performed in the corresponding myocardium. The alpha 1-adrenoceptor-mediated inotropic response was not changed while the beta-adrenoceptor-mediated response was substantially reduced in failing compared with non-failing myocardium. RESULTS: No change in potency for the agonists was observed at the alpha 1-adrenoceptors, while an increased potency for the agonists at the beta-adrenoceptors was found during heart failure. The lusitropic response to beta-adrenoceptor stimulation was intact during heart failure. No over all change in affinity or number of either adrenoceptor type was observed in receptor binding studies. The alpha 1-adrenoceptor-mediated inotropic response became dominating compared with the beta-adrenoceptor-mediated one in failing rat myocardium in contrast to the dominating role of the latter in non-failing myocardium. The attenuation of the beta-adrenoceptor-mediated inotropic response in rat failing myocardium was not because of a reduced number of receptors. CONCLUSION: Increasing contractility through stimulation of alpha 1-adrenoceptors in situ by the endogenous agonist may be an alternative way of inotropic support during heart failure and even more so during beta-adrenoceptor blockade.     

Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion

We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 500–504, November, 2006     

An assessment of the reserve potentials of the heart by using volume loading with the exclusion of a portion of the left ventricular myocardium from contraction

The reserve possibilities of the heart in dosed exclusion of part of the contractile myocardium of the left ventricle were determined by the initial functional condition of the "intact" myocardium. Overexertion by volume in exclusion of part of the myocardium from contraction is dangerous due to exhaustion of the myocardial contractility reserve, relative diminution of coronary circulation with the gradual increase of exertion and overloading of the lesser circulation, which are a secondary cause of the reduction of the reserve possibilities of the heart.     

The effect of opiate receptor agonists on the blood circulation in rats with hemorrhagic shock

The effect of intravenous infusion of agonists of mu-(DAGO) and delta-(DADL, DAAE) opiate receptors on mean arterial pressure and heart rate was studied in experiments on rats with dosed blood loss of up to 30% of calculated blood volume. Stimulation of mu-opiate receptors inhibited the drop of mean arterial pressure in hemorrhagic shock, whereas stimulation of delta-opiate receptors failed to produce such an effect. Preliminary injection of naloxone blocked the effects of mu-receptor stimulation.     

Cannabinoid Receptor Antagonists SR141716 and SR144528 Exhibit Properties of Partial Agonists in Experiments on Isolated Perfused Rat Heart

We studied the effect of selective cannabinoid receptor ligands on contractility of isolated Langendorff-perfused rat heart. It was found that 10-min perfusion of rat heart with a solution containing selective agonist of CB1 and CB2 receptors HU-210 (10 nM) decreased left ventricular developed pressure and maximum rates of contraction and relaxation. However, HU-210 had no effect on heart rate and end-diastolic pressure. Treatment with selective CB1 receptor antagonist SR141716 (1 µM) and selective CB2 receptor antagonist SR144528 (1 µM) decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. Ten-minute perfusion of rat heart with a solution containing selective agonist of CB1 and CB2 receptors HU-210 (10 nM) decreased cAMP concentration in the heart. CB receptor antagonists had little effect on cAMP concentration in the heart. The negative inotropic effect of HU-210 and CB receptor antagonists is probably mediated by activation of CB1 receptors. It can be hypothesized that the decrease in heart cAMP concentration is related to stimulation of CB2 receptors. Our results suggest that selective CB receptor antagonists SR141716 and SR144528 in a final concentration of 1 µM exhibit properties of partial CB receptor agonists.__________Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 5, pp. 512–516, May, 2005     

Regulation of cardiac functions by the L-arginine--nitric oxide system

It is shown that intracoronary infusion of L-arginine and sodium nitroprusside induces an increase in coronary flow (CF), myocardial contractility (MC) and heart rate (HR) in the isolated perfused heart of the rat. Three combinations of these effects have been observed in different experiments: generalized effect (increase of CF + MC + HR), a double effect in three variants (increase of CF + MC, CF + HR, MC + HR) and isolated effect (increase of CF or MC or HR). The data obtained suggest that an increase of CF is the main change induced by L-arginine in the isolated perfused heart, an increase of MC being secondary in relation to a CF increase, i.e. an increase of CF mediates an increase of MC (Gregg's phenomenon). A positive inotropic effect of sodium nitroprusside is the result mainly of its direct action on the myocardium and to a lesser extent due to a CF increase.     

Delta-opioid receptor activation prevents appearance of irreversible damages of cardiomyocytes and exacerbates myocardial contractility dysfunction during ischemia and reperfusion

It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min reperfusion. This effect was completely abolished by pretreatment with a delta-antagonist naltrindole or a non-selective agonist naloxone. It was found that preactivation of cardiac delta-OR exacerbates reperfusion contractility dysfunction of the heart. This effect was also eliminated by opioid receptor antagonists. It is suggested that stimulation of cardiac delta-OR prevents irreversible cardiac cell damage but exacerbates contractility dysfunction during ischemia and reperfusion in vitro.     

杭白菊提取液对抗缺血再灌注引起的离体大鼠心肌收缩功能下降

目的:观察杭白菊水提取液在缺血再灌注和缺氧/复氧过程中对离体心脏和心室肌细胞的影响,并探讨其作用机制。方法:采用Langendorff离体灌流心脏模型,观察心室收缩功能;用视频跟踪系统和细胞内双波长荧光系统分别记录单个心肌细胞收缩和i;测定心肌丙二醛(MDA)和超氧化物歧化酶(SOD)水平。结果:杭白菊(0.5g/L)可明显减轻缺血再灌注引起的离体灌流心脏左室发展压、最大收缩/舒张速率、冠脉流量和左室发展压与心率乘积的抑制作用;并明显减弱缺氧/复氧抑制心室肌细胞收缩幅度、最大收缩/舒张速度和细胞钙瞬态的作用。杭白菊处理的缺血再灌注组心肌SOD水平明显升高,MDA含量显著降低。结论:杭白菊可能通过对抗自由基的作用,从而减轻缺血再灌注和缺氧/复氧对心肌收缩功能的抑制。     

ATP as Modulator of Carbacholine Effect on Contractility of Rat Myocardium in Postnatal Ontogeny

We studied combined effect of 2-m-ATP, P₂ receptor agonist, and carbacholine, muscarinic M₂ cholinoreceptor agonist, on contractility of rat myocardium during the postnatal ontogeny. Activation of P₂ receptors can stimulate or attenuate the effects of carbacholine depending on animal age. 2-m-ATP potentiates the inhibitory effect of carbacholine on myocardial contractility in 14- and 100-day-old rats. In 21-day-old rats, activation of P₂ receptors prevented the negative effect of carbacholine on myocardial contractility. Activation of muscarinic M₂ receptors inhibited the inotropic effect of purine in all age groups.     

Appearance of adenosine triphosphate in the perfusate from working frog heart

Myosin was isolated from mouse, rat, rabbit, pig and bovine atrial and ventricular myocardium and Ca²⁺-ATPase activity was examined. In the mouse the ATPase activity of myosin was the same in atrial and ventricular myocardium. In larger animal species, the activity of atrial myosin ATPase was higher than that of ventricular myocardium and the larger the animal species the greater the divergence between the activities of atrial and ventricular myosin ATPase. The relevance of these observations to regulation of heart contractility is discussed.     

Activation of mu-opioid receptors and cardiomyocyte resistance to free radical damage

It has been found that after intravenous administration of selective agonist of mu-opioid receptors DAGO (0.1 mg/kg 15 min before heart excision) isolated rat heart becomes resistant to ischemia (45 min) and reperfusion (60 min) ex vivo. The in vivo pretreatment with DAGO prevented reperfusion injury of cardiac cells and decreased myocardial content of conjugated dienes during ischemia and reperfusion of the heart in vitro. In addition, similar mu-opioid receptor stimulation promotes a postischemic recovery of myocardial contractility in the postischemic period. However, this receptor activation does not affect heart tolerance to free radical damage during perfusion of isolated heart by a solution containing Fe(2+)-ascorbic acid.     

Receptor specificity of the antiarrhythmic effect produced by opioid peptides Dalargin and DADLE during myocardial reperfusion

Nonselective agonists of mu- and delta-opioid receptors dalargin (D-Ala2,Leu5,Arg6-enkephalin) and DADLE (D-Ala2,D-Leu5-enkephalin) administered immediately before coronary reperfusion in a dose of 0.1 mg/kg prevented the development of ventricular arrhythmias. Blockade of mu-opioid receptors abolished the antiarrhythmic effect of these peptides. Hence, antiarrhythmic activity of dalargin and DADLE is primarily associated with activation of mu-opioid receptors.     

Negative inotropic and chronotropic effects of δ-opioid receptor antagonists are mediated via non-opioid receptors

Ten-minute perfusion of intact isolated rat heart with Krebs-Henseleit solution containing δ-opioid receptor agonists (DPDPE, (−)-TAN-67) or δ-opioid receptor antagonists (naltrindole, TIPP[Ψ], ICI 174,864) at a final concentration of 0.1 mg/liter decreased HR, blood pressure in the left ventricle, and the rates of myocardial contraction and relaxation. Intravenous injection of δ-agonists (DPDPE, (−)-TAN-67, deltorphin II) or δ-antagonists (naltrindole, TIPP[Ψ], ICI 174,864) decreased HR in narcotized rats. Naloxone and naltrexone produced no effect on contractility and HR both in vivo and in vitro. Preliminary injection of naloxone and naltrexone did not prevent the negative chronotropic effect of ICI 174,864 in vitro. The negative inotropic and chronotropic effects of δ-opioid receptor antagonists are mediated by unknown non-opioid receptors in the heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 4, pp. 404–407, April, 2006     

Morphofunctional manifestations of cardioprotective effect of mu-opioid receptor stimulation in stress

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.     

Resistance of the myocardium to adrenalin in rats adapted to hypoxia

The intensity of the changes produced by adrenalin in the myocardium of rats adapted to hypoxia was studied after its administration to the intact animal and perfusion of the isolated heart. The changes were revealed by histochemical reactions for succinate dehydrogenase activity and staining for lipids. After intramuscular injection of a cardiotoxic dose of adrenalin (2.0 mg/kg) into adapted rats no damage to the myocardium was found, whereas perfusion of the isolated heart with adrenalin (20 g/ml) caused the formation of micronecroses of the cardiocytes. However, their volume was statistically significantly smaller than in the isolated heart of intact rats under similar conditions. Differences in the sensitivity of the myocardium in vivo and in vitro indicate that the phenomenon of protection of the myocardium against the harmful effects of adrenalin in rats adapted to hypoxia is manifested at the level of the intact organism. The increase in the resistance of the myocardium itself is probably due to an increase in the power of the metabolic systems during adaptation.Department of Pathological Physiology, Patrice Lumumba Peoples' Friendship University. Department of Geographic Pathology, Research Institute of Human Morphology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 9, pp. 265–268, September, 1977.