[Contribution of the endogenous opioid system to regulation of heart resistance to the arrhythmogenic effect of short-term ischemia and reperfusio].

Preliminary selective blockade of micro, delta1, delta2, kappa1, and kappa2 opioid receptors proved to have no effect on the incidence of ventricular arrhythmias during a 10-min coronary occlusion and subsequent reperfusion in ketamine-anesthetized rats. We propose that the endogenous opioid system has no considerable role in regulation of heart resistance to the arrhythmogenic effect of short-term local ischemia and subsequent reperfusion.

[The mechanism of antiarrhythmic action of the endogenous ORL1 receptor agonist nociceptin]. / K mekhanizmu aniaritmicheskogo deistviia éndogennogo agonista ORL! retseptorov Notsitseptina.

Prophylactic intravenous (i.v.) injections of a selective agonist of ORL1 receptors nociceptin (orphanin FQ) in a dose of 0.4 mg/kg prevented the development of aconitine-induced arrhythmia in rats narcotized with diethyl ether or chloralose. Pretreatment with L-NAME (50 mg/kg) completely abolished this effect of orphanin FQ, while the pretreatment with indomethacin (10 mg/kg) only attenuated the agonist effect, rather than abolished it completely. At the same time, pretreatment with hexamethonium (10 mg/kg) or glibenclamide (3 mg/kg) had no effect on the nociceptin-dependent cardiac tolerance to the arrhythmogenic action of aconitine. Intracerebroventricular (i.c.v.) infusion of orphanin FQ (36 microg) also prevented the onset of aconitine-induced arrhythmia, but this effect was completely abolished by hexamethonium. It is concluded that the antiarrhythmic action of nociceptin with respect to aconitine-induced arrhythmia upon i.v. and i.c.v. administration is explained by different mechanisms. In the former case, the effect of orphanin FQ is related to the activation of NO synthase and cyclooxygenase, while the central action involves the vegetative nervous system.

Role of ATP-sensitive K(+)-channels in antiarrhythmic and cardioprotective action of adaptation to intermittent hypobaric hypoxia.

Mature Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 30 sessions). This mode of adaptation enhanced heart tolerance to the arrhythmogenic action of 45-min coronary occlusion, but does not affect the infarction size/risk area ratio. In some series, the rats were exposed to more severe intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) followed by 20-min coronary occlusion and 3-h reperfusion one day after the last hypoxia session. In this case, adaptation reduced the infarction size/risk area ratio and enhanced cardiac tolerance to the arrhythmogenic effect of reperfusion, but had no effect on the incidence of ventricular arrhythmia during ischemia. We found that the cardioprotective and antiarrhythmic effects of adaptation to an altitude of 7000 m and the antiarrhythmic effect of 5000-m adaptation were mediated via activation of K(ATP) channels.

Myocardial resistance to ischemic and reperfusion injuries under conditions of chronic administration of opioid receptor agonists and antagonists.

Chronic treatment with opioid receptor ligands: nonselective peptide opioid receptor agonist dalargin (intraperitoneally in a dose of 1 mg/kg), selective nonpeptide kappa-receptor agonist GR 89696 (subcutaneously in a dose of 0.03 mg/kg), nonselectrive nonpeptide antagonist quadazocine (subcutaneously in a dose of 3 mg/kg) or naltrexone (subcutaneously in a dose of 10 mg/kg) for 20 day had no effect of the incidence of ischemic ventricular arrhythmias and the size of necrotic zone after coronary occlusion and reperfusion in rats in vivo.

Role of endogenous opioid receptor agonists in regulation of heart resistance to the arrhythmogenic action of short-term ischemia and reperfusion.

Preliminary selective block of mu-, delta1-, delta2-, and kappa-opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term immobilization of rats for 2 weeks improved heart resistance to the arrhythmogenic action of coronary occlusion and reperfusion. Selective mu-opioid receptor antagonist CTAP completely abolished, while selective delta- and kappa-opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of mu-opioid receptors play an important role in the adaptive improvement of heart resistance to arrhythmogenic factors, but are insignificant for the modulation of heart resistance to the arrhythmogenic action of short-term local ischemia-reperfusion in non-adapted animals.

Possible mechanism underlying the antiarrhythmic effect of peptides nociceptin and DALDA on the heart.

During aconitine-induced arrhythmias the antiarrhythmic effect of DALDA (Tyr-D-Arg-Phe-Lys-NH2) and nociceptin (orphanin FQ) administered intravenously depended on activation of nitric oxide synthase. K(ATP) channels were not involved in the realization of this effect. Endogenous prostanoids played a minor role in the antiarrhythmic effect of nociceptin and did not contribute to the protective influence of DALDA. The antiarrhythmic effect of orphanin FQ administered intravenously did not depend on functional activity of the autonomic nervous system. However, the effect of orphanin FQ after intracerebroventricular infusion was determined by changes in the state of this system.

[Role of ORL1 receptors in the regulation of cardiac resistance to arrhythmogenic effects ]. / O znachenii ORL1-retseptorov v reguliatsii ustoichivosti serdtsa k aritmogennym vozdeistviiam.

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.