Effect of Adrenoreceptor Stimulation on Peptidergic Regulation of Cardiac Activity in Newborn Rats.

We studied the effect of adrenoreceptor stimulation on the frequency of spontaneous activity and amplitude-time parameters of isometric contraction of the atrial myocardial strips from newborn rats, as well as the effect of Y receptor stimulation against the background of adrenoreceptor activation. After addition of Y1,5 receptor agonist [Leu31, Pro34] NPY (10-7 M), a tendency to a decrease in the effect of ß1,2-adrenoreceptor agonist isoproterenol (10-5 M) on the frequency of spontaneous activity and atrial myocardial contractility was observed. The age-related features of the effect of NPY on the frequency of spontaneous activity and contractility of myocardial strips from newborn and adult rats were revealed.

Mechanisms of Modulation of Adrenergic Regulation of Spontaneous Activity Rate and Atrial Myocardial Contractility in Early Postnatal Ontogeny in Rats.

We studied combined effect of the ß1,2-adrenoreceptor agonist isoproterenol and the Y1,5 receptor agonist [Leu31, Pro34]neuropeptide Y on the frequency of spontaneous activity and myocardial contractility in 21- and 100-day-old rats. Isoproterenol increased the frequency of spontaneous activity and reduced the main parameters of isometric contraction of the atrial myocardium. When [Leu31, Pro34]neuropeptide Y was added, the frequency of spontaneous activity and the negative inotropic and the positive chronotropic effects of isoproterenol were reduced in 100-day-old rats. In 21-day-olds rats, a tendency to a decrease in the effect of isoproterenol was observed.

Effect of Neuropeptide Y on Action Potential of Working Right Atrial Cardiomyocytes in Early Postnatal Ontogeny.

The effects of neuropeptide Y (10-9-10-6 M) on electrical activity of right atrial cardiomyocytes of rats aging 7, 21, and 100 days were examined in vitro. Neuropeptide Y affected the amplitude-temporal parameters of the action potential in these cells. It decreased the duration of repolarization phase in 7-day-old rats in concentrations of 10-8 and 10-7 M, in 21-day-old rats at 10-8 and 10-6 M, and in 100-day-old at 10-6 M. The data indicate elevation of total membrane potassium current under the action of neuropeptide Y.

Effect of Neuropeptide Y on Action Potential Generation in Working Cardiomyocytes of the Right Atrium in Rat Heart.

We studied the effect of neuropeptide Y in concentrations of 10-8-10-6 M on electrical activity of adult rat right atrial cardiomyocytes with preserved spontaneous activity. Neuropeptide Y was found to modulate the amplitude-time parameters of action potential: in concentrations of 10-7 and 10-6 M it reduced the membrane potential, increased the amplitude of action potential and duration of the repolarization phase, and reduced the frequency of action potential generation. In concentration of 10-6 M, neuropeptide Y produced stronger effect on the analyzed parameters, while in concentration of 10-8 M it produced no significant changes.

NPY1 Receptors Participate in the Regulation of Myocardial Contractility in Rats.

Selective agonist (Leu(31)Pro(34)NPY) and blocker (BIBP-3226) of NPY1 receptors were used to determine the type of NPY receptors involved in myocardial contraction. Experiments with isometric contraction of myocardial strips from mature rats showed that the agonist produced the most potent effect in a concentration of 10-7 M. In this concentration, Leu(31)Pro(34)NPY showed the greatest positive inotropic effect on the contraction of the atria and ventricles. In contrast, selective blocker BIBP-3226 reduced the force of myocardial contractions. Pretreatment of myocardial strips with this blocker abolished the positive inotropic effect of Leu(31)Pro(34)NPY, which attested to important role of NPY1 receptors in myocardial contraction.

Role of neuropeptide Y in myocardial contractility of rats during early postnatal ontogeny.

We studied the effect of neuropeptide Y in concentrations of 10(-10)-10(-6) M on myocardial contractility of rats at the age of 7, 21, and 100 days. Studying the isometric contraction of myocardial strips showed that neuropeptide Y decreases the force of myocardial contraction in 7-day-old rat pups. Exogenous neuropeptide Y produced a biphasic effect in 21-day-old rats, which was manifested in the increase and subsequent decrease in myocardial contractility. Neuropeptide Y had little effect on myocardial contractility of 100-day-old animals.

Involvement of P2Y(2,4) receptors in the regulation of myocardial contractility in growing rats.

Experiments with R2Y receptor blockers allowed identification of R2Y subtypes mediating the inhibitory effects of uridine triphosphate on myocardial contractility. In 100-day-old animals, the myocardial inotropic response to the administration of uridine triphosphate was mediated by R2Y2 receptors. R2Y4 receptors took part in the realization of negative inotropic response to uridine triphosphate in all age groups, but the most pronounced effects of this substance on myocardial contractility were found in 100-day-old rats. It was found that R2Y receptor blockers PPADS and reagent blue-2 affect amplitude-time parameters of myocardial contractility in rats of various ages.

[Interaction of adrenergic and purinergic receptors in the regulation of rat myocardial contractility in postnatal ontogeny].

ß-Adrenergic receptor agonist isoproterenol and purinergic receptor agonist 2-methylthio-ATP have a positive effect on the myocardial contractile force and show different efficiencies depending on the age of animals. The maximum inotropic effect of agonists on the ventricular myocardial contractility was observed in 21-day-old rat pups. The study of a combined effect of isoproterenol and 2-methylthio-ATP showed that an increase in the sympathetic regulatory effects on the heart of 21-day-old animals, against the background of a high functional activity of ß-adrenergic receptors and P2X receptors of the heart, a combined administration of the agonists led to a mutually complementing effect of an increase in the myocardial contractility.

Involvement of P2Y receptors in myocardial contractile activity of rats during postnatal ontogeny.

We studied the effect of uridine 5'-triphosphate in concentrations of 10(-10)-10(-6) M on myocardial contractile activity in 7-100-day-old rats. Analysis of isometric contraction of myocardial strips showed that uridine 5'-triphosphate reduced the strength of myocardial contraction in rats of all age groups. In 21- and 100-day-old rat pups, exogenous uridine 5'-triphosphate produced a stronger inhibitory effect than in 7-day-old animals. The negative inotropic effect of UTP was abolished under conditions of P2Y(4) purinoceptor blockade with reagent blue-2. These data indicate that the effect of UTP on the myocardium is realized via P2Y(4) purinoceptors.

ATP as modulator of carbacholine effect on contractility of rat myocardium in postnatal ontogeny.

We studied combined effect of 2-m-ATP, P(2) receptor agonist, and carbacholine, muscarinic M(2) cholinoreceptor agonist, on contractility of rat myocardium during the postnatal ontogeny. Activation of P(2) 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 P(2) receptors prevented the negative effect of carbacholine on myocardial contractility. Activation of muscarinic M(2) receptors inhibited the inotropic effect of purine in all age groups.

Role of P2X receptors in positive inotropic effect of rat myocardium during ontogeny.

Experiments with selective agonists and antagonists of purinoceptors allowed us to evaluate the subtype of P2X receptors. We showed that the myocardium of 14- 100-day-old rats contains functionally active P2X1 receptors. These receptors are involved in the realization of the positive inotropic effect of the atria and ventricles. Selective P2X1 receptor agonist beta,gamma-methylene-ATP induced a dose-dependent increase in the strength of atrial and ventricular contractions. P2X1 receptor antagonist TNP-ATP abolished the effect of the agonist in rats of all age groups.

[Purinergic regulation of rat heart function in ontogeny].

The effect of exogenous ATP and its analogs on heart function was studied in 14-100-day-old rats. Extracellular purines had a positive chronotropic effect on the heart. Intravenous administration of exogenous ATP and its stable analogs induced a dose-dependent increase in heart rate depending on animal age. The analysis of isometric contraction of myocardial strips demonstrated a dose-dependent positive inotropic effect of ATP. The family and subtype of the P2 receptors realizing the positive chronotropic and inotropic effects were identified using selective agonists and blockers. P2X receptors demonstrated the highest sensitivity during early postnatal ontogeny. The age-related pattern of the receptor response to exogenous purines indicated the heterochronic maturation of P2X and P2Y receptors in the myocardium.

Effect of ATP and its analogs on contractility of rat myocardium during ontogeny.

The effects of P2-receptor agonists on myocardial contractility were examined in rats aging 14-100 days. ATP and its stable analog 2-methylthio-ATP potentiated the contraction force of isolated myocardial strips in a dose-dependent manner. The agonist concentrations producing the positive inotropic effect increased from days 14 to 100 of life. The efficiency of extracellular purines depends on animal age: in 14- and 56-day rats the positive inotropic effects of ATP and 2-methylthio-ATP were similar, while in 100-day rats ATP produced more pronounced effect than 2-methylthio-ATP.

Role of P2X and P2Y receptors in rat myocardial contractility during ontogeny.

Stable agonist of P2 receptors 2-methylthio-ATP and selective antagonists of P2X and P2Y receptors PPADS and reactive blue-2 were used for evaluation of the role of P2 receptors in positive contractile reaction of atrial and ventricular myocardium in rats. PPADS significantly moderated the effects of 2-methylthio-ATP in 14-, 21-, and 56-day-old rat pups, but potentiated them in 100-day-old rats. Under conditions of reactive blue-2 treatment, the positive effect of the agonist was preserved in the atria and ventricles in all age groups and was age-dependent.

Role of purinoceptors in cardiac function in rats during ontogeny.

Intravenous injection of exogenous ATP (10(-4) M) to rats aging 21, 56, and 100 days increased the heart rate by the 15th sec postinjection. Stable ATP analogue alpha,beta-methylene-ATP in an equimolar concentration increased the heart rate in rats aging 56 and 100 days (by the 15th second after treatment), but had no effect on 21-day-old animals. alpha,beta-Methylene-ATP in a concentration of 10(-7) M increased the heart rate in 21-day-old rat pups, which attests to high sensitivity of P2 purinoceptors. Administration of ATP and alpha,beta-methylene-ATP after treatment with nonselective purinoceptor antagonist suramin did not increase the heart rate in rats of different age groups. Infusion of ATP and its stable analogue after administration of selective P2Y receptor antagonist reactive blue 2 increased the heart rate in rats of different age groups. These changes reflect activation of P2X receptors in the heart.

Age-related differences in the response of blood stroke volume to stimulation of the sympathetic ganglion in rats with beta-adrenoceptor blockade.

Blood stroke volume in rats aging 21 and 56 days decreased during beta-adrenoceptor blockade with propranolol, but increased again by the 15th minute after treatment. Suprathreshold stimulation of the stellate ganglion decreased the stroke volume and increased the heart rate in control animals. Electrical stimulation after beta-adrenoceptor blockade was followed by a further decrease in stroke volume in young rats. In 100-day-old animals this parameter remained unchanged, while the cardiac output improved.

Effect of beta-adrenoceptor blockade on cardiac activity in rats during postnatal ontogeny.

Electrical stimulation of the right stellate ganglion produces a positive chronotropic effect in 21-, 56-, and 100-day-old rats. The response of the heart rate to suprathreshold stimulation increased from the 21st to 100th day. By contrast, during beta-adrenoceptor blockade the heart rate response decreased. The data suggest that the role of beta-adrenoceptor in the regulation of cardiac chronotropic function increased with age.

Effect of electrical stimulation of right stellate ganglion on cardiac function in rats during postnatal ontogeny.

In all examined age groups of rats, the threshold amplitude of stellate ganglion stimulation is higher for the positive chronotropic effect than for the inotropic effect. The stimulation produced a more pronounced effect on stroke volume than on heart rate.

Effect of exogenous ATP on cardiac activity in rats.

In vivo effects of exogenous ATP on cardiac activity were studied on adult rats. Intravenous administration of ATP produced a positive chronotropic effect, but did not affect the stroke volume. This was due to activation of type II purine receptors, rather than due to the influence of ATP hydrolysis products, since P1 receptor agonist adenosine was ineffective. The blockade of beta-adrenoceptors and muscarinic receptors did not modify the positive chronotropic effect of ATP, which indicated that this action was not realized via sympathetic or parasympathetic nerves. ATP applied against the background of atropine blockade produced a 4-fold increase in the variability of heart rate typical of activation of the parasympathetic myocardial regulation.