The effects of 4-pentenoic and pentanoic acids on the isolated rat atria

The peak developed tension and the pacemaker frequency of the isolated atria from fed and fasted rats, declined progressively during the incubation in a glucose-free medium containing 2-deoxyglucose. The atria from fed rats exhibited a faster decline than those from fasted rats, which was associated to a slower triacylglycerol lipolysis. 4-Pentenoic acid inhibited the lipolysis of both groups of atria but did not alter the atrial contractile performance. However, it enhanced the decline of the pacemaker frequency in the atria from fasted rats whereas, in contrast, it alleviated the decline in the fed atria. n-Pentanoic acid ameliorated the impairment of the contractile and pacemaker activities in both groups of atria, without affecting the lipolysis. It was concluded that, since the inhibition of the intramyocardial lipolysis did not correlate with changes of the atrial functions, 4-pentenoic acid was not appropriate to assess about the contribution of endogenous triacylglycerol to the maintenance of the atrial contractile and pacemaker activities.     

The effects of endogenous opioids on tension development of isolated, electrically stimulated rat atria

The possible inotropic effects of all three classes of endogenous opioids were tested alone or in combination with noradrenaline, adrenaline, or carbachol on electrically stimulated atria isolated from male Sprague-Dawley rats. Noradrenaline (6.0 and 12 microM) and adrenaline (4.0 and 8.0 microM) injections caused marked but transient (5 min) dose-related increases in atrial tension compared with preinjection control values, whereas carbachol (0.14 and 1.4 microM) caused a more potent and prolonged (over 15 min) dose-related decrease in atrial tension development. Adrenal enkephalins (0.3-4.0 microM) of methionine enkephalin, leucine enkephalin, Met-enkephalin-Arg6-Phe7, and Met-enkephalin-Arg6-Gly7-Leu8, beta-endorphin (0.2-2.0 microM), or dynorphin A(1-13) (0.2-2.0 microM) did not change atrial tension for a 15-min postadministration test period. In addition, these opioids did not affect the positive inotropic effects of noradrenaline (12 microM) or adrenaline (8.0 microM) or the negative inotropic actions of carbachol (1.4 microM) when the same doses of noradrenaline, adrenaline, or carbachol were given alone. These data indicate that endogenous opioids given in micromolar concentrations tested did not affect atrial tension development of electrically stimulated rat atria. Comparing these data with those of past literature, it is suggested that circulating endogenous opioids probably do not have any direct effects on the rat myocardium to affect myocardial contractility.     

The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility

The effects of the lipoxygenase products of arachidonic acid, 5- and 12-hydroxyeicosatetraenoic acid (5- and 12-HETE) and leukotriene B4 (LTB4), on the spontaneous contractility of lower uterine segment human myometrial strips obtained prior to labour have been studied in vitro. 5-HETE gave a dose- dependent (10-500ng) increase in both the rate of contractions and overall contractility of myometrial strips while 12-HETE and LTB4 had no effect at the same concentrations. Prostaglandin F2 alpha (50ng) contracted all myometrial strips in a similar pattern to 5-HETE but was approximately 10 times more potent. The effect of 5-HETE may be direct or perhaps indirect via interaction with the cyclo-oxygenase pathway. The findings do not disprove the contention that the onset of parturition may be characterised by a switch in arachidonic acid metabolism in intra-uterine tissues from lipoxygenase to cyclo-oxygenase products.     

The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility

The effects of the lipoxygenase products of arachidonic acid, 5- and 12-hydroxyeicosatetraenoic acid (5- and 12-HETE) and leukotriene B₄ (LTB₄), on the spontaneous contractility of lower uterine segment human myometrial strips obtained prior to labour have been studied . 5-HETE gave a dose- dependent (10–500ng) increase in both the rate of contractions and overall contractility of myometrial strips while 12-HETE and LTB₄ had no effect at the same concentrations. Prostaglandin F₂ (50ng) contracted all myometrial strips in a similar pattern to 5-HETE but was approximately 10 times more potent. The effect of 5-HETE may be direct or perhaps indirect via interaction with the cyclo-oxygenase pathway. The findings do not disprove the contention that the onset of parturition may be characterized by a switch in arachidonic acid metabolism in intra-uterine tissues from lipoxygenase to cyclo-oxygenase products.     

The synthesis of noradrenaline by isolated guinea-pig atria

1. The initial rate of formation of noradrenaline by isolated atria from a physiological concentration of tyrosine was measured. 2. Study of the time-course of the formation led to the conclusion that newly formed noradrenaline enters a fraction of the total pool. Synthesis and turnover was maintained for at least 1·5hr. In this time it was not possible to increase the concentration in the storage pool by employing high concentrations of precursor. 3. Preincubation of the tissue with noradrenaline resulted in an accumulation within the tissue and inhibited new formation. It is suggested that this indicates the existence of a physiological mechanism to limit the synthesis of noradrenaline, avoid saturation of storage sites and enable the `re-uptake' process to operate. 4. The amount of noradrenaline formed from 3-hydroxytyramine (dopamine) was considerably greater than from tyrosine. The kinetic constants of the reactions are in agreement with the view that hydroxylation of tyrosine to dihydroxyphenylalanine (dopa) is rate-limiting.     

Influence of the human blood serum on contractility and beta-adrenoreactyvity of the isolated human myocardium

On strips of the isolated myocardium of right hearts auriculum of the 43 patients with ischemic illness of heart and 9 patients with heart diseases of various ethyology at statement venous canule during aorto-coronary shunting, estimated influence of adrenaline (10(-9)-10(-4) g/ml) on amplitude caused by electrostimulus (1H, 5ms, 25-30 V) contractions, and also inotropic and adrenomodulation activity of serum blood (in dilution 1 : 10000, 1: 1000, 1 : 500, 1: 100, 1 : 50, 1: 10 and 1 : 5) nonpregnant women. Direct dependence of amplitude of contraction on size of fraction of of blood emission on Teyholts is revealed. It means, that strips of right auriculum myocardium reflect contractility of a left ventriculum myocardium. Adrenaline in concentration 10(-7)-10(-6) g/ml dependent of dose raised amplitude of the caused contraction not influencing it in concentration of 10(-9) and 10(-8) g/ml (the constant of dissotiation has 2 x 10(-7) g/ml), that as a whole, speaks about decrease in efficiency of activation beta-AP. Blood Serum in dissolutions 1 : 10000-1 : 50 did not influence on amplitude of contraction, and in dissolutions 1 : 10 and 1 : 5 strengthened it, that speaks presence in blood the endogenous activator of myocyte contractility (EAMC). Serum showed beta-adrenomodulation activity that speaks presence in it endogenous sensitizer of beta-adrenoreceptors (ESBAR) and endogenous blocker of beta-adrenoreceptors (EBBAR). In particular, in experiences with adrenaline in subthreshold concentration (10(-8) g/ml) serum showed ESBAR-activity (in dissolutions 1 : 1000, 1 : 500, 1 : 100 and 1 : 50), and in experiences with adrenaline in as much as possible effective concentration (10(-6) g/ml) serum showed ESBAR-activity (in dissolutions 1 : 50 and 1 : 10) and EBBAR-activity (in dissolutions 1:500) Hence, containing in blood serum endogenous modulators of beta-adrenoreactivity - ESBAR and EBBAR can modulate efficiency of beta-adrenoreceptors activation of human cardiomyocytes. It speaks about perspectivity of application of ES BAR analogues in cardiology.     

Dopamine 4-sulfate: effects on isolated perfused rat heart and role of atria

We studied the effects of sulfate conjugate of dopamine on the isolated perfused rat heart (Langendorff preparation). In the experimental group, we removed atria from half number of the hearts. In the hearts with intact atria, dopamine 4-sulfate significantly improved the DT (developed tension), +dT/dt max (maximal rate of contraction), -dT/dt max (maximum rate of relaxation) over baseline values. But when atria were removed, dopamine 4-sulfate had no effect on the mechanical functions of heart. We analysed the effluent perfusate for the free and conjugated catecholamines. In the control group (no drug), and when atria were excised, the free catecholamine levels were negligible. But when the atria were kept intact, the effluent contained significant amount of free dopamine (DA), and norepinephrine (NE). These data suggested that dopamine sulfate had no direct effect on the ventricular muscle of rat heart, but was converted within the atrial tissues into free catecholamines which might be responsible for the positive inotropic actions.     

Pharmacologic effects on mouse isolated atria of immunoglobulins directed against class I histocompatibility antigens

Sera from alloimmunized mice exert potent inotropic and chronotropic effects on mouse isolated atria. In this report, we present data showing that both total immunoglobulins and purified IgG from alloimmunized mice were able to exert per se these effects. The pharmacologic effects of IgG were parallel to its cytotoxic titer but not to its immunofluorescence titer. The specificity of the inotropic and chronotropic effects was studied by using several interstrain immunizations and target atria. It was observed that only the sera from mice immunized with H-2-disparate cells were able to exert pharmacologic effects on atria; these effects were evident not only on atria from the immunizing strain, but also on atria from other strains having identical H-2 but different backgrounds. Neither normal sera nor sera from animals immunized against non-H-2 differences were active. The effect of sera, total immunoglobulins, and purified IgG were blocked by propranolol, suggesting the involvement of beta-adrenoreceptor in the reaction.     

Effects of methylpalmoxirate on isolated rat atria.

The aim of the investigation was to assess whether endogenous triacylglycerol contributes to the maintenance of the contractile and pacemaker activities of the isolated atria from fed and fasted rats. To attain this information, the atria were treated with methylpalmoxirate which is a potent inhibitor of carnitine palmitoyltransferase I. In the presence of glucose, methylpalmoxirate abolished the lipolysis without affecting peak developed tension or the atrial rate. When exposed to a substrate-free medium containing 2-deoxyglucose, the atria displayed a progressive fall of the pacemaker frequency, a pronounced decay of contractile strength and the appearance of contracture. These derangements appeared faster in the atria from fed rats coinciding with a smaller triacylglycerol mobilization. Methylpalmoxirate suppressed triacylglycerol breakdown, increased the contracture strength, accelerated the fall of the atrial rate and in a significant number of fasted atria it led to a complete cessation of the spontaneous contractions. The decline of the peak tension was not altered by the inhibitor, probably because the contractile strength was too weak in the glucose-free medium, so that additional negative inotropic effects were not detectable. These data suggest that exogenous glucose in addition to that derived from glycogen meet the atrial energy requirements when the fatty acid oxidation is hindered. The deleterious effects exerted by methylpalmoxirate after the glucose metabolism was eliminated indicate that endogenous triacylglycerol supports, at least partly, the atrial functions.     

Adrenergic receptors of isolated snake atria

Cardiac adrenergic receptors in snakes were examined using an isolated atria preparation of Naja naja and Ptyas korros. Treatments included an examination of the atrial responses to selective alpha- and beta-adrenergic agonists and antagonists. In both species, both phenylephrine and isoproterenol produced dose-dependent increases in the atrial beating rate and tension. Phenylephrine-induced increases were characterized with a high affinity and low affinity components. These positive chronotropic and inotropic effects produced by phenylephrine and isoproterenol were abolished with propranolol and in the phenylephrine-induced response phentolamine also attenuated the low affinity response and blocked the high affinity response. With catecholamines depletion via 6-OH dopamine or reserpine, the high affinity component in the phenylephrine-induced response was no longer observed. It is concluded that beta-adrenoceptors are the predominant post-synaptic adrenoceptors in snake atria. Stimulatory presynaptic alpha-adrenoceptors for modulating noradrenaline release may also be present.     

Positive inotropic effect of ethylephrine on the isolated rat atria

Ethylephrine, a sympathomimetic amine which belongs to the phenolamine group, was assayed on the driven left rat atrium. The frequency response curve was performed for norepinephrine and ethylephrine. The maxima was attained for both compounds at 1 Hz. The agonist under study has an inotropic action less potent than the classical catecholamines. Propranolol (10(-8) and 10(-7) M) produced a parallel shift to the right in the log dose-response curves of ethylephrine with no decrease in the maximal response, indicating that the antagonism was competitive. In the presence of cocaine or with reserpine-pretreatment the sensitivity of the preparation to the amine did not vary. The alpha-blocker, phentolamine (10(-8) to 3.10(-5) M) did not possess an inotropic effect per se. In contrast, phentolamine, delivered to the bath beforehand, did not block the agonist. However at 10(-8) and 10(-7) M increase the maximal response both in normal and reserpinized preparations. It is suggested that ethylephrine is a direct inotropic preparation. It is suggested that ethylephrine is a direct inotropic agent on the driven left rat atrium and its effects are mediated by beta-receptors. The results also indicate the lack of evidence that ethylephrine has any action on the alpha-receptors.     

Interaction of clonidine with chronotropic agents on isolated right atria

Clonidine was administered to isolated guinea pig right atria in order to characterize its chronotropic activity and its interaction with other chronotropic agents at the postjunctional level. Clonidine either had no significant effect (10(-7)--10(-4) M) or decreased (10(-3) M) atrial rate. Pretreatment of the atria with clonidine noncompetitively antagonized (10(-6)--10(-4) M) the positive chronotropic actions of isoproterenol, and competitively antagonized (10(-4) M) the negative chronotropic actions of pilocarpine. At doses of 10(-6) or 3 X 10(-6) M, clonidine also noncompetitively antagonized the positive chronotropic effects of 4-methylhistamine and glucagon. The results show that clonidine antagonizes both adrenergic and cholinergic influences on atrial rate at the postjunctional level and suggest that the antagonism of adrenergic influences does not involve a direct interaction with beta-adrenergic receptors.     

Comparative studies on effects of estrogens and progesterone on the contractility of isolated uterine horns of rats

The effect of estrogens on the myometrial contractility of 70 isolated uterine horns of rats was investigated; 40 of the rats had been treated with progesterone and 30 with estrogen. Contractions were recorded isotonically in solutions with extracellular potassium concentration of 2.5 to 40 mM. The contractility of the myometrium of rats treated with estrogens was observed to be similar to the optimum contractility during labor, with the characteristic high amplitude of tension, low initial tension, and good coordination of contractions. The contractility of the uterine horns treated with progesterone was almost 1/2 lower and showed worse coordination of contractions. The difference between progesterone and estrogen is expressed through the quantitatively and qualitatively different influences on the motor function of the uterus.     

Contractile effects of endothelins on isolated human ureter

The aim of our study was to investigate mechanism of action of endothelins 1, 2 and 3 on spontaneous activity, tone and intraluminal pressure of human ureter. Both longitudinal tension and intraluminal pressure were recorded from the isolated segments of proximal human ureter. Endothelins 1, 2 and 3 (5.35x10(-11) M - 5.05x10(-8) M) produced concentration-dependent tonic contraction and sustained increase in intraluminal pressure of isolated preparations of human ureter. Endothelins 1 and 3 produced also concentration-dependent inhibition of spontaneous, phasic contractions of the isolated preparations. Selective antagonist of ET(A) receptors BQ123 and selective antagonist of ET(B) receptors BQ788 produced significant inhibition of endothelin-1-induced tonic contraction (pA(2)=8.80 and 6.55, respectively) and increase in intraluminal pressure (pA(2)=8.68 and 7.02, respectively), while they did not affect endothelin-1-induced inhibition of spontaneous activity. Endothelin 1 produces increase in tone and intraluminal pressure of isolated human ureter acting on both ET(A) and ET(B) receptors, the first one being functionally more important. Only endothelins 1 and 3 inhibit spontaneous, phasic activity of human ureter, but this effect was not blocked by selective antagonists of ET(A) and ET(B) receptors.