Isolated Rat Atria Research Articles

Effects of cocaine on several adrenergic system parameters

1. The effect of acute and chronic administration of cocaine on the sympathetic nervous system in the cardiac tissue and the adrenal glands of rats were studied. 2. Both with acute and chronic administration of the drug, the concentration-response curve to (−)-norepinephrine on the isolated rat atria was shifted to the right, with a lower p D 2. 3. The endogenous ventricular norepinephrine levels remain unchanged after acute injections of cocaine, but when the drug was administered chronically, the endogenous neurotransmitter content were augmented about 50%. 4. The tyrosine hydroxylase activity in atria and adrenal homogenates decreased after chronic injections of cocaine, while it was not observed any modifications in the enzyme activity after acute administrations of the drug.

Modification of the contractile activity of isolated rat atria by lectin-activated T-lymphocyte subsets

We had previously shown that human T-lymphocytes (ERFC) that had been activated for a short time with phytohemagglutinin (PHA) produced positive inotropic and chronotropic effects on spontaneously beating rat atria (Sterin-Borda, L., et al, Naunyn Scmiedeberg's Arch. Pharmacol. 324, 58, 1983). In this study, we first prepared T4-rich (T4) and T8-rich (T8) cells from ERFC by selective lysis with OKT4 and OKT8 monoclonal antibodies and rabbit complement. Then, we tested the effect of PHA-stimulated T4 (PHA-T4) and T8 (PHA-T8) on beating rat atria. PHA-T4 cells stimulated the tension and the frequency of contraction of isolated rat atria by a mechanism that involved the generation of the slow reacting substance of anaphylaxis (SRS-A), since both 10 −5 M nordihydroguaiaretic acid (NDGA) and 10 −7 M FPL-55712 were effective inhibitors. On the other hand, PHA-T8 cells decreased the tension of beating atria. Indomethacin (10 −6 M) could not block the depressor effect. Cell-free PHA-T4 supernatants reacted with the heart tissue similarly to whole PHA-T4 cells. Since NDGA or FPL-55712 treated organs did not respond to active PHA-T4 supernatants, the lipoxygenase system of the auricles seems to be required for the reaction and the active metabolites appear to derive mainly from the heart. Our results suggest that PHA-activated “helper/inducer” cells release soluble factors that can in turn trigger the lipoxygenase metabolic pathway of arachidonic acid in the heart, generating the active leukotrienes responsible for the positive inotropic and Chronotropic effects.

8-bromo-cGMP improves energy state in hypoxic rat atria.

8-bromo-cGMP (1 X 10(-4) M) was found to prevent the hypoxia-induced decrease in creatine phosphate (CrP) and ATP in isolated rat atria. An increase in ADP was also seen after 8-bromo-cGMP treatment, while the AMP level remained unchanged. 8-bromo-cGMP administration resulted in a higher energy charge during the initial state of hypoxia. 8-bromo-cGMP did not affect heart rate or contractility during hypoxia. These results suggest that cGMP improves the energy state of the heart cell in hypoxia. The exact mechanism(s) of these effects is not known but an improvement of oxidative phosphorylation might, quantitatively, account for the changes.

The effect of bromoacetylalprenololmentane on rat atrial tension development and β-adrenoreceptors

In isolated rat atria, 1 μM bromoacetylalprenololmentane shifted the tension development curve for isoproterenol to the right of the control curve. After a 2 h washout period, no significant recovery of the isoproterenol concentration-response curve had occurred. Pretreatment of rat atrial membranes with 1 μM bromoacetylalprenololmentane resulted in an 83% decrease in the concentration of β-adrenoceptors with no change in the KD value for [125I]iodocyanopindolol binding to the receptors left. The results indicated that bromoacetylalprenololmentane was an irreversible β-blocker.

Mechanism(s) of the hypotensive effect of synthetic 1-O-octadecyl-2-O-acetyl-glycero-3-phosphorylcholine.

The mechanism of the hypotensive effect of 1-O-octadecyl-2-O-acetyl-glycero-3-phosphorylcholine (C18- AGPC ) was examined. Synthetic C18- AGPC caused dose-dependent hypotension in conscious rats. The activity was almost the same in DOCA and renal hypertensive rats. This suggests that it is not a renin inhibitor. Hypotension also appeared in pithed rats. This suggests that the effect is not due to a central mechanism. Hypotension did not result from platelet aggregation or bronchial constriction. Since C18- AGPC suppressed not only the pressor response to noradrenaline but also to angiotensin II and vasopressin, and furthermore, did not disturb the dose-response curve of noradrenaline in the isolated aorta, the possibility of the agent being an alpha-adrenergic antagonist is ruled out. In the PGF2 alpha-contracted rat aorta. C18- AGPC caused marked vasodilation, which disappeared after removal of the endothelium. Perfusion pressure decreased in the blood-perfused rat hindquarters but not in the Tyrode solution-perfused ones. C18- AGPC induced a positive inotropic effect in isolated rat atrium. The hypotensive effect of synthetic C18- AGPC seems to be mainly due to endothelium-dependent vasodilation.

Effects of ciguatoxin and maitotoxin on isolated rat atria and rabbit duodenum

Ciguatoxin atoxin and maitotoxin, extracted from a species of moray-eel, Gymnothorax javanicus, and from a wild dinoflagellate, Gambierdiscus toxicus, were tested on rat atria and rabbit duodenum. Biphasic inotropic and chronotropic responses with excitatory and inhibitory components were observed. The effects of agents such as reserpine, propranolol, phentolamine, atropine and manganese ions were investigated. We conclude that, at the dosage levels used, ciguatoxin acts mainly at the nerve endings, while maitotoxin exerts prominent toxic effects on muscles.

Comparison of three β-amino anilides: IQB-M-81, lidocaine and tocainide, on isolated rat atria

The effects of a new β-amino anilide, IQB-M-81, on electrical and mechanical activity of isolated rat atria were studied and compared with those of lidocaine and tocainide. In spontaneously beating right atria IQB-M-81 produced a dose-dependent decrease in rate, contractile force and maximum following frequency and prolonged the sinus node recovery time and the effective refractory period of atrial fibers. The negative inotropic effect was not modified by pretreating the atria with atropine or practolol. In isolated right atria IQB-M-81 did not block the positive chronotropic and inotropic responses to isoprenaline but shifted the dose-response curve to the right. IQB-M-81 and lidocaine, but not tocainide, reduced in a dose-dependent manner the slow contractions induced by isoprenaline in K-depolarized right atria. These results suggest that in contrast to other β-amino anilides, IQB-M-81 exerted a negative chronotropic effect and that it presented a class I antiarrhythmic effect on isolated rat atria. A possible class IV antiarrhythmic effect is also discussed.

Effect of phytohemagglutinin-stimulated human lymphocytes on isolated rat atria. Participation of lipoxygenase products of arachidonic acid metabolism.

The effect of phytohemagglutinin (PHA) stimulated human lymphocytes on the contractile activity of isolated rat atria was studied. Increased isometric developed tension (IDT) and higher frequency of contractions (FC) were observed shortly after contact of PHA-activated lymphocytes with spontaneously beating rat atria. Since pre-exposure of the lymphocytes to PHA was not necessary and the pharmacologic effects were demonstrated immediately after addition of the lectin, division of the effector cells as a requisite for their action was excluded. Experiments performed with the antibiotic crystallized from Streptomyces chartreusenis, Ca2+-ionophore A-23187, yielded similar effects. Lymphocyte fractionation studies showed that T-lymphocyte-rich and T-lymphocyte-depleted cell fractions had opposite effects on IDT and FC. The inotropic and chronotropic effects were not modified by (-)-propranolol or antihistaminics. Inhibitor of the synthesis of prostaglandins enhanced the action of PHA-activated lymphocytes but inhibitors of the lipoxygenase pathway: 5,8,11,14-eicosatetraynoic acid (ETYA) and nordihydroguaiaretic acid (NDGA) prevented the increment of IDT and FC. Also, FPL55712, an antagonist of SRS-A abolished the positive inotropic and chronotropic effects of PHA-activated lymphocytes on rat atria. Therefore, a central role for SRS-A in this reaction is suggested.

Adenosine reduces catecholamine contractile responses in oxygenated and hypoxic atria.

The properties of adenosine attenuation of catecholamine-elicited increases in peak contractile force, rate of force development, and rate of relaxation were studied in isolated rat atria. Adenosine, at a concentration that did not cause a direct depressant effect by itself, was capable of reducing by approximately 15% the increase in the contractile parameters elicited by isoproterenol. This reduction was not overcome by elevating the catecholamine concentration. The adenosine reduction was prevented by theophylline or the presence of adenosine deaminase. The reduction appears to be independent of the acetylcholine-mediated reduction of catecholamine responses. Adenosine reduced the positive inotropic responses elicited by norepinephrine and epinephrine but not phenylephrine. Adenosine deaminase in oxygenated atria potentiated the catecholamine-elicited contractile responses and reduced the progressive fall of the elevated contractile responses observed with continual catecholamine stimulation. In hypoxic atria adenosine deaminase potentiated the positive inotropic responses observed with catecholamine stimulation. The results suggest that an adenosine-specific mechanism is capable of attenuating the elevation in contractility elicited by beta-adrenergic stimulation. In addition, endogenous adenosine may be responsible, in part, for the reduction of catecholamine-mediated contractile responses in oxygenated and hypoxic myocardial tissue.

The effect of the beta-adrenoreceptor antagonist Ro03-7894 on rat atrial tension development and (−)-[ 3H]dihydroalprenolol binding to cardiac and lung membranes

The ability of 1-(5-chloracetylaminobenzfuran-2-yl)-2-isopropylaminoethanol (Ro03-7894) to irreversibly inactivate beta-adrenoreceptors was studied. In isolated rat atria Ro03-7894 (500 μM) depressed and shifted the tension development curve for isoproterenol to the right. After a 2 hour washout period the dose response curve for isoproterenol was further depressed. At a lower dose of Ro03-7894 (50 μM), the isoproterenol dose response curve was also depressed and shifted to the right although after a 2 hour washout, the sensitivity to isoproterenol was restored but the maximum response was still depressed. Ro03-7894 (50 μM) also depressed the tension development response to increasing concentrations of external calcium. The concentration of Ro03-7894 that inhibited (−)-[ 3H]dihydroalprenolol (DHA) binding by 50% in cardiac and lung membranes was 20 μM. Incubation of rat ventricular or lung membranes for 1 hour with 100 μM Ro03-7894 followed by washing did not change the concentration of beta-adrenoreceptors or the K D values for [ 3H]DHA binding. Furthermore, neither the concentration of beta-adrenoreceptors nor the K D for [ 3H]DHA binding was changed in cardiac and lung membranes at 4 or 24 hours after an i.p. injection of 20 mg/kg of Ro03-7894. The results suggested that Ro03-7894 was a relatively weak beta-adrenoreceptor antagonist which under the conditions used did not irreversibly inactivate the receptor but probably depressed tension development in intact atria nonspecifically.

Electrophysiological and mechanical effects of sulphinpyrazone on isolated rat atria.

Clinical trials suggest that sulphinpyrazone reduces the incidence of sudden death in patients having suffered a myocardial infarction. To investigate possible direct antiarrhythmic properties of sulphinpyrazone, we carried out experiments on spontaneously beating and electrically stimulated isolated rat atrial preparations. Dose-response curves for electrophysiological and mechanical effects of sulphinpyrazone were obtained. Increasing doses of sulphinpyrazone decreased the spontaneous atrial frequency, prolonged the sinus node recovery time after overdrive pacing, slightly increased the electrical threshold for excitation and decreased the contractile force. Although the mechanism by which sulphinpyrazone may reduce the incidence of sudden cardiac death is still not settled, the present study demonstrates direct electrophysiological and mechanical effects of the drug at high concentrations.

A comparison of Josamycin with macrolides and related antibiotics on isolated rat atria

The effects of macrolide (josamycin, erythromycin, spiramycin and oleandomycin) and related antibiotics (clindamycin and lincomycin) were examined and compared in spontaneously beating right atrial preparations and in electrically driven left atrial preparations of rats. Josamycin and erythromycin (10 −7−10 −4 M) produced a dose-dependent decrease in rate, contractile force and maximum following frequency and prolonged the sinus node recovery time and the refractory period. The negative inotropic effect of josamycin was not modified by pretreating the atria with atropine or with a mixture of antagonists containing phentolamine, practolol, diphenhydramine, cimetidine, methysergide and indomethacin. In isolated right atria, josamycin did not block the positive inotropic and choronotropic responses to isoprenaline but shifted the dose-response curve to Ca to the right. Josamycin and erythromycin reduced in a dose-dependent manner the slow responses induced in K-depolarized right atria by isoprenaline but this effect was reversed by increasing the Ca concentration in the bathing media. These findings demonstrate a direct negative inotropic effect of josamycin and suggest that this effect could in some way be explained by inhibiting transmembrane Ca influx into atrial cells. The clinical significance of these results is discussed.

Chronic exercise does not alter the chronotropic response of isolated rat atria to catecholamines.

Atria isolated from rats after 7 weeks of exercise training beat at a slower rate than did atria from sedentary controls. There is no significant difference between the chronotropic responses of the 2 groups to epinephrine or norepinephrine.

Influence of 2.45-GHz CW microwave radiation on spontaneously beating rat atria.

The chronotropic and inotropic effects of 2.45-GHz continuous wave (CW) microwave radiation were investigated in the isolated spontaneously beating rat atria. Isolated atria were placed in specially designed tubes inserted into a waveguide exposure system. The atria were then irradiated for a period of 30 min, followed by a 30-min recovery period. The control atria were prepared simultaneously and sham exposed. Experiments were conducted at two temperatures, 22 and 37 degrees C, and two specific absorption rates, 2 mW/g and 10 mW/g. At both temperatures the rate of atrial contraction was not altered by a 30-min exposure at either 2 or 10 mW/g. The average rate (beats per min) was approximately 100 for both the control and exposed atria at 22 degrees C and 215 beats per min for both the control and exposed atria at 37 degrees C. In addition, no inotropic effects on the spontaneously beating atria were noted at any exposure level. These data suggest that 2.45-GHz CW microwave radiation at these intensities has no overt effect on these variables in isolated rat atria.

P-27 - Age differences in the positive inotropic effect of phenylephrine on isolated rat atria

P-27 - Age differences in the positive inotropic effect of phenylephrine on isolated rat atria

Influence of hypothyroid status on dopamine-induced positive chronotropic and inotropic effects on isolated rat atria.

The involvement of alpha- and beta-adrenoceptors in dopamine (DA)-induced positive chronotropic and inotropic effects was investigated in isolated atria from euthyroid and hypothyroid rats. Propranolol at 3 x 10(-7) M remarkably inhibited the positive chronotropic effect of DA in both euthyroid and hypothyroid rats, and 1 x 10(-6) M phentolamine inhibited the effects of DA in the presence of propranolol in hypothyroid rats. Propranolol remarkably inhibited the positive inotropic effect of DA in both euthyroid and hypothyroid rats, while phentolamine was effective only in hypothyroid rats. In atria from reserpinized rats, the pD2-values for DA in both chronotropic and inotropic effects were reduced, but effectiveness of propranolol or phentolamine on DA-induced positive chronotropic and inotropic effects in euthyroid and hypothyroid rats was similar to that in non-reserpinized rats. In hypothyroid rats, DA increased the maximal rate of tension development, which was inhibited by both phentolamine and propranolol. DA shortened the duration of contraction. DA in the presence of phentolamine significantly shortened the duration of contraction but did not in the presence of propranolol. In conclusion the DA-induced positive chronotropic effect is mainly produced by beta-adrenoceptor stimulation in both euthyroid and hypothyroid rats, and also by a alpha-adrenoceptors to some extent in hypothyroid rats. The DA-induced positive inotropic effect is produced by alpha- as well as beta-adrenoceptor stimulation in both groups. However, alpha-adrenoceptors were involved to a greater extent in hypothyroid rats than in euthyroid rats. The stimulation of alpha-adrenoceptors by DA causes an increase in the maximal rate of tension development without a significant change in the duration of contraction, and the stimulation of beta-adrenoceptors by DA causes an increase in the maximal rate of tension development and shortening of the duration of contraction.

Extracellular calcium concentration and calcium blocking agents on the action of ouabain on isolated rat atrium

Summary The influences of calcium blocking agents and different[Ca 2+ ] o on the non toxic (positive inotropism without changes in frequency or resting tension) and toxic (positive chronotropism, negative inotropism, contracture, arrhythmia) effects of ousbain upon isolated rat stris were explored. Decreasing the [Ca 2 ] o from 1.2 to 0.3 mM or tresting the auricles with verapamil, D-600 or diltiazem potentisted the positive inotropic influences of ouabain and attenuated and delayed the onset of toxic actions. On the contrary increasing [Ca 2+ ] o from 1.2 to 2.7 mM, reduced the non toxic effect of ouabain and facilitated the toxic action of the drug. These findings suggest that factors known to induce changes in the intracellular calcium concentration (i.e. calcium blocking agents, and variable extracellular calcium concentrations) produce a remarkable modification of the influence of ouabain on rat myocardium.

Influence of acid-base alterations on myocardial sensitivity to catecholamines.

The influence of "respiratory" and "metabolic" acid-base alterations on the myocardial sensitivity to catecholamines was studied in the isolated rat atria. The ability of noradrenaline for increasing the atrial rate was enhanced during alkalosis and conversely, it was decreased by acidosis. These changes in sensitivity shifted the concentration-effect curve for noradrenaline to the right by about 0.5 log unit when the pH was lowered from 7.60 to 7.00. No changes in the maximum attainable response were detected. Essentially the same shifts of the concentration-effect curves were obtained with changes in pH brought about by altering the pCO2 or at constant pCO2. The decrease in the pH produced a similar shift to the right of the concentration-effect curve for isoprenaline, after the extraneuronal uptake inhibition by hydrocortisone and also in atria tissue with low content of endogenous noradrenaline (reserpine-pretreated and newborn rats). The ability of isoprenaline for increasing cyclic AMP levels in atrial tissue was also enhanced by alkalosis and decreased by acidosis. However, the shift to the right of the concentration-effect curve for cyclic AMP induced by the decrease in the pH was greater than the shift detected in the chronotropic-effect curve. In addition a decrease in the maximum increment of cyclic AMP was detected under acidosis, in spite of equal maximal chronotropic response. Our results support the hypothesis that the alterations in the sensitivity to catecholamines induced by the changes in pH are not due to a release of endogenous noradrenaline nor to alterations of the mechanisms which remove catecholamines from the biophase. The fact that cyclic AMP response to catecholamines was also reduced by acidosis strongly suggests that the mechanism(s) involved is located in the earlier steps of the events leading to the chronotropic effect of the beta-agonists.

The relation between reduced protein degradation and elevated adenosine 3',5'-monophosphate in isolated rat atria.

HomeCirculation ResearchVol. 49, No. 3The relation between reduced protein degradation and elevated adenosine 3',5'-monophosphate in isolated rat atria. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessAbstractPDF/EPUBThe relation between reduced protein degradation and elevated adenosine 3',5'-monophosphate in isolated rat atria. D S O'Hara, G D Curfman, C G Trumbull, S M Sandler and T W Smith D S O'HaraD S O'Hara Search for more papers by this author , G D CurfmanG D Curfman Search for more papers by this author , C G TrumbullC G Trumbull Search for more papers by this author , S M SandlerS M Sandler Search for more papers by this author and T W SmithT W Smith Search for more papers by this author Originally published1 Sep 1981https://doi.org/10.1161/01.RES.49.3.609Circulation Research. 1981;49:609–617 Previous Back to top Next FiguresReferencesRelatedDetails September 1, 1981Vol 49, Issue 3Article InformationMetrics Download: 53 Copyright © 1981 by American Heart Associationhttps://doi.org/10.1161/01.RES.49.3.609 Originally publishedSeptember 1, 1981 PDF download

Qualitative differentiation of positive inotropic effects of isoprenaline and 8-bromo-cAMP in isolated rat atria: Timo Metsä-Ketelä. Department of Biomedical Sciences, University of Tampere, Tampere, Finland

Qualitative differentiation of positive inotropic effects of isoprenaline and 8-bromo-cAMP in isolated rat atria: Timo Metsä-Ketelä. Department of Biomedical Sciences, University of Tampere, Tampere, Finland