Actions of mescaline on isolated rat atria.

Mescaline, in concentrations of 5 x 10(-4) and 1 x 10(-3) M, produced negative chronotropic and positive inotropic responses in isolated, spontaneously beating rat atria. In tissues driven at a constant rate, the inotropic response was diminished greatly, indicating that the increment in the force of contraction was secondary to the reduction in rate. These chronotropic and inotropic responses were not altered consistently by pretreatment with the histamine antagonists chlorpheniramine and metiamide.     

Effect of phytohemagglutinin-stimulated human lymphocytes on isolated rat atria

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.     

In vitro effect of 6-hydroxydopamine on isolated rat atria

In vitro treatment with 6-hydroxydopamine (6-OHDA), but not with oxidized 6-hydroxydopamine, caused transient, positive inotropic and chronotropic responses in the isolated rat atria. In the presence of rat blood plasma, the excitatory effect of 6-hydroxydopamine persisted unless the drug was washed out by fresh medium. 6-Hydroxydopamine failed to elicit the excitative response in the atria obtained from reserpinized rats or rats treated with 6-hydroxydopamine in vivo. In vitro treatment with 6-hydroxydopamine did not cause the development of supersensitivity to noradrenaline. Cocaine and desipramine, but not bretylium, inhibited the excitative action of 6-hydroxydopamine. No tachyphylaxis developed after repeated exposure to 6-hydroxydopamine in vitro. Propranolol, but not phentolamine, blocked the excitatory effect of 6-hydroxydopamine. It is thus concluded that in vitro treatment with 6-hydroxydopamine may cause atrial stimulation by an indirect action involving the release of catecholamines as a result of its displacement at the nerve ending.     

Comparison of the electrophysiological effects of two neuroleptics, melperone and thioridazine, on isolated rat atria

The effects of the two neuroleptics, melperone (a butyrophenone) and thioridazine (a phenothiazine), were compared on the electrical and mechanical activity of isolated rat atria. Both electrically stimulated and spontaneously beating atria were used. Melperone was found to prolong the effective refractory period while the threshold for electrical stimulation i.e. the excitability, was almost unaffected. Thioridazine caused a similar prolongation of the effective refractory period, but also decreased the excitability significantly. In contrast to melperone, thioridazine had a negative inotropic effect. The spontaneous pacemaker activity was depressed and the sinus node recovery time increased to a greater extent after melperone than after thioridazine. The results taken together with other recent data support the hypothesis that melperone may be a type III anti-arrhythmic according to the classification of Vaughan Williams, in contrast to thioridazine which has a quinidine-like action (type I). The results also indicate that melperone in addition to prolonging the effective refractory period, may act as an anti-arrhythmic agent by depressing automaticity.     

Effects of morphine on isolated right atria of the rat.

1. The present study describes the effects of morphine in the absence or presence of naloxone or atropine in the isolated right atria of the rat. 2. Morphine significantly decreased the auricular chronotropism. 3. The maximal effect was 10 +/- 1.0%. 4. Similar results were obtained in reserpinized animals (13 +/- 0.2% maximum). 5. Naloxone (5 x 10(-7) or 5 x 10(-6) M) did not change the inhibitory effects induced by morphine. 6. The maximal effect obtained with morphine in the presence of atropine (5 x 10(-7) M) was 9 +/- 0.1% similar to that obtained with morphine alone. 7. These results suggest that opioid or vagal mechanisms may not be involved in the cardiac inhibitory effects induced by morphine.     

Toxicity of tricyclic antidepressants to isolated rat hepatocytes

A series of tricyclic antidepressant drugs was tested for cytotoxicity as measured by enzyme leakage from isolated rat hepatocytes. The relative potency appeared to be: chlorimipramine / amitriptyline /- nortriptyline / desipramine / protriptyline /` imipramine. The presence of a chloro-substituent in position R₃ increased apparent cytotoxicity, and the dibenzylcycloheptene nucleus seems to be more toxic than the corresponding phenothiazine or imminodibenzyl moieties.     

Uptake of 5-hydroxytryptamine in rat isolated atria.

1. The mode of 5-hydroxytryptamine (5-HT) uptake by the rat isolated atria was studied and compared to noradrenaline (NA) uptake. 2. Rat isolated atria were incubated with 14C-5-HT (46 microM) or 3H-NA 0.4 microM). After washing, the radioactivity fixed in atria was counted and the total NA, 5-HT and 5-hydroxyindol-3-acetic acid (5-HIAA) atria contents were measured by HPLC. 3. 14C-5-HT uptake was reduced in atria from 6-hydroxydopamine (100 mg/kg, i.p., 48 hr before experiments) or reserpine (2.5 mg/kg, i.p., 24 and 48 hr before experiments) pretreated rats. 4. The incubation of atria with 5-HT (50 microM) at the same time as 3H-NA reduced the 3H-NA value fixed. 5. Addition of desipramine (1 microM) or hydrocortisone (150 microM) before the incubation of atria with 14C-5-HT was without any effect on 14C-5-HT uptake. In contrast, fluvoxamine (1 microM) or indalpine (5 microM) caused a slight inhibition. 6. These data indicate that 5-HT is taken into the NA storage vesicles within the atria sympathetic nerves. This uptake does not use the NA carrier and involves partly the 5-HT carrier. An extraneuronal accumulation was noticed and a part of it is intracellular.     

Interaction between noradrenaline and diltiazem in rat isolated atria

1. The present study describes the effects of diltiazem (DIL) on noradrenaline (NA) activity in the isolated right atria of the rat. 2. Interactions between DIL and NA showed that DIL significantly shifted the concentration-response curve of NA to the right in a concentration-dependent manner. 3. The antagonist between DIL and NA is not consistent with a competitive antagonist since the slope is significantly lower than the unity. 4. A high calcium solution (4.5 mM) significantly increased the chronotropic effects of noradrenaline. 5. These results suggest that influx of calcium through calcium antagonist sensitive channels may be involved in linking of chronotropic responses to activation of alpha 1-adrenoceptors.     

Mechanisms of frequency-induced potentiation of contractions in isolated rat atria

Summary Mechanisms underlying the potentiation of contractions after periods of high frequency stimulation (post-stimulation potentiation; PSP) and periods of rest (rest potentiation; RP) were investigated in isolated rat atria. Transmembrane action potentials were not changed during PSP and RP and were superimposable upon the pre-test action potentials. However, the⁴⁵Ca content of atrial strips was significantly increased during PSP, which indicates a net gain in intracellular Ca.⁴⁵Ca content was not changed during RP. PSP and RP were increased in magnitude in atria pre-treated with gallopamil (2.5 mol/l). This effect was due to a greater depression by gallopamil of the pre-test contractions than the potentiated post-test contractions. In contrast, PSP was abolished in atria exposed to 7.5 mmol/l [Ca]_o and a transient depression of the post-test contractions was seen. RP was also abolished by high Ca medium, but contractions were not depressed after periods of rest. RP, but not PSP, was unmasked when gallopamil was added to high Ca medium to decrease the size of the basal contractions. Conversely, ryanodine (100 nmol/l) abolished RP but did not affect PSP. With ryanodine present, PSP was greatly increased when the extracellular Ca concentration was increased to 5 mmol/l, whereas RP remained abolished. These results suggest that PSP may reflect an increased transsarcolemmal influx of extracellular Ca, possibly mediated through Na-Ca exchange. In contrast, the mechanism suggested for RP is a transient increase in contractile Ca resulting from an intracellular redistribution of Ca to release sites in the sarcoplasmic reticulum.     

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

Ciguatoxin 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.     

The effects of ouabain on isolated atria of the ground squirrel; comparison with rat and rabbit atria

Summary Simultaneous measurements of membrane potentials and contractile tension were obtained from isolated atria of ground squirrels, rabbits and rats during exposure to ouabain.At 31°C, the spontaneously beating atria of the ground squirrel were more sensitive to the arrhythmic effects of ouabain than were atria from the other two species. The concentration of ouabain which produced arrhythmias in the ground squirrel, rabbit and rat atria within an exposure period of 100 min were 3·10^–7 M, 2·10^–6 M and 8·10^–5 M respectively. Membrane potentials in the ground-squirrel atria were unchanged in the presence of ouabain, although the force of atrial contractions was augmented. The rabbit and rat atria, on the other hand, showed a progressive decline in the duration, rising velocity and height of their action potentials, and these changes became most significant just before the appearance of arrhythmias. A positive inotropic effect was also noted in these species during treatment with ouabain.At 15°C, ouabain (2·10^–5 M) prevented the increase in size of the action potential which normally occurs in the ground-squirrel atria when they are cooled, and also accentuated the fall in level of the resting membrane potential. These changes resulted in arrest of the squirrel atria at 15°C in the presence of ouabain. In a normal medium the ground-squirrel atria continue to beat at temperatures near 0°C.With 4 Figures in the TextDedicated to Professor Otto Krayer with the best wishes of the authors.Fellow of the Rockefeller Foundation. Permanent address: Department of Pharmacology, University of Chile, Santiago, Chile.Supported by Research Grant HE-05702 from the National Institutes of Health, Bethesda, Maryland, U.S.A.     

Effects of antidepressants on isolated,electrically stimulated rat epididymal fat pads

The isolated, electrically stimulated rat epididymal fat pad in vitro was tested under various conditions as a model for neuronally induced lipolysis. A 24-hr fast, or a preincubation without electrical stimulation, decreased spontaneous lipolysis as measured by glycerol release; however, only slight alterations were seen in the response of the pads during a 40-min period of electrical stimulation. Spontaneous (nonstimulated) lipolysis was reduced by pretreatment with alpha-methyl-paratyrosine-methylester and increased by pretreatment with reserpine; both of these treatments abolished the response to stimulation. The effects of addition of a variety of agents to the incubation medium confirm the role of a sympathetic nervous-cyclic 3′,5′-adenosine-monphosphate mediated response system.     

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.     

Safety of dietary supplements: chronotropic and inotropic effects on isolated rat atria

We investigated the effects of dietary supplements on atria isolated from male Wistar rats. The examined supplements, which are increasingly used in Japan, those were Ginkgo biloba extract (GBE), catechins, isoflavones, sodium iron chlorophyllin and sodium copper chlorophyllin. GBE at 100-1000 microg/ml significantly increased the beat rate and the contractile force. Catechins at 1-100 microg/ml significantly potentiated the contractile force but did not effect the beat rates. However, isoflavones, sodium iron and sodium copper chlorophyllins did not change the contractile force or the beat rates. To identify the active ingredient of GBE, ginkgolide B, quercetin and amentoflavone on the atria were tested. Ginkgolide B weakened the contractile force. Quercetin potentiated the contractile force at only 30 microg/ml. Amentoflavone significantly increased the beat rate. From these findings, amentoflavone and quercetin were considered to be the principal ingredients of GBE producing the positive chronotropic and inotropic actions, respectively. In the case of catechins, (-)-epigallocatechin gallate (EGCg), one of the principal ingredients, produced inotropic actions. These findings suggest that there are some dietary supplements which affect cardiac function, such GBE and catechins.     

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

The age-dependent differences in the involvement of alpha-adrenoceptors in the positive inotropic effect of phenylephrine (Phe) were examined in isolated atria of male Wistar rats 6 weeks (6W), 10 weeks and 7 months (7M) of age. The maximal increase in tension development induced by Phe increased with age, whereas the EC50 values for the positive inotropic effect of Phe did not change with age. The inhibitory effect of phentolamine on the response to Phe increased with age. Propranolol caused only slight inhibition of the effect of Phe in both 6W and 7M rats, and the EC50 values for Phe in the presence of propranolol did not change significantly with age. The EC50 values for isoprenaline and 5-hydroxytryptamine in 7M rats were higher than those in 6W rats. In 7M rats, the duration of the tension development was only slightly affected by Phe in the presence or absence of propranolol, but it was markedly decreased by Phe in the presence of phentolamine. The dose-response curve for Phe was markedly shifted to the left by papaverine in 6W rats, but slightly in 7M rats. The dose-response curve for isoprenaline was markedly shifted to the left by papaverine in both groups. These results are consistent with effects of Phe being mediated by both alpha- and beta-adrenoceptors in both 6W and 7M rats, but there is a shift in the balance from rather more beta-receptors in the young animals to more alpha-receptors in the adults.     

Cardiovascular effects of isorhamnetin and quercetin in isolated rat and porcine vascular smooth muscle and isolated rat atria

Isorhamnetin and quercetin produced endothelium-independent vasodilator effects in rat aorta, rat mesenteric arteries, rat portal vein and porcine coronary arteries. The effects of the two flavonoids were similar in arteries stimulated by noradrenaline, KCl, U46619 or phorbol esters but the two flavonoids were more potent in the coronary arteries than in the aorta. At high concentrations, they also induced a positive inotropic effect in isolated rat atria. Therefore, at least part of the in vivo effects of quercetin may result from its conversion to isorhamnetin which is the main metabolite of quercetin found in plasma. The arterial, venous and coronary vasodilator effects may contribute to the protective effects of flavonoids in ischaemic heart disease observed in epidemiological studies.