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1.
The effects of 4-aminopyridine (4-AP) on the chronotropic and inotropic responses to intramural parasympathetic nerve stimulation and to injection of acetylcholine (ACh) into the sinus node artery were investigated after treatment with propranolol in the isolated, blood-perfused dog atrium. 4-AP (3-100 micrograms) induced positive chronotropic and inotropic effects and 300 micrograms of 4-AP induced biphasic, negative and positive effects. The negative responses to 4-AP were completely blocked by 10 micrograms of atropine. 4-AP (more than 30 micrograms) potentiated significantly the negative chronotropic and inotropic responses to intramural parasympathetic nerve stimulation at a frequency of 3-30 Hz. The potentiation of the responses to stimulation was greater at a low than at a high frequency of stimulation. Potentiation of the chronotropic effect was greater than that of the inotropic one. 4-AP in the doses used did not change the negative chronotropic and inotropic responses to injection of ACh into the sinus node artery. These results suggest that the potentiation by 4-AP of the cardiac responses to parasympathetic nerve stimulation was due to an increase in release of ACh from nerve terminals but not to an increase in responsiveness at the effector site.  相似文献   

2.
Summary The influence of bivalent manganese ions (Mn++) on the positive inotropic effect of adrenaline, theophylline, and digitoxigenin was studied in isolated, electrically driven left guinea-pig auricles in phosphate-free Tyrode's solutions with different extracellular calcium concentrations ([Ca]e; 0.45; 1.8; 7.2 mM).Mn++ (0.1–50 mM) exerted a dose-dependent negative inotropic effect which was dependent on [Ca]e: Raising [Ca]e decreased the inhibitory action of Mn++. The negative inotropic effect of Mn++ was exclusively due to a decrease in the rate of tension development; the time to peak tension and the duration of contraction remained unchanged.In a solution containing 0.45 mM Ca, pretreatment with 0.1 mM Mn+ significantly diminished the positive inotropic effect of adrenaline (10–9-10–5 g/ml) and theophylline (5×10–6-10–3 g/ml), but did not influence the effect of digitoxigenin (2×10–7-2×10–6 g/ml). The depression of the positive inotropic effect of adrenaline and theophylline with higher concentrations of Mn+ (0.35–2.25 mM, producing a negative inotropic effect of about 50%) was influenced by the [Ca]e. The effect of Mn+ was most evident at 0.45 mM Ca, less pronounced (but significant) at 1.8 mM Ca and was not observed at 7.2 mM Ca. With the same concentrations of Mn+, however, the positive inotropic effect of digitoxigenin was only slightly decreased at 0.45 mM Ca, was not changed at 1.8 mM Ca and was increased at 7.2 mM Ca.As Mn+ selectively blocks the inward movement of Ca ions across the membrane of the myocardial cell during depolarisation, it is tentatively concluded from these experiments that the positive inotropic effect of adrenaline and theophylline may be due at least partially to an increase of the Ca influx during the excitation process, whereas the positive inotropic effect of digitoxigenin seems to be independent of this mechanism.
Herrn Dr. K. Löffelholz aus unserem Institut sind wir für die fluorometrische Adrenalinbestimmung zu Dank verpfiichtet. Außerdem danken wir Fräulein G. Rose für ihre Hilfe bei der Durchführung der Experimente.  相似文献   

3.
Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 mol/l).After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue.The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.  相似文献   

4.
Summary In the electrically driven papillary muscle of the cat's right ventricle theophylline, caffeine and theobromine exerted a positive inotropic action. Log. dose-effect regression lines for the three drugs were parallel; the effect of theophylline was significantly greater than those of caffeine and theobromine. The range of concentrations used was 1/32–1/2 mM/1.In the spontaneous beating atrium of the cat the purines enhanced both rate and force of contractions; differences in action between theophylline and the other drugs studied were not as pronounced as in papillary muscle.Threshold determinations were performed in papillary muscles and strength-duration curves were plotted. Excitability was increased by theophylline and diminished by theobromine. Caffeine did not produce any significant effect.The refractory period of the myocardium was shortened by theophylline and to a lesser extent by caffeine; it was not altered by theobromine. Occasionally spontaneous beating occurred in papillary muscles when high doses of theophylline were added.The significance of the results is discussed and findings concerning contractility are compared to those obtained by other authors under similar conditions.

Mit 4 Textabbildungen  相似文献   

5.
1. The inotropic effect of a Ca2+-entry stimulator, CGP28392, (CGP) was compared in rat and frog myocardium in a concentration- and time-dependent manner. 2. Frog preparations exhibited a persistent positive inotropic effect following prolonged treatment with CGP. 3. Compared to amphibian myocardium, rat ventricular muscle exhibited a biphasic time-dependent response to CGP: an initial increase in the twitch tension amplitude of 30% was changed to a reduction of 80% below the control level during prolonged exposure to CGP (stimulation frequency, 0.2 Hz). 4. Following prolonged incubation with CGP, the resting-state contraction was decreased and the negative force-frequency relation was converted into a positive one in rat muscle. 5. Since sarcoplasmic reticulum (SR) is the major source of Ca2+ in a rested-state contraction, inhibition by CGP suggests an additional, intracellular action of the Ca2+ channel activator on SR-Ca2+ release in rat myocardium.  相似文献   

6.
Histamine is known to enhance the contractility of the human myocardium in vitro. We have observed that when the H2-receptor antagonist cimetidine (or ranitidine) blocks the positive inotropic effect of histamine in spontaneously beating pectinate muscles isolated from human right atrial appendage, a negative inotropic effect is unmasked. This decrease in contractility is independent of changes in rate, as it occurs in preparations paced at constant rate, is mimicked by the H1-receptor agonist 2-(2-thiazolyl)-ethylamine (ThEA) and is abolished by the H1-antagonist pyrilamine. Thus, the negative inotropic effect of histamine appears to be mediated by H1-receptors. Our data indicate that the inotropic response of the human myocardium to histamine consists of two opposing components: an increase in contraction, mediated by H2-receptors, and a decrease in contraction, mediated by H1-receptors. Given the widespread use of H2-blockers and the multitude of clinical conditions in which histamine is released, there may well be circumstances in which an H1-response predominates. This could result in a decrease in myocardial contractility.  相似文献   

7.
Zusammenfassung Die Wirkung des Adrenalins auf die isometrische Kontraktion des Meerschweinchen-Papillarmuskels wurde in Abhängigkeit von der äußeren Calcium- und Natriumkonzentration bei 25° und 35°C bei konstanter Reizfrequenz (1/sec) untersucht.Adrenalin wirkt auf den Papillarmuskel positiv inotrop durch eine Vergrößerung der Anstiegssteilheit.Die Kurven der Abhängigkeit der Kontraktionskraft und der Anstiegssteilheit von der äußeren Calciumkonzentration werden durch Adrenalin nach links, zu niedrigeren Calciumkonzentrationen hin, verschoben.Das Ausmaß der inotropen Adrenalinwirkung, gemessen an der Linksverschiebung der Calciumwirkungskurven bei halber maximaler Calciumwirkung, ist bei 25° und 35°C annähernd gleich.Die Anstiegszeit (t 1) der Kontraktion bei 25° wird durch Adrenalin (4,8·10–8 M) bei allen Calciumkonzentrationen verkürzt. Bei 35° wird die Anstiegszeit erst bei höheren Adrenalinkonzentrationen (1,5·10–7 M) und nur bei höherer Calciumkonzentration (6,4 mM) signifikant verkürzt.Die Erschlaffungszeit (t 2) wird bei 25° durch Adrenalin (4,8·10–8 M) bei den Calciumkonzentrationen 0,2 und 0,4 mM verlängert (P<0,001) und bei höheren Calciumkonzentrationen (1,6–12,8 mM) verkürzt. Bei 35° wird die Erschlaffungszeit (t 2) bei 0,4 mM Ca durch Adrenalin (1,5·10–7 M) nur gering verlängert; bei Calciumkonzentrationen über 0,8 mM wird sie durch Adrenalin verkürzt.Bei 25° können bei niedrigen Calciumkonzentrationen unter der Einwirkung von Adrenalin in der Erschlaffungsphase zweite Kontraktionsgipfel auftreten.Das Ausmaß der positiv inotropen Adrenalinwirkung wird durch Verringerung der äußeren Natriumkonzentration (osmotischer Ausgleich durch Saccharose bzw. Lithiumchlorid) nicht vermindert. Darin unterscheidet sich die inotrope Wirkung des Adrenalins von derjenigen herzwirksamer Glykoside.
Summary The action of epinephrine on the isometric contraction curve of the guinea-pig papillary muscle was studied in dependence on the concentration of calcium and sodium ions in the incubation medium at 25° and 35°C and at a constant stimulation frequency of 1 sec–1.In accordance with the results of other investigators it was found that the positiv inotropic action of epinephrine on cardiac muscle is due to an increase in contraction steepness.The dependence of force and steepness of contraction on the outer calcium concentration is shifted by epinephrine to the left to lower calcium concentrations. The inotropic action of epinephrine, measured by the degree of shifting the calcium dose response curve at half maximal action of calcium, is approximately the same at 25° and 35°C.At 25°C epinephrine shortens the peak time of contraction (t 1) at all calcium concentrations. At 35°C peak time is shortened significantly by epinephrine only at high concentrations of epinephrine (1,5·10–7 M) and of calcium (6,4 mM).The relaxation time (t 2) at 25°C is prolonged by epinephrine (4,8·10–8 M) at low calcium concentrations (0.2–0.4 mM) and shortened at higher calcium concentrations (1.6–12.8 mM). At 35°C the relaxation time is only minimal prolonged at a low calcium concentration (0.4 mM Ca, 1.5·10–7 M epinephrine) and it is shortened at higher calcium concentrations.During the relaxation phase of contraction second contraction peaks can appear due to the action of epinephrine at 25°C and low calcium concentrations.The positiv inotropic activity of epinephrine is not diminished if the sodium concentration of the incubation medium is decreased. In this respect the inotropic action of epinephrine differs from that of cardiac active glycosides.


Mit 9 Textabbildungen  相似文献   

8.
1. The effect of the phosphatase inhibitor, cantharidin (3-300 microM) on force of contraction was studied in isolated electrically driven right ventricular trabeculae carneae from human myocardium. 2. The positive inotropic effect of cantharidin started at a concentration of 100 microM with a positive inotropic effect to 199% and to 276% of the predrug value in nonfailing and failing human hearts, respectively. 3. Under basal conditions the contraction time parameters were prolonged in human heart failure vs. nonfailing preparations. However, the positive inotropic effect of cantharidin did not affect contraction time parameters. Thus, time to peak tension, time of relaxation and total contraction time were not shortened by cantharidin in nonfailing and failing preparations. 4. The phosphatase activity was unchanged in preparations from failing hearts compared to nonfailing hearts. 5. Cantharidin inhibited phosphatase activity in a concentration-dependent manner. The IC50 value of cantharidin was about 3 microM in both nonfailing and failing human myocardium. 6. The positive inotropic effect of cantharidin was similar in nonfailing and failing human hearts, accompanied by a similar inhibitory effect of cantharidin on the phosphatase activity. The positive inotropic effect of cantharidin in failing hearts was as strong as the effect of isoprenaline in nonfailing hearts. 7. It is concluded that the treatment with a phosphatase inhibitor may offer a new positive inotropic modality for the treatment of human heart failure.  相似文献   

9.
The purpose of the present study was to characterize adenosine receptors in human atrial and ventricular preparations as well as in nonfailing and failing human ventricular myocardium. Using the antagonist radioligand 3H-DPCPX, A1-adenosine receptors were identified in human atrial and ventricular myocardial membranes. The rank order of potency of agonists and antagonists as well as the influence of Gpp(NH)p on agonist high affinity binding were similar in atrial and ventricular myocardium, indicating that the same receptor type probably couples in a similar guanine nucleotide-dependent way to different effectors producing the “direct” or “indirect” effects on myocardial force on contraction. The density and coupling of ventricular adenosine receptors as well as the antiadrenergic, “indirect” effect following their stimulation were not different in failing human myocardium, despite an increase in G-proteins. Thus, enhanced antiadrenergic effects of A1-adenosine receptors do not contribute to the reduction of cAMP-dependent positive inotropic effects in heart failure. © 1993 Wiley-Liss, Inc.  相似文献   

10.
In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M2-subtype that couple via a pertussis toxin-sensitive Gi-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as beta-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac Gi-activity is increased.  相似文献   

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