A negative inotropic effect of acetylcholine in the presence of several phosphodiesterase inhibitors

Summary The phosphodiesterase inhibitors papaverine, theophylline and 3-isobutyl-1-methylxanthine (IBMX) reveal a negative inotropic effect of acetylcholine in cat ventricular heart muscle. This effect is unrelated to -adrenoceptor stimulation and possibly mediated by the accumulation of cyclic GMP.I thank Mrs Petra Lauck for help. This work was supported by the Deutsche Forschungsgemeinschaft.     

Papaverine enhances the negative inotropic effect of acetylcholine in rat auricles

Summary The negative inotropic effect of acetylcholine in rat left auricles is enhanced in the presence of the phosphodiesterase inhibitor papaverine. This result favours the idea of a cyclic GMP-mediated action of acetylcholine in the heart.I thank Lydia Paragnik for help. This research was supported by a grant from the Deutsche Forschungsgemeinschaft.     

The role of calcium in the negative inotropic effect of lanthanum

Summary Lanthanum reduces the rate of calcium fast exchanging processes, whereas the slowly exchanging phase is not modified. Experimental data also confirm the importance of calcium fast exchanging fraction in regulating contractile force of cardiac muscle.     

A negative inotropic response of cat atria to sympathetic nerve stimulation or norepinephrine

Zusammenfassung Isolierte, sympathisch innervierte Katzenvorhöfe wurden durch den rechten Nervus accelerans mit Impulsen von 1–5 msec Dauer und mit einer Frequenz von 0.5–60 Impulsen/sec stimuliert. In allen Präparaten wurde eine positiv chronotrope Wirkung beobachtet, während nur in 52% der Fälle eine inotrope Wirkung nachweisbar war. Bei 26% war die Kontraktionsstärke nicht beeinflusst, während bei 22% eine negativ inotrope Wirkung festgestellt wurde, für deren Variieren bis jetzt keine Erklärung gefunden werden konnte.

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Formerly pre-doctoral Fellow (U.S.P.H.S. Grant No. 5-T4-CA-5012).

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Pre-doctoral Fellow (U.S.P.H.S. Grant No. 5-T4-CA-5012).

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Established investigator of the American Heart Association.     

Positive and negative inotropic effects of carbachol on the embryonic chick atrium

The effect of carbachol on twitch tension of atrial preparations from chick embryos of different incubation ages (3–14 days) was studied. At every age carbachol evoked negative (at low concentrations) and positive (at higher concentrations) inotropic responses. Maximal response values for both effects increased with age; in 3- and 5-day atria the positive inotropic response prevailed. The muscarinic antagonist pirenzepine inhibited the positive (on 5-day atria) and negative (on strips of 14-day atria) inotropic effects of carbachol with pA₂ values of 6.8 and 8.0, respectively, suggesting that muscarinic receptors mediating these effects belong to different receptor subtypes.     

Positive and negative inotropic effects of carbachol on the embryonic chick atrium.

The effect of carbachol on twitch tension of atrial preparations from chick embryos of different incubation ages (3-14 days) was studied. At every age carbachol evoked negative (at low concentrations) and positive (at higher concentrations) inotropic responses. Maximal response values for both effects increased with age; in 3- and 5-day atria the positive inotropic response prevailed. The muscarinic antagonist pirenzepine inhibited the positive (on 5-day atria) and negative (on strips of 14-day atria) inotropic effects of carbachol with pA2 values of 6.8 and 8.0, respectively, suggesting that muscarinic receptors mediating these effects belong to different receptor subtypes.     

Flavonoid compounds are potent inhibitors of cyclic AMP phosphodiesterase

Summary The inhibitory activity of 19 flavonoid molecules on cyclic AMP breakdown by a commercial beef heart phosphodiesterase preparation is reported. 7 compounds are active in the micromolar range, 2 of which have a potency equivalent to that of papaverine. Some structure activity relationships are drawn.This investigation was partially supported by grants from the Centre National de la Recherche Scientifique (ATP 2315) and from the Institut National de la Santé et de la Recherche Médicale (CRL 75.1.188.5).     

Flavonoid compounds are potent inhibitors of cyclic AMP phosphodiesterase.

The inhibitory activity of 19 flavonoid molecules on cyclic AMP breakdown by a commercial beef heart phosphodiesterase preparation is reported. 7 compounds are active in the micromolar range, 2 of which have a potency equivalent to that of papaverine. Some structure activity relationships are drawn.     

Ergot alkaloids and phosphodiesterase; 'in vitro' activities in several rat brain areas

The 'in vitro' activity of ergotamine, dihydroergocristine, dihydroergocornine and dihydroergocryptine on the phosphodiesterase system at low and high Km in several rat brain areas was examined. These drugs were found to exert an inhibitory effect in all the areas examined with regard to both systems, and particularly on low substrate concentration phosphodiesterases.     

The effect of levamisole on phosphodiesterase activity

Summary Phosphodiesterase activity of mouse liver homogenates was estimated in presence and absence of levamisole. The enzyme activity was 1394 and 1399 nmoles/mg protein/30 min respectively. Our data show that levamisole does not affect the phosphodiesterase activity.     

Study of the characteristics of the inotropic effect of insulin in rabbit papillary muscle

Summary The effect of insulin was examined with emphasis on the alteration in the force-frequency relation. The results show that insulin does not change the time to peak tension nor the time of contraction. The inotropic effect was significant and did not depend upon the frequency of stimulation. However, there was a definite dependence of the magnitude of the inotropic effect on temperature. Previous studies have indicated that the inotropic effect is not a result of increased substrate availability or changes in cAMP phosphodiesterase activity. These results and those reported here are consistant with the hypothesis that insulin's inotropic effect is due to increases in intracellular Ca⁺⁺.This work was supported by a grant from the U. S. Public Health Service HL-02285.     

Ergot alkaloids and phosphodiesterase; ‘in vitro’ activities in several rat brain areas

Summary The ‘in vitro’ activity of ergotamine, dihydroergocristine, dihydroergocornine and dihydroergocryptine on the phosphodiesterase system at low and high K_m in several rat brain areas was examined. These drugs were found to exert an inhibitory effect in all the areas examined with regard to both systems, and particularly on low substrate concentration phosphodiesterases. Acknowledgments. Ergot alkaloids were a generous gift of Poli Industria Chimica, Milan.     

Acute toxicity of dimethylnitrosamine in the presence of inhibitors of DMN demethylase

Summary The LD₅₀ of DMN was determined in groups of mice in the presence of inhibitors of DMN demethylase. Piperonyl butoxide, dibutylnitrosamine and nitrososarcosine had no effect on the acute toxicity of DMN. Diethylnitrosamine and DMN were markedly synergistic. All mice treated with 100 mg/kg diethylnitrosamine and 10.7 mg/kg DMN died. These results suggest that DMN demethylase may not be involved in theaacute toxicity of DMN.We thank Dr.D. B. Couch, Mr.E. J. Greene and Dr.A. E. Munson for their technical assistance.     

Study of the characteristics of the inotropic effect of insulin in rabbit papillary muscle.

The effect of insulin was examined with emphasis on the alteration in the force-frequency relation. The results show that insulin does not change the time to peak tension nor the time of contraction. The inotropic effect was significant and did not depend upon the frequency of stimulation. However, there was a definite dependence of the magnitude of the inotropic effect on temperature. Previous studies have indicated that the inotropic effect is not a result of increased substrate availability or changes in cAMP phosphodiesterase activity. These results and those reported here are consistant with the hypothesis that insulin's inotropic effect is due to increases in intracellular Ca++.