Halothane Restores the Altered Force-Frequency Relationship in Failing Human Myocardium

Background The terminally failing human myocardium exerts a negative force-frequency relationship (FFR), whereas a positive FFR occurs in nonfailing myocardium. To study the possibility of pharmacologically influencing this defect of the failing human heart, the effect of halothane on the basal FFR and the FFR in the presence of isoproterenol and ouabain was investigated. Methods Experiments were performed on isolated, electrically driven (0.5-2 Hz, 37 degrees C, Ca2+ 1.8 mmol/l) ventricular preparations. Myocardium from human failing and nonfailing hearts was obtained at cardiac surgery. To further characterize the studied myocardium, the positive inotropic effect of isoproterenol and the density of beta-adrenoceptors were measured using the radioligand 125I-CYP. Results Halothane produced a negative inotropic effect. The anesthetic (0.38 mmol/l) reversed the negative FFR in failing myocardium, antagonized the effect of isoproterenol (0.1 mumol/l) on FFR, and restored the FFR in the presence of ouabain. Conclusions Halothane restores the FFR in human failing myocardium possibly by influencing the intracellular Ca2+ homeostasis. These findings provide evidence that pharmacologic interventions, e.g., during anesthesia, may influence contractility also as a result of a depressed or enhanced FFR.

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Cardiotoxins from cobra Naja oxiana change the force of contraction and the character of rhythmoinotropic phenomena in the rat myocardium

Доклады Академии наук ◽

10.31857/s0869-56524875578-583 ◽

2019 ◽

Vol 487 (5) ◽

pp. 578-583

Author(s):

A. S. Averin ◽

M. E. Astashev ◽

T. V. Andreeva ◽

V. I. Tsetlin ◽

Yu. N. Utkin

Keyword(s):

Positive Inotropic Effect ◽

Stimulation Frequency ◽

Inotropic Effect ◽

Force Frequency ◽

Rat Myocardium ◽

Frequency Range ◽

High Concentration ◽

Irreversible Damage ◽

Frequency Relationship ◽

Positive Force

The study of the influence of cobra Naja oxiana cardiotoxins on the contractility of the rat papillary muscles and its rhythm-inotropic characteristics has that the presence of toxins induces a slight contractility decrease in the stimulation frequency range up to 0,1 Hz. In the stimulation frequency range from 0,1 to 0,5 Hz a positive inotropic effect is found. However, the positive inotropic effect is replaced by a negative one with further increase in the frequency up to 3 Hz. In the presence of cardiotoxins, the positive force-frequency relationship in the region of 1-3 Hz, characteristic of healthy rat myocardium, disappears and relationship becomes completely negative. L‑type calcium channel blocker nifedipine does not affect the changes induced by toxins, while a high concentration (10 mM) of calcium prevents the effects of cardiotoxins on the muscle. The results obtained show that the impairment of the force-frequency relationship occurs long before the development of irreversible damage in the myocardium and may be the first sign of the pathological action of cardiotoxins.

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Abstract 1469: Diastolic dysfunction induced by Flecainide but not Amiodarone

Circulation ◽

10.1161/circ.116.suppl_16.ii_303 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Egbert Bisping ◽

Christian Pagel ◽

Andre Wilken ◽

Karl Toischer ◽

Burkert Pieske

Keyword(s):

Atrial Fibrillation ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Negative Inotropic Effect ◽

Human Myocardium ◽

Inotropic Effect ◽

Force Frequency ◽

Inotropic Effects ◽

Rabbit Myocardium ◽

Negative Inotropic Effects

Diastolic dysfunction is a significant risk factor for the development and progression of atrial fibrillation. Flecainide (Flec) and Amiodarone (AM) are frequently used in patients with atrial fibrillation but their impact on diastolic function has not been evaluated yet. We tested the effect of Flec and AM on systolic and diastolic performance in isolated muscle strips from failing human and nonfailing rabbit myocardium. Isolated ventricular trabeculae contracted isometrically at 1 Hz, Ca2+ 2.5 mmol/L, 37°C. Flec (0.01 – 100 μmol/L, dissolved in water) showed a concentration dependent negative inotropic effect in human myocardium (13 ± 2 vs. 3 ± 0.5 mN/mm 2 at base vs. 100 μmol/L; p< 0.05). This was associated with a significant prolongation of the relaxation time RT95 and an increase of diastolic tension (Dias) by 35 ± 9 % (at 100 μmol/L; p< 0.05). Water alone had no effect. Calcium transients measured by Aequorin technique declined proportionally to developed force after Flec. In contrast, AM (0.01 – 100 μmol/L, dissolved in 2% benzyl alcohol and 10% polsorbate) showed identical negative inotropic effects to solvent alone (maximally by 16 ± 8 %), and neither AM nor its solvent affected diastolic tension or relaxation times. Flec (3 μmol/L) resulted in a significant impairment of the Force frequency relationship (FFR) at 0.5–3.0 Hz in human myocardium. This was related to a decline in systolic force and a rise in Dias at high frequencies (at 3 Hz by 32 ± 12 % in control and 87 ± 25 % after Flec, p < 0.05 vs. control). In nonfailing rabbit myocardium (1.0–5.0 Hz) Dias decreased by 11 ± 10 % (n.s.) in control but raised by 65 ± 25 % after Flec, p < 0.05). AM (100 μmol/L) had no significant effect on FFR, whereas its solvent tended to impair the FFR by a decline in systolic performance. Conclusion: Flec exerts calcium dependent negative inotropic effects in human myocardium and significantly impairs diastolic function. The latter is observable not only in human failing myocardium with preexisting diastolic dysfunction but also in nonfailing animal myocardium. In contrast AM shows no compound specific negative inotropic effect and no change in diastolic function. In patients treated with Flec attention should be turned to the potential of the drug to deteriorate diastolic function.

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Calcium channels and excitation–contraction coupling in cardiac cells. II. A pharmacological study of the biphasic contraction in guinea-pig papillary muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-285 ◽

1987 ◽

Vol 65 (9) ◽

pp. 1832-1839 ◽

Cited By ~ 3

Author(s):

E. Honoré ◽

M. M. Adamantidis ◽

B. A. Dupuis ◽

C. E. Challice ◽

P. Guilbault

Keyword(s):

Guinea Pig ◽

Papillary Muscle ◽

Positive Inotropic Effect ◽

Pharmacological Study ◽

Negative Inotropic Effect ◽

Cardiac Cells ◽

Inotropic Effect ◽

Free Solution ◽

Contraction Coupling ◽

Rich Solution

Biphasic contractions were obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) in the presence of 0.3 μM isoproterenol. Mn2+ ions inhibited the two components of contraction in a similar way. Nifedipine and particularly Cd2+ ions specifically inhibited the second component of contraction. Isoproterenol and BAY K 8644 markedly increased the amplitude of the second component (P2) of contraction. Nevertheless, a moderate positive inotropic effect of isoproterenol was found on the first component (P1) of contraction when excitability was restored by 0.2 mM Ba instead of isoproterenol. Acetylcholine and hypoxia decreased the amplitude of the second component of contraction to a greater extent. In the presence of digoxin or Na+-free solution, P1was strongly increased. When sarcoplasmic reticular function was hindered by 1 mM caffeine or in the presence of Ca2+-free Sr2+ solution, digoxin always induced a negative inotropic effect on P2. Inversely in these conditions the transient positive inotropic effect of Na+-free solution was strongly reduced. These results are consistent with the hypothesis that the late component of contraction is triggered by the slow inward Ca2+ current and that the early component is due to Ca2+ release from the sarcoplasmic reticulum.

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Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.4.h1239 ◽

1990 ◽

Vol 259 (4) ◽

pp. H1239-H1246 ◽

Cited By ~ 1

Author(s):

M. Karmazyn ◽

M. P. Moffat

Keyword(s):

Calcium Channel ◽

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Bay K 8644 ◽

Inotropic Effect ◽

Receptor Interaction ◽

Inotropic Effects ◽

Coronary Pressure ◽

Low Concentrations ◽

Rat Hearts

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.

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Force-frequency relationship and inotropic stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure

The Clinical Investigator ◽

10.1007/bf00235525 ◽

1992 ◽

Vol 70 (5) ◽

Cited By ~ 33

Author(s):

M. B�hm ◽

K. Ros�e ◽

U. Schmidt ◽

C. Schulz ◽

R.H.G. Schwinger ◽

...

Keyword(s):

Heart Failure ◽

Medical Treatment ◽

Human Myocardium ◽

Force Frequency ◽

Frequency Relationship ◽

Inotropic Stimulation

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Comparative effect of procainamide and lidocaine on myocardial contractility

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y69-169 ◽

1969 ◽

Vol 47 (12) ◽

pp. 1038-1042 ◽

Cited By ~ 4

Author(s):

M. Nahas ◽

J. Lachapelle ◽

G. M. Tremblay

Keyword(s):

Myocardial Contractility ◽

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Left Ventricular ◽

Isolated Rat Heart ◽

Inotropic Effect ◽

Comparative Effect ◽

Heart Perfusion ◽

Biphasic Effect ◽

Therapeutic Doses

The effect of procainamide and lidocaine on myocardial contractility was studied in an isovolumic isolated rat heart perfusion preparation following the Langendorff technique. As a measure of myocardial contractility, the left ventricular intracavitary pressure and maximum dp/dt were determined and were found to be depressed proportionately to the dose of these agents. At the same concentration, lidocaine showed a more negative inotropic effect than procainamide (although the former seems clinically innocuous at therapeutic doses). In addition, procainamide produced in about one-half of the experiments a biphasic effect characterized by a slight transitory positive inotropic effect followed by a negative inotropic effect.

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Vasoactive intestinal peptide has a direct positive inotropic effect on isolated human myocardial trabeculae

Clinical Science ◽

10.1042/cs1010637 ◽

2001 ◽

Vol 101 (6) ◽

pp. 637-643 ◽

Cited By ~ 7

Author(s):

Ole SAETRUM OPGAARD ◽

Mikael KNUTSSON ◽

René DE VRIES ◽

Beril TOM ◽

Pramod R. SAXENA ◽

...

Keyword(s):

Left Ventricle ◽

Vasoactive Intestinal Peptide ◽

Right Atrium ◽

Human Heart ◽

Positive Inotropic Effect ◽

Contractile Force ◽

Inotropic Effect ◽

Inotropic Effects ◽

The Right ◽

Ventricular Trabeculae

The aim of the present study was to assess the inotropic effects of vasoactive intestinal peptide (VIP) on isolated myocardial trabeculae from the right atrium and the left ventricle of human hearts. Furthermore, using reverse transcriptase-PCR, we wanted to determine the presence of mRNAs encoding the three cloned human VIP receptors, VPAC1, VPAC2 and PAC1. The trabeculae were paced at 1.0Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. VIP had a potent positive inotropic effect in some of the atrial and ventricular trabeculae tested. This effect was almost completely blocked by the VIP-receptor antagonist VIP-(6-28). mRNAs encoding the human VPAC1, VPAC2 and PAC1 receptors were detected in human myocardial trabeculae from both the right atrium and the left ventricle. In conclusion, VIP has a direct positive inotropic effect in both the atria and the ventricles of the human heart. The presence of mRNAs for the VPAC1, VPAC2 and PAC1 receptors suggest that VIP may mediate its effect via these receptors.

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