scholarly journals Negative Inotropic Effect of BGP-15 on the Human Right Atrial Myocardium

2020 ◽  
Vol 9 (5) ◽  
pp. 1434
Author(s):  
Nóra Lampé ◽  
Dániel Priksz ◽  
Tamás Erdei ◽  
Mariann Bombicz ◽  
Rita Kiss ◽  
...  
Keyword(s):  
Direct Effect ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Right Atrial ◽  
Maximal Response ◽  
Diabetic Patients ◽  
Atrial Myocardium ◽  
Human Right ◽  
Inotropic Effects ◽  
Negative Inotropic Effects

Cardiovascular morbidity and mortality carry great socioeconomic burden worldwide that mandates the development of new, efficacious therapeutic agents with limited adverse effects. O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime (BGP-15) is a known, well-tolerable drug candidate that exerts beneficial effects in several disease models. As BGP-15 has a significant structural similarity with propranolol, it arose that BGP-15 might also have a direct effect on the heart. Thus, in the present work, we investigated the effect of BGP-15 and propranolol on the contractility of isolated, paced, human right atrial samples (obtained from patients undergone open-heart surgery), with or without previous isoproterenol (ISO) stimulation (evoking an indirect or direct effect, respectively). We found that both BGP-15 and propranolol exerted direct as well as indirect negative inotropic effects on the atrial myocardium, reaching similar maximal response. However, BGP-15 had considerably smaller potency than propranolol regarding both types of negative inotropy. In addition, BGP-15, in contrast to propranolol, had a significantly greater indirect negative inotropic effect on samples exhibiting strong response to ISO. Moreover, the indirect negative inotropic effect of BGP-15 was significantly greater on samples derived from diabetic patients than on samples obtained from non-diabetic ones. Our results suggest that the enhanced ISO sensitivity is associated with the diabetic state, and BGP-15 exerts greater negative inotropic effect on the human atrial myocardium in both conditions (as compared to the atrial tissue that is not ISO oversensitive and/or diabetic). Additionally, the negative inotropic effects of BGP-15 and propranolol seem to be mediated by in part different molecular pathways in the atrial myocardium.

Abstract 1469: Diastolic dysfunction induced by Flecainide but not Amiodarone

Circulation ◽  
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.

Effects of Desflurane in Senescent Rat Myocardium

2006 ◽  
Vol 105 (5) ◽  
pp. 961-967 ◽  
Author(s):  
Sandrine Rozenberg ◽  
Sophie Besse ◽  
Julien Amour ◽  
Benoît Vivien ◽  
Benoît Tavernier ◽  
...  
Keyword(s):  
Negative Inotropic Effect ◽  
Left Ventricular ◽  
Inotropic Effect ◽  
Shortening Velocity ◽  
Adult Rats ◽  
Inotropic Effects ◽  
Beta Adrenoceptor ◽  
Low Load ◽  
Positive Effect ◽  
Negative Inotropic Effects

Background The myocardial negative inotropic effects of desflurane are less pronounced than those of other halogenated anesthetics, partly because of intramyocardial catecholamine store release. However, the effects of desflurane on aging myocardium are unknown, whereas aging is known to be associated with an attenuation of catecholamine responsiveness. Methods The effects of desflurane (1.9-9.3 vol%) were studied in left ventricular papillary muscle of adult and senescent rats (29 degrees C; 0.5 mm Ca; stimulation frequency 12 pulses/min). The inotropic effects were compared under low and high loads, using the maximum unloaded shortening velocity and maximum isometric active force, and without or with alpha- and beta-adrenoceptor blockade. Results Desflurane induced a moderate positive inotropic effect in adult rats but a negative inotropic effect in senescent rats. After alpha- and beta-adrenoceptor blockade, desflurane induced a comparable negative inotropic effect in adult and senescent rats. No lusitropic effect under low load was observed, whereas desflurane induced a slight but significant positive lusitropic effect under high load similar between the two groups of rats. This positive effect was abolished by adrenoceptor blockade. Conclusion The authors' study suggests that desflurane does not induce significant intramyocardial catecholamine release in senescent myocardium, a result that should be integrated in the well-known alteration in the catecholamine response during aging.

Mechanism of the Negative Inotropic Effect of Thiopental in Isolated Ferret Ventricular Myocardium 

1995 ◽  
Vol 82 (2) ◽  
pp. 436-450 ◽  
Author(s):  
Philippe R. Housmans ◽  
Turkan S. Kudsioglu ◽  
Jonathan Bingham
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Negative Inotropic Effect ◽  
Ventricular Myocardium ◽  
Underlying Mechanism ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Beta Adrenoceptor ◽  
Force Peak ◽  
Human Ventricular Myocardium ◽  
Negative Inotropic Effects

Background Thiopental's myocardial depressant effects are well known and most likely involve some alteration in intracellular Ca2+ homeostasis. The aim of this study was to investigate the mechanisms of thiopental's negative inotropic effects and its underlying mechanism in isolated ferret ventricular myocardium (which shows physiologic characteristics similar to human ventricular myocardium), and in frog ventricular myocardium, in which Ca2+ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. Methods The authors analyzed the effects of thiopental after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca2+ transient detected with the Ca(2+)-regulated photoprotein aequorin. Thiopental's effects also were evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine and in frog ventricular strips with little or no SR function. Results At concentration &gt; or = 10(-4) M, which is in the high range of the clinically encountered free plasma thiopental concentrations, thiopental decreased contractility and the amplitude of the intracellular Ca2+ transient. At equal peak force, peak aequorin luminescence in 10(-4) M thiopental and [Ca2+]0 &gt; 2.25 mM was slightly smaller than that in control conditions at [Ca2+]o = 2.25 mM. This indicates that thiopental causes a small increase in myofibrillar Ca2+ sensitivity. After inactivation of sarcoplasmic reticulum Ca2+ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca2+ influx, thiopental caused a further decrease in contractility and in the amplitude of the intracellular Ca2+ transient, and thiopental's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Thiopental, &gt; or = 10(-4) M, decreased contractility in frog ventricular myocardium. Conclusions These findings indicate that the direct negative inotropic effect of thiopental results from a decrease in intracellular Ca2+ availability. At least part of thiopental's action is caused by inhibition of transsarcolemmal Ca2+ influx. These effects become apparent at concentrations routinely present during intravenous induction with thiopental.

scholarly journals Evaluation of Negative Inotropic Effects of a Isoquinoline Alkaloid N-14

2021 ◽  
Vol 4 (3) ◽  
pp. 01-05
Author(s):  
Inoyat Jumayev
Keyword(s):  
Muscle Contraction ◽  
Papillary Muscle ◽  
Heart Muscle ◽  
Rat Heart ◽  
Cyclopiazonic Acid ◽  
Negative Inotropic Effect ◽  
Isoquinoline Alkaloid ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Negative Inotropic Effects

In studies, the alkaloid 1-(2-Chloro-4,5-methylenedioxyphenyl)-2-hydroxyethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (N-14) had a negative inotropic effect on the activity of the papillary muscle contraction of the rat heart detected. Ca2+ ions from SR play an important role in the process of contraction of the heart muscle. With this in mind, the negative inotropic effect of the N-14 alkaloid was investigated with the modification of the accumulation processes of Ca2+ ions to SR. To clarify this, we examined the effects of the alkaloid being studied on SERCA2a and RyR2. To do this, the inhibitor of SERCA2a - cyclopiazonic acid (CPA) and RyR activator caffeine, which provide the accumulation of Ca2+ ions in SR, were used.

Mechanism of the negative inotropic effects of α1-adrenoceptor agonists on mouse myocardium

2003 ◽  
Vol 81 (8) ◽  
pp. 783-789 ◽  
Author(s):  
Daya R Varma ◽  
Hansjorg Rindt ◽  
Sylvain Chemtob ◽  
Shree Mulay
Keyword(s):  
Adult Mouse ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Adult Mice ◽  
Pkc Isoforms ◽  
Adrenoceptor Agonists ◽  
Inotropic Responses ◽  
Negative Inotropic Effects

This study was done to identify the mechanism of the α1-adrenoceptor (AR) mediated negative inotropic effects of phenylephrine (PE) on adult mouse myocardium. As reported by others, we also found that the nonselective α1AR agonist PE produced a negative inotropic effect on ventricular strips from adult mice that was inhibited by the α1AAR antagonist 5-methylurapidil (5MU) but not by the α1BAR antagonist chloroethylclonidine (CEC) or the α1DAR antagonist BMY 7378. The selective α1AAR agonist A61603 also produced a negative inotropic effect, which was antagonized by 5MU. Phorbol 12,13-dibutyrate (activator of all PKC isoforms) mimicked the negative inotropic responses to PE and A61603. The negative inotropic effects of PE were inhibited by bisindolylmaleimide (inhibitor of all PKC isoforms) but not by Gö 6976 (inhibitor of Ca2+-dependant PKC). Rottlerin, an inhibitor of Ca2+-independent PKCδ, antagonized the negative inotropic effects of PE and A61603. PE and A61603 increased the translocation of PKCδ, which was prevented by rottlerin. These data suggest that the α1AR-mediated negative inotropy on adult mouse myocardium is signaled by Ca2+-independent PKCδ.Key words: phorbol 12,13-dibutyrate, 5-methylurapidil, BMY 7378, chloroethylclolidine, Ca2+-dependant PKC isoforms, α1A-adrenoceptor.

Myocardial Effects of Halothane and Isoflurane in Hamsters with Hypertrophic Cardiomyopathy 

1997 ◽  
Vol 87 (6) ◽  
pp. 1406-1416 ◽  
Author(s):  
Benoit Vivien ◽  
Jean-Luc Hanouz ◽  
Pierre-Yves Gueugniaud ◽  
Yves Lecarpentier ◽  
Pierre Coriat ◽  
...  
Keyword(s):  
Isometric Force ◽  
Negative Inotropic Effect ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Low Load ◽  
Cardiomyopathic Hamsters ◽  
Negative Inotropic Effects

Background The effects of halothane and isoflurane on myocardial contraction and relaxation in diseased myocardium are not completely understood. Methods The effects of equianesthetic concentrations of halothane and isoflurane on inotropy and lusitropy in left ventricular papillary muscles of healthy hamsters and those with genetically induced cardiomyopathy (strain BIO 14.6) were investigated in vitro (29 degrees C; pH 7.40; Ca2+ 2.5 mM; stimulation frequency, 3/min) in isotonic and isometric conditions. Results Halothane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (1.5 vol%, active isometric force (AF): 19 +/- 8% vs. 28 +/- 11% of control values; P &lt; 0.05). Isoflurane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (2.0 vol%, AF: 64 +/- 13% vs. 75 +/- 11% of control values; P &lt; 0.01). However, the negative inotropic effects of halothane and isoflurane were not different for cardiomyopathic or healthy hamsters when their concentrations were corrected for minimum alveolar concentration (MAC) values in each strain. Halothane induced a negative lusitropic effect under low load, which was more important in cardiomyopathic hamsters, suggesting a greater impairment in calcium uptake by the sarcoplasmic reticulum. In contrast, isoflurane induced a moderate positive lusitropic effect under low load in healthy but not in cardiomyopathic hamsters. Halothane and isoflurane induced no significant lusitropic effect under high load. Conclusions Halothane and isoflurane had greater negative inotropic effects in cardiomyopathic than in healthy hamsters. Nevertheless, no significant differences in their inotropic effects were noted when concentrations were correlated as a multiple of MAC in each strain.

scholarly journals Post-operative atrial fibrillation is associated with a pre-existing structural and electrical substrate in human right atrial myocardium

2016 ◽  
Vol 220 ◽  
pp. 580-588 ◽  
Author(s):  
Junaid A.B. Zaman ◽  
Leanne Harling ◽  
Hutan Ashrafian ◽  
Ara Darzi ◽  
Nigel Gooderham ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Right Atrial ◽  
Atrial Myocardium ◽  
Human Right ◽  
Post Operative Atrial Fibrillation

Desflurane-induced postconditioning of diabetic human right atrial myocardium in vitro

2010 ◽  
Vol 36 (1) ◽  
pp. 21-28 ◽  
Author(s):  
S. Lemoine ◽  
C. Durand ◽  
L. Zhu ◽  
C. Ivasceau ◽  
O. Lepage ◽  
...  
Keyword(s):  
Right Atrial ◽  
Atrial Myocardium ◽  
Human Right

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

1990 ◽  
Vol 259 (4) ◽  
pp. H1239-H1246 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document