The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+exchanger function

The mechanisms of the positive inotropic action of a new synthetic tetrahydroisoquinoline compound, SL-1, were investigated in isolated rat cardiac tissues and ventricular myocytes. SL-1 produced a rapidly developing, concentration-dependent positive inotropic response in both atrial and ventricular muscles and a negative chronotropic effect in spontaneously beating right atria. The positive inotropic effect was not prevented by pretreatment with reserpine (3 mg/kg) or the α-adrenoceptor antagonist prazosin (1 μM), but was suppressed by either the β-adrenoceptor antagonist atenolol (3 μM) or the K+ channel blocker 4-aminopyridine (4AP, 1 mM). In the whole-cell recording study, SL-1 increased the plateau level and prolonged the action potential duration in a concentration-dependent manner and decreased the maximum upstroke velocity [Formula: see text] and amplitude of the action potential in isolated rat ventricular myocytes stimulated at 1.0 Hz. On the other hand, SL-1 had little effect on the resting membrane potential, although it caused a slight decrease at higher concentrations. Voltage clamp experiments revealed that the increase of action potential plateau and prolongation of action potential duration were associated with an increase of Ca2+ inward current (ICa) via the activation of β-adrenoceptors and a prominent inhibition of 4AP-sensitive transient outward K+ current (Ito) with an IC50 of 3.9 μM. Currents through the inward rectifier K+ channel (IKl) were also reduced. The inhibition of Ito is characterized by a reduction in peak amplitude and a marked acceleration of current decay but without changes on the voltage dependence of steady-state inactivation. In addition to the inhibition of K+ currents, SL-1 also inhibited the Na+ inward current (INa) with an IC50 of 5.4 μM, which was correlated with the decrease of [Formula: see text]. We conclude that the positive inotropic effect of SL-1 may be due to an increase in Ca2+ current mediated via partial activation of β-adrenoceptors and an inhibition of K+ outward currents and the subsequent prolongation of action potentials.Key words: SL-1, tetrahydroisoquinoline, inotropic and chronotropic action, action potential, Na+, Ca2+, and K+ currents.

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Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00337.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. H1034-H1042 ◽

Cited By ~ 19

Author(s):

Shivani Mittra ◽

Jean-Marc Hyvelin ◽

Qixian Shan ◽

Fai Tang ◽

Jean-Pierre Bourreau

Keyword(s):

Cardiac Tissue ◽

Ventricular Myocytes ◽

Marked Decrease ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Prolonged Incubation ◽

Cell Contractility ◽

Rat Ventricular Myocytes ◽

Cell Shortening ◽

Cox Inhibitor

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions. However, the direct inotropic effect of ADM on normal and compromised cardiomyocytes is not clear. In rat ventricular myocytes, ADM produced an initial (<30 min) increase in cell shortening and Ca2+ transient and, on prolonged incubation (>1 h), a marked decrease in cell shortening and Ca2+ transient. Both effects were sensitive to inhibition by the ADM antagonist ADM-(22–52). The increase and decrease in cell shortening and Ca2+ transient were attenuated by pretreatment with indomethacin [a nonspecific cyclooxygenase (COX) inhibitor], nimesulide and SC-236 (specific COX-2 inhibitors), and tranylcypromine (a prostacyclin synthase inhibitor); SQ-29548 (a thromboxane receptor antagonist) was without effect. Cells isolated from LPS-treated rats that were in the late, hypodynamic phase of septic shock also showed a marked decrease in cell shortening and Ca2+ transient. Because ADM is overexpressed in sepsis, we repeated the above protocol in cells isolated from LPS-treated rats. At 4 h after LPS injection, ADM levels markedly increased in plasma, ventricles, and freshly isolated ventricular myocytes. Decreases in cell shortening and Ca2+ transient in LPS-treated cells were reversed by pretreatment with ADM-(22–52). Anti-ADM (rat) IgG also reversed the decrease in cell shortening and other parameters of cell kinetics. Indomethacin, SC-236, and tranylcypromine restored cell contractility and the decrease in Ca2+ transient, whereas SQ-29548 had no effect, implying that prostacyclin played a role in both effects. However, with regard to cell-shortening kinetics, indomethacin and SQ-29548 decreased the amount of time taken by the cells to return to baseline, whereas SC-236 and tranylcypromine did not, implying that not only prostacyclin, but also thromboxane, is involved. The results indicate that ADM interacts with COX to yield prostanoids, which mediate its negative inotropic effect in LPS-treated rat ventricular myocytes.

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Antagonistic Actions of Halothane and Sevoflurane on Spontaneous Ca2+Release in Rat Ventricular Myocytes

Anesthesiology ◽

10.1097/00000542-200607000-00013 ◽

2006 ◽

Vol 105 (1) ◽

pp. 58-64 ◽

Cited By ~ 8

Author(s):

Mark D. Graham ◽

Philip M. Hopkins ◽

Simon M. Harrison

Keyword(s):

Sarcoplasmic Reticulum ◽

Positive Inotropic Effect ◽

Ventricular Myocytes ◽

Inotropic Effect ◽

Release Process ◽

Rat Ventricular Myocytes ◽

Fura 2 ◽

Threefold Increase ◽

Subcellular Target ◽

Isolated Rat

Background Halothane has been reported to sensitize Ca(2+) release from the sarcoplasmic reticulum (SR), which is thought to contribute to its initial positive inotropic effect. However, little is known about whether isoflurane or sevoflurane affect the SR Ca(2+) release process, which may contribute to the inotropic profile of these anesthetics. Methods Mild Ca(2+) overload was induced in isolated rat ventricular myocytes by increase of extracellular Ca(2+) to 2 mM. The resultant Ca(2+) transients due to spontaneous Ca(2+) release from the SR were detected optically (fura-2). Cells were exposed to 0.6 mM anesthetic for a period of 4 min, and the frequency and amplitude of spontaneous Ca(2+) transients were measured. Results Halothane caused a temporary threefold increase in frequency and decreased the amplitude (to 54% of control) of spontaneous Ca(2+) transients. Removal of halothane inhibited spontaneous Ca release before it returned to control. In contrast, sevoflurane initially inhibited frequency of Ca(2+) release (to 10% of control), whereas its removal induced a burst of spontaneous Ca(2+) release. Isoflurane had no significant effect on either frequency or amplitude of spontaneous Ca(2+) release on application or removal. Sevoflurane was able to ameliorate the effects of halothane on the frequency and amplitude of spontaneous Ca(2+) release both on application and wash-off. Conclusions Application of halothane and removal of sevoflurane sensitize the SR Ca(2+) release process (and vice versa on removal). Sevoflurane reversed the effects of halothane, suggesting they may act at the same subcellular target on the SR.

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Reactive oxygen species partially mediate high dose angiotensin II-induced positive inotropic effect in cat ventricular myocytes

Cardiovascular Pathology ◽

10.1016/j.carpath.2015.01.002 ◽

2015 ◽

Vol 24 (4) ◽

pp. 236-240 ◽

Cited By ~ 3

Author(s):

Alejandra M. Yeves ◽

Claudia I. Caldiz ◽

Ernesto A. Aiello ◽

María C. Villa-Abrille ◽

Irene L. Ennis

Keyword(s):

Reactive Oxygen Species ◽

Angiotensin Ii ◽

Positive Inotropic Effect ◽

Ventricular Myocytes ◽

Reactive Oxygen ◽

Inotropic Effect ◽

High Dose ◽

Oxygen Species

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Involvement of diacylglycerol/protein kinase C pathway in endothelin-1-induced negative inotropic effect in mouse ventricular myocytes

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2006.08.100 ◽

2006 ◽

Vol 41 (6) ◽

pp. 1069-1070

Author(s):

K NISHIMARU ◽

T ARIMOTO ◽

Y TAKEISHI ◽

I KUBOTA ◽

M ENDOH

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Ventricular Myocytes ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Endothelin 1 ◽

Kinase C

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Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.4.h1449 ◽

1996 ◽

Vol 271 (4) ◽

pp. H1449-H1455 ◽

Cited By ~ 26

Author(s):

J. I. Goldhaber ◽

K. H. Kim ◽

P. D. Natterson ◽

T. Lawrence ◽

P. Yang ◽

...

Keyword(s):

Methyl Ester ◽

Ventricular Myocytes ◽

Negative Inotropic Effect ◽

Cell Length ◽

Inotropic Effect ◽

Tnf Alpha ◽

Adult Rabbit ◽

Cell Shortening ◽

Rabbit Ventricular Myocytes ◽

In Cells

The mechanism of the acute negative inotropic effect of tumor necrosis factor-alpha (TNF-alpha) was studied in enzymatically isolated adult rabbit ventricular myocytes. In cells loaded with fura 2 acetoxymethyl ester (AM) and paced intermittently at 0.2 Hz, TNF-alpha at doses < or = 10,000 U/ml caused a significant reduction in active cell shortening at 20 min, without reducing the amplitude of the accompanying intracellular Ca2+ concentration ([Ca2+]i) transient. Similar results were obtained in cells loaded with indo 1-AM and paced continuously at 0.2 Hz during exposure to TNF-alpha (10,000 U/ml). The effect of TNF-alpha on cell shortening could be prevented by the nitric oxide (NO) synthase blocker NG-nitro-L-arginine methyl ester (L-NAME) but not its inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME). The NO scavenger hemoglobin also attenuated the effects of TNF-alpha. TNF-alpha also caused a significant increase in diastolic cell length without any change in diastolic [Ca2+]i. The effect on cell length was prevented by L-NAME but not D-NAME. In cells loaded with the pH indicator seminaphthorhodafluor-AM, TNF-alpha did not alter pH sufficiently to account for the negative inotropic effect. These data suggest that high doses of TNF-alpha can acutely induce NO synthesis in isolated myocytes and reduce contractility by decreasing myofilament [Ca2+]i responsiveness. The mechanism of this altered myofilament [Ca2+]i response is unknown but does not appear to be pH mediated.

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A novel phospholipase C- and cAMP-independent positive inotropic mechanism via a P2 purinoceptor

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.5.h2380 ◽

1997 ◽

Vol 273 (5) ◽

pp. H2380-H2387 ◽

Cited By ~ 12

Author(s):

Ernest Podrasky ◽

David Xu ◽

Bruce T. Liang

Keyword(s):

Phospholipase C ◽

Positive Inotropic Effect ◽

Ventricular Myocytes ◽

Inositol Phosphates ◽

Inotropic Effect ◽

Maximal Increase ◽

Cyclic Monophosphate ◽

Myocyte Contractility ◽

Novel Model ◽

Potency Order

Although ATP, acting through a P2 purinoceptor, can stimulate a pronounced positive inotropic effect in cardiac ventricular myocytes, the receptor-effector mechanism that underlies this stimulatory cardiac action is not well understood. The objectives of the present study were to develop the cultured chick embryo ventricular myocytes as a novel model for the cardiac P2 purinoceptor and to determine the mechanism underlying its positive inotropic effect. ATP caused an 89 ± 8.9% ( n = 14 cells) increase in the myocyte contractility, with an efficacy and potency order of ATP > ADP > AMP ≫ adenosine. 2-Methylthio-ATP (2-MeS-ATP) but not α,β-methylene-ATP was able to stimulate myocyte contractility, with a maximal increase of 54 ± 2.6% ( n = 11 cells). Although UTP potently stimulates phosphoinositide hydrolysis, it had an only modest positive inotropic effect (27 ± 7% maximal increase; n = 8 cells). In contrast to previous suggestions, the 2-MeS-ATP-stimulated positive inotropic response does not require the action of phospholipase C (PLC), such as that of the inositol phosphates; the UTP effect on contractility appears to be mediated via the 2-MeS-ATP-sensitive P2 receptor. The PLC inhibitor U-73122 had no effect on the 2-MeS-ATP-stimulated increase in contractility, providing further evidence against a role for PLC in the inotropic effect of 2-MeS-ATP. An adenosine 3′,5′-cyclic monophosphate-independent Ca2+ entry-stimulating mechanism appears to underlie a direct coupling of the receptor to stimulation of the myocyte contractility. This new PLC- and adenosine 3′,5′-cyclic monophosphate-independent positive inotropic mechanism represents a target for developing novel positive inotropic therapeutics.

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Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: impact on swelling-induced negative inotropic effect

Cardiovascular Research ◽

10.1093/cvr/cvu230 ◽

2014 ◽

Vol 104 (3) ◽

pp. 456-466 ◽

Cited By ~ 8

Author(s):

Luis Alberto Gonano ◽

Malena Morell ◽

Juan Ignacio Burgos ◽

Raul Ariel Dulce ◽

Verónica Celeste De Giusti ◽

...

Keyword(s):

Nitric Oxide ◽

Ventricular Myocytes ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Nitric Oxide Release ◽

Hypotonic Swelling ◽

Cardiac Ventricular Myocytes

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Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00388.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. H1842-H1847 ◽

Cited By ~ 16

Author(s):

Shivani Mittra ◽

Jean-Pierre Bourreau

Keyword(s):

Ventricular Myocytes ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Paracrine Factor ◽

Inotropic Effects ◽

Prolonged Incubation ◽

Rat Ventricular Myocytes ◽

Cell Shortening ◽

Adult Rat

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (<30 min) increase in cell shortening and Ca2+ transients and a marked decrease in both on prolonged incubation (>1 h). Both effects were sensitive to ADM antagonist ADM-(22–52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of Gi proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from Gs-coupled to PTX-sensitive, PKA-dependent Gi coupling by ADM in ARVMs. The ADM-mediated Gi-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22–52) and PTX. The decrease in cell shortening and Ca2+ transients in LPS-treated ARVMs could be reversed back with ADM-(22–52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of Gi signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.

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