Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts

Chen, Qun; Camara, Amadou K.S.; Rhodes, Samhita S.; Riess, Matthias L.; Novalija, Enis; Stowe, David F.

doi:10.1016/s0008-6363(03)00524-8

Cited by 13 publications

(27 citation statements)

References 29 publications

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“…Although both F 385 and F456 decline over time, time control studies showed that the F385-to-F456 ratio (F385/F456) remained stable, indicating that effective measured [Ca 2ϩ ] was unchanged (31). The F385/F456 was converted to [Ca 2ϩ ] after correcting for background autofluorescence and noncytosolic fluorescence (see APPENDIX), as has been described in detail previously (7,10,26,27,30). Developed LVP after indo 1 loading was also not significantly altered over 3 h in the absence of ischemia.…”

Section: Measurement Of Myoplasmic Free Ca 2ϩ In Intact Heartsmentioning

confidence: 99%

“…Next, hearts were subjected to 30 min of global ischemia, and inotropic drugs were again infused for 2 min after 30-min reperfusion. The concentrations of inotropic drugs were the approximate half-maximal effective dose concentrations, as previously established (10,27). Eight control hearts were not exposed to inotropic interventions before or after global ischemia.…”

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

“…At the end of each experiment, MnCl 2 (100 M) was infused for 10 min to quench the myoplasmic indo 1 Ca 2ϩ signal to correct for the nonmyoplasmic fraction (see APPENDIX). All analog signals were digitized and recorded at 125 Hz for later analysis by using MATLAB as previously described (7,10,26,27).…”

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

“…]/dtmin and dLVP/dtmin). These indexes have been described previously (7,10,27 (Fig. 2B) was applied to all three segments during drug administration before and after global ischemia.…”

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

“…The effects of drugs on static relationships between [Ca 2ϩ ] and LVP (peak values, rates of rise and fall, etc.) were presented in earlier articles (7,10). For this study, we compared how positive inotropic drugs with different mechanisms of action alter the dynamic phase-space relationship between [Ca 2ϩ ] and LVP before and after ischemia and reperfusion (IR) injury.…”

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confidence: 99%

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Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Rhodes¹,

Ropella²,

Camara³

et al. 2006

Journal of Applied Physiology

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. Ischemia-reperfusion injury changes the dynamics of Ca 2ϩ -contraction coupling due to inotropic drugs in isolated hearts. J Appl Physiol 100: 940 -950, 2006. First published November 10, 2005 doi:10.1152/japplphysiol.00285.2005.-Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca 2ϩ ] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37°C, 1.25 mM CaCl 2). [Ca 2ϩ ] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca 2ϩ -contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 M) worsened, whereas dopamine (8 M) improved Ca 2ϩ -contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 M) improved Ca 2ϩ -contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 M) did not alter Ca 2ϩ -contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca 2ϩ flux before and after ischemia. Dynamic indexes based on LVP- [Ca 2ϩ ] diagrams (area, shape, position) can be used to identify and measure alterations in Ca 2ϩ -contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.phase-space diagrams; cooperativity; guinea pigs; linear model POSITIVE INOTROPIC DRUGS ARE frequently administered to patients with left ventricular (LV) dysfunction to improve cardiac output (19). These agents mostly act by increasing myoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]) ("upstream" mechanism) but may also enhance Ca 2ϩ binding to troponin C on the actin (TnCA) myofilament ("central" mechanism) or alter cross-bridge kinetics ("downstream" mechanism). Several classes of inotropic drugs act selectively through these mechanisms to improve Ca 2ϩ -contraction coupling. ␤-adrenergic and dopaminergic agonists (e.g., dobutamine and dopamine) increase myoplasmic cAMP concentrations to promote protein kinase-induced phosph...

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Section: Measurement Of Myoplasmic Free Ca 2ϩ In Intact Heartsmentioning

confidence: 99%

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

“…]/dtmin and dLVP/dtmin). These indexes have been described previously (7,10,27 (Fig. 2B) was applied to all three segments during drug administration before and after global ischemia.…”

Section: Experimental Protocol and Data Collectionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Rhodes¹,

Ropella²,

Camara³

et al. 2006

Journal of Applied Physiology

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The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

MacGowan

2005

Cardiovasc Drugs Ther

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To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.

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Levosimendan: Molecular mechanisms and clinical implications

Papp

Édes

Fruhwald

et al. 2012

International Journal of Cardiology

264

118

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Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts

Cited by 13 publications

References 29 publications

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

Levosimendan: Molecular mechanisms and clinical implications

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Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts

Cited by 13 publications

References 29 publications

Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts

Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts

The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

Levosimendan: Molecular mechanisms and clinical implications

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Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts