| New inotropic concepts: rationale for and differences between calcium sensitizers and phosphodiesterase inhibitors. | |
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MedLine Citation:
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PMID: 9142431 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Positive inotropic compounds may be harmful in the long-term treatment of chronic congestive heart failure because they may induce a calcium overload, unwanted changes in cross-bridge kinetics and an acceleration in heart rate. As a result of all three alterations, energy consumption would be increased. Different pharmacological modes of action may have different effects on the molecular mechanisms underlying the positive inotropic effect, and hence on myocardial energy consumption. Therefore, we studied the effects of a variety of cardiotonic agents on the heat released from small guinea pig papillary muscles contracting isometrically at an experimental temperature of 21 degrees C and a stimulation frequency of 12 per minute using rapid antimony-bismuth thermopiles. We were able to define the economy of muscle contraction, which was lowest with phosphodiesterase inhibitors and highest with calcium sensitizers. Compared with an increase in extracellular calcium concentration, beta 1-adrenoceptor stimulators and phosphodiesterase inhibitors profoundly decrease the economy of myocardial contraction, and calcium-sensitizers (pimobendan and EMD-53998) slightly increase myocardial economy, whereas ouabain and the calcium channel agonist BAY K 8644 have no effect on this parameter. In addition, we provide evidence that acceleration of heart rate may be harmful not only from an energetic point of view: an increase in heart rate may also decrease the contractility of the failing human myocardium (inverse force-frequency relationship). Taking these observations into consideration, an "optimal' positive inotropic compound should have no, or even negative, chronotropic effects, should not be mediated by increases in calcium transients, and should decelerate, rather than accelerate, cross-bridge kinetics. |
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Authors:
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C Holubarsch |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cardiology Volume: 88 Suppl 2 ISSN: 0008-6312 ISO Abbreviation: Cardiology Publication Date: 1997 |
Date Detail:
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Created Date: 1997-07-10 Completed Date: 1997-07-10 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 1266406 Medline TA: Cardiology Country: SWITZERLAND |
Other Details:
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Languages: eng Pagination: 12-20 Citation Subset: IM |
Affiliation:
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Department of Cardiology and Angiology, University of Freiburg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium / pharmacology* Cardiotonic Agents / pharmacology* Deoxyepinephrine / pharmacology Energy Metabolism Guinea Pigs Heart Failure / physiopathology Humans Imidazoles / pharmacology Isoproterenol / pharmacology Myocardial Contraction / drug effects* Myocardium / metabolism Papillary Muscles / drug effects Phosphodiesterase Inhibitors / pharmacology* Pyridazines / pharmacology Pyridones / pharmacology Quinolines / pharmacology Thiadiazines / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Imidazoles; 0/Phosphodiesterase Inhibitors; 0/Pyridazines; 0/Pyridones; 0/Quinolines; 0/Thiadiazines; 119615-63-3/olprinone; 120223-04-3/EMD 53998; 501-15-5/Deoxyepinephrine; 74150-27-9/pimobendan; 7440-70-2/Calcium; 7683-59-2/Isoproterenol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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