Abstract
The present study was aimed at investigating the effect of two Ca++ sensitizers, EMD 57033 (without significant phosphodiesterase inhibition) and ORG 30029 (with phosphodiesterase inhibition), in myocardium from nonfailing and failing human hearts. In nonfailing myocardium both EMD 57033 and ORG 30029 increased force of contraction by 280 ± 27% and 94 ± 13%, respectively (n = 6); the time to 80% relaxation (t 80%) by 278 ± 45% and 155 ± 21%; and diastolic force by 28 ± 8% and 12 ± 3%, respectively. In trabeculae from failing myocardium, the increase in active force was similar to that in nonfailing trabeculae (EMD, 305 ± 30%; ORG, 88 ± 12% (n = 6)). However, the increase in t 80% (EMD, 378 ± 56%; ORG, 230 ± 26%) and diastolic force (65 ± 12%; 24 ± 5%) was more pronounced in failing myocardium. EMD had no effect on the peak of the [Ca++]itransient; however, it prolonged the time course of the [Ca++]i transient in both nonfailing and failing myocardial fibers. ORG increased the peak of the Ca++ transient and prolonged the time course in preparations from both nonfailing and failing hearts. Both EMD and ORG shifted the [Ca++]-force relationship toward lower [Ca++] (EMD > ORG).The Ca++ sensitizers EMD 57033 and ORG 30029 increased active force development in nonfailing and failing human myocardium, but both impaired relaxation in failing myocardium to a greater extent than in nonfailing human myocardium in a concentration-dependent fashion.
Footnotes
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Send reprint requests to: Dr. J. K. Gwathmey, Cardiovascular Diseases & Muscle Research Laboratories, Harvard Medical School, Bldg B1, Room 146, 220 Longwood Avenue, Boston, MA 02115.
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↵1 This work is supported in part by RO1 HL 49574 and R44 HL52249 (to J.K.G.), by the German Research Foundation (DFG) (to U.S.) and by a stipend support from CVD Inc. (to P.H.).
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↵2 Established Investigator of the American Heart Association.
- Abbreviations:
- EMD 57033
- (+)-5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl-6- methyl-3,6-dihydro-2H-1,3,4-thiadiazino-2-one
- ORG 30029
- N-hydroxy-5,6,-dimethoxy-benzo-[β]thiophene-2-carboximide hydrochloride
- pCa
- −log[Ca++]
- t80%
- time to 80% relaxation
- EGTA
- ethylene glycol-bis(β-aminoethyl ether)
- MOPS
- 3-[N-morpholino]propanesulfonic acid
- TES
- N-tris[hydroxymethyl]methyl-2-aminoethanesulfonic acid
- TnC
- troponin C
- PDE
- phosphodiesterase
- SR
- sarcoplasmic reticulum
- Received February 6, 1996.
- Accepted July 12, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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