ISSN:
1573-4919
Keywords:
pimobendan
;
calcium sensitivity
;
skinned fiber bundles
;
heart failure
Source:
Springer Online Journal Archives 1860-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
Abstract UD-CG 212 Cl, (Fig. 1: 4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyrid azinone), is the primary metabolite of the positive inotropic agent pimobendan (UDCG 115 BS, Acardi®). Our previous studies [16] showed in detergent extracted preparations of canine ventricular muscle that sub-nanomolar concentrations of UD-CG 212 Cl increased submaximal myofilament force, but only when the activation state had been altered by relatively high (5-10 mM) concentrations of inorganic phosphate (Pi) or relatively low (20 µM) concentrations of MgATP. In the present study, we investigated the effects of UD-CG 212 Cl on the pCa-force relationship of detergent extracted bundles of human cardiac fibers before and after addition of Pi. As expected, treatment with 5 mM Pi depressed maximal force at pCa 4.5 by 27.0 ± 0.4% (mean ± SEM). Force generated at the half-maximally activating Ca2+ concentration (pCa50) of control fibers (5.98 ± 0.2) was significantly (p 〈 .05) reduced following the addition of 5 mM Pi (pCa50 = 5.69 ± 0.3). The addition of UD-CG 212 Cl over a range of concentrations (10--11〉-10--6 M) had no effect on Ca2+-sensitivity under control conditions, but in the presence of 5 mM Pi, there was a 23.1 ± 0.1% increase in the percent maximal force at pCa5.9. Ca2+-sensitivity was also significantly increased in the presence of Pi and 10-8 M UD-CG 212 Cl (pCa50 = 5.74 ± 0.3, p 〈 .05). We conclude that UD-CG 212 Cl potentially increases sub-maximal force of human ventricular myofilaments with an inotropic action depending on a state of myofilament activation associated with ischemic conditions.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1006827012495
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