Effect of trimetazidine and verapamil on the cardiomyopathic hamster myosin phenotype

Abstract

1 In this study we investigated whether long-term trimetazidine (anti-ischaemic drug) therapy alters the ventricular myosin heavy chain (MHC) isoform composition in a model of cardiomyopathy. 2 MHC isoforms were analysed in the native state by electrophoresis in a pyrophosphate buer. Myosin isoform patterns were studied in cardiac muscle from cardiomyopathic hamsters (CMH) of the BIO 14 : 6 strain during the time course of the disease and compared with those of healthy golden hamsters (F1B). The correlation between myosin pro®le and Ca 2+ -activated ATPase activity was determined from 220 days. 3 At the stage of insuciency (350 days), CMH presented the most abnormal phenotype with 53% V1-24% V3 compared to 79% V1-7% V3 (P50.001), in F1B. Trimetazidine was administered to cardiomyopathic hamsters from the early stage of active disease (30 days) to the congestive stages (220 ± 350 days). Within 65 days, trimetazidine treatment, in CMH and F1B, reduced V1 to a low level (53% and 62%, respectively), which remained constant throughout the treatment. This level was similar to that in 220 and 350 days-old untreated-CMH. In sharp contrast, a standard calcium blocker, verapamil, administered to CMH in the same conditions resulted in a higher V1 (about 70%) and higher global myosin ATPase activity from 220 days. 4 Previous results in terms of hypertrophy and survival, compared to these results, suggest that verapamil and trimetazidine treatments reveal a disssociation between ventricular hypertrophy and isomyosin distribution. In addition, the shift in favour of V3 may not necessarily be an aggravating factor of the disease but an adaptative compensatory event.

Trimetazidine Revisited: A Comprehensive Review of the Pharmacological Effects and Analytical Techniques for the Determination of Trimetazidine

“…Long‐term oral treatment with TMZ efficiently decreased Ca 2+ overload and hypertrophy in cardiomyopathic Syrian hamster (CMH) of the strain BIO 14:6, which is a model for both cardiac and skeletal muscle abnormalities, to the levels of normal Syrian hamsters (F1B) (D'hahan et al 1997). The same authors later attempted to prevent the redistribution of myosin phenotype from V1 to V3 with TMZ and a Ca 2+ channel blocker, verapamil, but failed to show an association between the effects of the drugs on hypertrophy and on myosin isoforms (D'hahan et al 1998). The authors concluded that the positive effects with long‐term TMZ therapy might be related to the maintenance of V3 isoform that has a lower ATPase activity and thus utilizes less energy through an unknown mechanism (D'hahan et al 1998).…”

“…The same authors later attempted to prevent the redistribution of myosin phenotype from V1 to V3 with TMZ and a Ca 2+ channel blocker, verapamil, but failed to show an association between the effects of the drugs on hypertrophy and on myosin isoforms (D'hahan et al 1998). The authors concluded that the positive effects with long‐term TMZ therapy might be related to the maintenance of V3 isoform that has a lower ATPase activity and thus utilizes less energy through an unknown mechanism (D'hahan et al 1998).…”

Heart Cell Transplantation Improves Heart Function in Dilated Cardiomyopathic Hamsters

“…The cardiomyopathy is apparent at Ϸ10 weeks of age and becomes clinically apparent at 17 weeks of age. [13][14][15][16][17][18][19][20] Therefore, BIO 53.58 hamsters provide a good model of dilated cardiomyopathy. We used 4-week-old BIO 53.58 hamster cardiomyocytes as transplant donors.…”

Effects of long-term anti-ischemic drug treatment on Na,K-ATPase isoforms in cardiomyopathic hamsters

“…Trimetazidine exerts its protective effects by preventing ATP levels from decreasing and limiting free radical, proton, sodium and calcium ion accumulation in cardiomyocytes (20)(21)(22). The efficacy of trimetazidine administered to young animals has been previously reported in CMH (9,(23)(24); however, it is not known whether trimetazidine can also preserve cardiac NKA activity and isoform expression in the CMH model and in long-term follow-up. Using the experimental design of a trimetazidine treatment with a long-term follow-up, the present study aimed to i) characterize NKA activity in relation to the expression of its α and β subunits in the CMH model, ii) determine whether long-term trimetazidine treatment could prevent NKA alterations and iii) define the relationship between membrane NKA changes and cardiac hypertrophy.…”