Isradipine prevents the development of spontaneously occurring cardiac necrosis in cardiomyopathic hamster

Abstract

Recent studies on the heart necrotizing process at the early stages of hamster polymyopathy have led us to believe that this hereditary disease derives from an anomalous transmembrane ion flux due to the presence of slow Na+ channels that contribute to intracellular Na+ accumulation which promote intracellular Ca2+ overload via the Ca2+ influx through the Na+-Ca2+ exchanger. In the present study, we investigated the potential beneficial effect of chronic treatment with a dual L-type Ca2+ and slow Na+ channel blockers isradipine, on the development of necrosis in myopathic hamster hearts. Young cardiomyopathic (CM) hamsters (CMH) were treated with isradipine (0.1 mg x kg(-1) x day(-1)) and nifedipine (1 mg x kg(-1) x day(-1)) for 4 consecutive weeks. Microscopic assessments were carried out in staged serial paraffin sections of heart ventricles from tissues freshly dissected at autopsy. In comparison with control nontreated hearts, which exhibited numerous necrotic calcific foci, myolytic lesions, and dilated right ventricle, isradipine treatment prevented, in a significant manner, all the above spontaneous pathological changes, while nifedipine had no effect. Our present observations provide evidence for the first time that in vivo treatment with a DHP Ca2+ channel blocker, isradipine, is cardioprotective against the development of necrosis in hereditary cardiomyopathy in the hamster. It is possible that the protective effect of isradipine in CMH could be largely due to the indirect blockade of Ca2+ influx through the Na+-Ca2+ exchanger as well as to possible direct blockade of Ca2+ influx through the T-type Ca2+ channel.

Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy

“…These results suggest that HF leading to early death of HCMHs is not fully due to the increase in NHE-1 density. As was previously suggested, the EMD-insensitive increase in necrosis as well as increases in [Na + ] i and [Ca 2+ ] i could be due in part to the continual presence of the slow sodium channel (Bkaily and Jacques 1994;Jacques et al 2003) and a decrease in the expression of cardiac Na + -K + ATPase (Watanabe et al 1998). However, EMD completely prevented the development of hypertrophy and HF as well as the increase in NHE-1 density, in addition to preventing the premature death of HCMHs.…”

“…Longitudinal sectioning of the heart (at least 30 sections) permits a good quantitative assessment of the lesions throughout the heart (Chahine et al 2005). Serial 5 m paraffin sections were stained with hematoxylin-phloxine-saffron Proschek 1984, 1994;Jacques et al 2003;Chahine et al 2005). Von Kossa's silver staining method was used to estimate myocardial calcification Chahine et al 2005).…”

“…As described previously (Jasmin and Proschek 1984;Jacques et al 2003;Chahine et al 2005), necrosis was measured using a double-blind procedure and an arbitrary scale of 0-3 (Jasmin and Proschek 1984;Jacques et al 2003;Chahine et al 2005). A maximum score of 3.0 indicates that the damage exceeded 50%, whereas lower scores correspond to moderate and mild severity changes Proschek 1984, 1994;Chahine et al 2005).…”

Na+–H+exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

“…1), intracellular sodium overload (Fig. 2) is one of the earliest pathological signs (Bkaily et al , 2017Chahine et al 2005;Jacques et al 2003). The latter was found to be, in part, a consequence of the development of intracellular acidosis and the resulting sodium influx via the Na + -H + exchanger NHE-1 (Fig.…”

“…2) awaits elucidation. For further information concerning sodium overload and NHE-1 in DMD and BMD, the reader should refer to key references (Bkaily et al 1990(Bkaily et al , 2015(Bkaily et al , 2017Al-Khoury et al 2006;Chahine et al 2005;Jacques et al 1997Jacques et al , 2003Honoré et al 2008). …”