REDUCED MYOCARDIAL NA-PUMP CAPACITY IN CONGESTIVE-HEART-FAILURE FOLLOWING MYOCARDIAL-INFARCTION IN RATS(, K+)

We examined changes in expression and function of the cardiac Na+, K+- pump in a post-infarction rat model of hypertrophy and congestive hear t failure (CHF). Myocardial infarction was induced by ligation of the left coronary artery in Wistar rats and hearts were obtained from anim als with CHF and from sham operated rats after 6 weeks. In the CI-IF g roup the ratio of heart weight to body weight was 70% greater compared to sham (P<0.05) and all left-ventricular end-diastolic pressures (L VEDP) were above 15 mmHg. The expression of the alpha(1)- and beta(1)- subunits (mRNA and protein) of the Na+, K+-pump was not significantly different in CHF and sham. As compared to sham the alpha(2) isoform, m RNA and protein levels were lower in CHF hearts by 25 and 55%, respect ively, whereas the alpha(3) isoform mRNA was greater by 120% in CHF, T he alpha(3) protein was not detectable in sham, but a prominent band w as seen in CHF. Cell volume of isolated cardiomyocytes was 30% larger in CHF. Cardiomyocytes containing the Na+ sensitive fluorescent dye SB FI were loaded to an intracellular Na+ concentration ([Na+](i) of abou t 140 mM in a K+- and Mg2+-free medium (140 mM Na+, free Ca2+ of 10(-8 ) M). To avoid back leak of Na+ and to ensure no voltage effects on th e Na+, K+-pump extracellular Na+ was subsequently removed, and 6 mar M g2+ was added to the superfusate, The Na+, K+-pump was then reactivate d by 10 mM Rb+. SBFI fluorescence ratio decreased mono-exponentially w ith a time constant (tau) of 191 +/- 15 in sham (n = 8) and 320 +/- 38 s in CHF (n = 9) rats (P < 0.01). These changes in fluorescence indic ate that the maximum rate of decline of [Na+](i) from 100 to 35 mM was 39% (P < 0.005) slower in CHF compared to sham, whereas maximum pump rate per cell was not significantly altered (9.0 +/- 0.7 fmol/s in sla m and 7.1 +/- 0.7 fmol/s in CHF cells). The [Na+](i) which caused 50% pump activation (k(0.5)) was also not altered in CHF (40 mM in both gr oups). We conclude that the number of Na+, K+-pumps per cell was maint ained in CHF, but an isoform switch of the alpha(3)-replacing the alph a(2)-isoform occurred. However, maximum Na+, K+-pump rate in terms of rate of change of [Na+](i) was significantly attenuated in CHF, most l ikely as a result of increased cell size. (C) 1998 Academic Press.