CHANGES IN L-TYPE CALCIUM-CHANNEL ABUNDANCE AND FUNCTION DURING THE TRANSITION TO PACING-INDUCED CONGESTIVE-HEART-FAILURE

Objective: The development of congestive heart failure (CHF) is accomp anied by left ventricular (LV) and myocyte contractile dysfunction. Ho wever. time-dependent cellular and ionic events which contribute to th e initiation and progression of CHF remain unclear. This study tested the central hypothesis that changes in L-type Ca2+ channel current (I- Ca) and abundance (B-max) are early events in the transition to CHF. M ethods: LV fractional shortening by echocardiography, isolated LV myoc yte shortening velocity by videomicroscopy, I-Ca by voltage-clamp, and B-max by [H-3]nitrendipine binding were determined at each week durin g the progression of pacing-induced CHF in pigs (240 bpm; n = 6/week; for 3 weeks). Myocyte and L-type Ca2+ channel function were determined under basal conditions and after beta-adrenergic receptor stimulation with 25 nM isoproterenol. Results: After 1 week of pacing, myocyte an d L-type Ca2+ current responses to beta-adrenergic receptor stimulatio n were reduced by 20% from control values and was accompanied by ol er a 210% increase in plasma catecholamine levels. After 2 weeks of paci ng, reductions in LV fractional shortening and myocyte shortening velo city from control values (20 +/- 1 vs. 34 +/- 2% and 36.7 +/- 2.9 vs. 50.6 +/- 2.4 mu m/s, respectively, P < 0.05) were paralleled by decrea sed I-Ca (2.47 +/- 0.10 vs. 3.63 +/- 0.25 pA/pF, P < 0.02) and B-max ( 149 +/- 16 vs. 180 +/- 12 fmol/mg, P < 0.03), After 3 weeks of pacing, LV fractional shortening was reduced by over 50%, myocyte shortening velocity by 37%, and I-Ca and B-max were reduced by over 25% from cont rol values. Furthermore, after 3 weeks of pacing, the I-Ca/B-max ratio was reduced from control values (16.2 +/- 0.9 vs. 20.6 +/- 1.2 [fA/pF ]/[fmol/mg], P < 0.03), which suggests functional defects in the remai ning L-type Ca2+ channels. Conclusions: An early event during the tran sition to pacing-induced CHF was diminished beta-adrenergic receptor a ugmented L-type Ca2+ current, which was followed by an absolute loss o f steady-state L-type Ca2+ current and channel abundance. The developm ent of severe CHF was accompanied by a loss of Ca2+ carrying capacity through residual channels. These unique findings suggest that a contri butory molecular mechanism for the initiation and progression of CHF i s changes in the structure and function of the L-type Ca2+ channels. ( C) 1998 Elsevier Science B.V.