Regional expression and functional characterization of the L-type Ca2+-channel in myocardium from patients with end-stage heart failure and in non-failing human hearts.

Abstract The purpose of the present study was to investigate the expression and functional relevance of sarcolemmal L-type Ca 2+ -channels in failing and non-failing human myocardium. The protein expression of sarcolemmal L-type Ca 2+ -channels was determined with 3 H-(+)-PN 200-110-binding experiments and Western blot analysis using a specific antibody against the α 1 -subunit in membrane preparations of ventricular and atrial myocardium from both failing ( n =15) and non-failing hearts ( n =8). The gene expression of the ion conducting pore of the L-type Ca 2+ -channel was examined with Northern blot technique in human failing and non-failing RNA. For normalization the RNA expression of calsequestrin was used. In electrically driven ventricular papillary muscle strips and auricular trabeculae, the responses to nifedipine and Ca 2+ as parameters of myocardial function were studied. The protein expression as measured by 3 H-(+)-PN 200-110-binding (B max ) and Western Blot analysis with calsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both were reduced in atrial compared to ventricular tissue in failing and non-failing hearts. The K D remained unchanged. Calsequestrin levels were unaltered in failing and non-failing hearts. The gene expression of the α 1 -subunit was similar in human failing and non-failing hearts. The L-type Ca 2+ -channel antagonist nifedipine reduced force of contraction with the same potency and efficiency in ventricular failing and non-failing myocardium. In contrast, the potency of nifedipine was higher in atrial than in ventricular tissue. Consistently, atrial myocardium from patients with dilated cardiomyopathy was more sensitive towards Ca 2+ than those of the control group. In conclusion, the altered Ca 2+ -homeostasis in failing human myocardium may be less due to changes in sarcolemmal L-type Ca 2+ -channel expression or function than due to an altered intracellular Ca 2+ -handling.