Naoya Satoh

Early changes in excitation-contraction coupling: transition from compensated hypertrophy to failure in Dahl salt-sensitive rat myocytes

OBJECTIVE The aims were to (1) define the early changes in excitation-contraction coupling during the transition from cardiac hypertrophy to heart failure, and (2) to clarify the causal relationship between mechanical dysfunction and abnormal Ca2+ handling in the Dahl salt-sensitive rat model. METHODS Myocardial contractile function was assessed in whole heart perfusion studies. In separate experiments, isolated left ventricular myocytes from Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats were paced at a physiological rate of 5Hz and cell shortening (CS) and [Ca2+]i measured simulataneously by video-edge detection and fura-2 fluorescence. RESULTS DS hearts developed hypertrophy after 4 weeks of a high-salt diet (4WHSD), as indicated by a 26% increase (p < 0.01) in the heart to body weight ratio and a 21% increase (p < 0.01) in cell width. Heart failure developed after 12 weeks of a high-salt diet (12WHSD), as indicated by an 11% increase (p < 0.01) in the lung wet to dry weight ratio. Furthermore, in DS-12WHSD hearts, the diastolic pressure-volume relationship had shifted rightward. DR rats did not develop hypertension and seved as age-matched controls. A 31% (p < 0.05) increase in the %CS in DS-4WHSD myocytes compared to DR-4WHSD myocytes with a trend of a parallel increase in Ca2+ transient amplitude was found. There was no difference in the Ca2+ transient parameters between DR and DS at 12WHSD, but an 18% (p < 0.01) decrease occurred in peak [Ca2+]i in DS myocytes between 4WHSD and 12WHSD. In DS-12WHSD, the time to peak shortening and the time from peak shortening to 50% and 90% relaxation was significantly prolonged by 27%, 44%, and 38%, respectively, as compared to the age-matched DR myocytes. CONCLUSION Our results indicated that: (I) normal Ca2+ homeostasis is preserved at the stage of compensated hypertrophy; (2) the early signs of isolated myocyte dysfunction were a prolongation of the shortening and relaxation time course without an abnormal time course of the Ca2+ transient. Thus, in the hypertensive Dahl salt rat model, abnormal Ca2+ handling appears neither to precede nor initiate the transition to failure.

Chronic α-Adrenergic Receptor Stimulation Modulates the Contractile Phenotype of Cardiac Myocytes In Vitro

BackgroundHeart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic &agr;-adrenergic (&agr;-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes. Methods and ResultsAdult rat ventricular myocytes in culture were exposed to &agr;-ADR stimulation (norepinephrine + propranolol) for 48 hours. &agr;-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca2+-ATPase and Ca2+ release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na+-Ca2+ exchanger by 70% and 39%, respectively. After washout of the &agr;-ADR agonist, simultaneous measurement of [Ca2+]i transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca2+]i amplitude and myocyte shortening were decreased in &agr;-ADR–treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca2+]i and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na+ channel activator veratridine was shifted leftward in &agr;-ADR–stimulated myocytes (EC50, 21.6±4.6 versus 105.8±10.5 nmol/L, P <0.001). ConclusionsChronic &agr;-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca2+-ATPase and the Ca2+ release channel that are associated with decreases in [Ca2+]i and contractility. &agr;-ADR stimulation simultaneously increases Na+-Ca2+ exchanger expression, thereby increasing sensitivity to intracellular Na+.