Systemic hypertension is a major risk factor for developing cardiac hypertrophy and heart failure, yet the molecular mechanism linking hypertension to the heart diseases remain unclear.In this study, we used the spontaneously hypertensive rat (SHR) to identify a window period when the animals had just developed hypertension but not yet developed hypertrophy.This window period allows us to study the effect of hypertensive stress on remodeling of the Ca2+ signaling system without the confounding effects of hypertrophy.Methods: Whole-cell voltage clamp and epi-fluorescence microscopy techniques were used to simultaneously measure the L-type Ca2+ current and the intracellular Ca2+ concentration, [Ca2+]i, in isolated ventricular myocytes.Western blot was used to measure the expression and phosphorylation levels of calmodulin and CaMKⅡ.Results: Our study reveals that remodeling of the cardiac Ca2+ signaling system occurs at the onset of hypertension,prior to the development of hypertrophy.(1) The systolic [Ca2+]i transient becomes larger, while the diastolic [Ca2+]i remains unchanged.(2) The augmented [Ca2+]i transient is caused by increased gain of Ca2+-induced Ca2+ release from sarcoplasmic reticulum (SR), in absence of any change in the L-type Ca2+ current.(3) The SR Ca2+ load remains unchanged.(4) The Ca2+ spark amplitude remains the same.These data indicate an increase in the frequency of Ca2+spark occurrence, which points to a modulation of the ryanodine receptor (RyR) at onset of hypertension.(5) Quantitative Western blot show that Ca2+-calmodulin dependent protein kinase Ⅱ (CaMKⅡ) activity is increased.This should lead to increased CaMKⅡ phosphorylation of RyR and increased RyR activity.conclusion: Taken together, our results show that the onset of hypertension causes an immediate increase in the Ca2+-calmodulin-CaMKⅡ signaling.The elevated [Ca2+]i transient contributes to enhanced myocardial contraction as an acute response to the increased afterload.The augmented Ca2+-CaM-CaMKⅡ signaling is expected to induce cardiac hypertrophy and heart failure upon a prolonged exposure to hypertension.