Background-We tested the hypothesis that I Ca,L is important to the development of cardiac memory. Methods and Results-The effects of L-type Ca 2ϩ channel blockade and ␤-blockade were tested on acutely anesthetized and on chronically instrumented, conscious dogs. Short-term memory (STM) was induced by 2 hours of ventricular pacing and long-term memory (LTM) by ventricular pacing for 21 days. STM dogs received placebo, nifedipine, or propranolol, and LTM dogs received placebo, atenolol, or amlodipine. AT 1 receptor blockade (candesartan) and ACE inhibition (trandolapril) were also tested in LTM. Microelectrodes were used to record transmembrane potentials from isolated epicardial and endocardial slabs using a protocol simulating STM in intact animals. Left ventricular epicardial myocytes from LTM or sham control dogs were dissociated, and I Ca,L was recorded (whole-cell patch-clamp technique). Evolution of STM and LTM was attenuated by I Ca,L blockers but not ␤-blockers. Neither AT 1 receptor blockade nor ACE inhibition suppressed LTM. In microelectrode experiments, pacing induced an epicardial-endocardial gradient change mimicking STM that was suppressed by nifedipine. In patch-clamp experiments, peak I Ca,L density in LTM and control were equivalent, but activation was more positive and time constants of inactivation longer in LTM (PϽ0.05). Conclusions-I Ca,L blockade but not ␤-adrenergic blockade suppresses cardiac memory. LTM evolution is unaffected by angiotensin II blockade and is associated with altered I

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Abstract-Cardiac memory (CM) has short-(STCM) and long-term (LTCM) components modulated by calcium and angiotensin II. LTCM is associated with reduced I to and Kv4.3 mRNA levels. Because the cAMP response element binding protein, CREB, contributes to CNS memory transcription, we hypothesized that it might be a transcriptional factor in CM, influenced by calcium and angiotensin II. We studied STCM in dogs that were AV sequentially paced (AVP) for 2 hours or sham-operated. STCM was evaluated with ECG and vectorcardiogram (VCG), and subepicardial biopsies were taken at 5 to 120 minutes and investigated for CREB. LTCM was studied in dogs paced for 3 weeks and in sham controls. At 3 weeks the heart was excised, biopsies obtained, and CRE binding tested. STCM induction occurred in AVP dogs but not in sham or AVP dogs treated with saralasin or nifedipine. Nuclear CREB was significantly decreased at 2 hours in the AVP no-drug group only. LTCM dogs manifested reduced binding of nuclear proteins to CRE, and CRE binding activity in the promoter region of Kv4.3. In conclusion, there is an association between STCM induction and decreased nuclear CREB that is angiotensin-modulated and calcium-dependent. Moreover, the decreased CRE binding after 3 weeks of AVP combined with CRE binding activity in the Kv4. emory is a form of remodeling common to many organ and cell systems and is widely studied in neural tissues. [1][2][3][4][5] Classically, neuronal memory has been considered as short-or long-term. 3,4 Long-term memory requires new protein synthesis, whereas short-term memory is thought to result from protein phosphorylation. 3 Changes in transcription are associated with long-term neural memory, for which the cAMP response element (CRE) binding protein, CREB, is a major factor. 3 Cardiac memory (CM) shares a number of characteristics with that in CNS 5 and has been studied similarly in terms of short-6,7 and long-term 7,8 processes. Paralleling CNS, CM can be induced by electrical shocks. In heart, these are initiated by ventricular pacing. 7,8 Expression of short-term CM (STCM) and long-term CM (LTCM) is related to the transient outward potassium current, I to . In the setting of LTCM, specifically, I to is decreased in magnitude and altered in kinetics. Moreover, both STCM and LTCM are prevented by pharmacological blockade of I Ca,L , while STCM induction is prevented by AT 1 receptor blockade as well. This suggests roles for angiotensin II-modulated, 9 calcium-dependent processes in CM evolution. 10 CM not only represents a nonpathological form of cardiac remodeling, but it has been implicated in the modulation of repolarization in ventricles 8 and atria 11 and in modulation of drug actions on the heart. 7,12 Both our own earlier data 8 and the neurophysiological literature 3,4 suggest that a continuum of mechanisms link STCM and LTCM. In heart, this would imply a set of interrelated and contemporaneous processes initiated by ventricular pacing: one modifying the existing channel proteins that determine repolarization to ...