Role of L-Type Calcium Channels in Pacing-Induced Short-Term and Long-Term Cardiac Memory in Canine Heart

Abstract

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

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

“…12 Changing the I to and I Ca,L current size is realized by changing g to and g Ca,L , respectively. Plotnikov et al 49 observed a more positive activation and slower inactivation of I Ca,L in patch-clamp experiments. To account for the shift in I Ca,L activation, I Ca,L kinetics are changed by adaption of the dynamics of activation gating variable d. In the Courtemanche-Ramirez-Nattel model, the dynamics of d are defined by…”

“…Furthermore, we model the changes in I Ca,L kinetics as observed by Plotnikov et al 49 after ventricular pacing.…”

“…In contrast, no evidence for ''atrial memory'' has been found in the goat. 69 Experimental results indicate that both the transient outward potassium (K + ) current (I to ) 57 and the L-type calcium (Ca 2+ ) current (I Ca,L ) 7,49 are involved in electrical remodeling after changing the activation sequence in the ventricles. Yu et al 72 observed a reduction in I to current size, which explains disappearance of the notch in the AP after remodeling.…”

“…Yu et al 72 observed a reduction in I to current size, which explains disappearance of the notch in the AP after remodeling. Plotnikov et al 49 reversed the activation sequence in the canine heart from epicardium to endocardium by pacing the left ventricle. After 21 days, they isolated epicardial myocytes and compared I Ca,L current size and kinetics to I Ca,L in control (normally stimulated) epicardial myocytes.…”

“…These changes in I Ca,L kinetics probably contribute to the increased APD and plateau height observed after pacing. 49 After 2 h of pacing the canine left ventricle, Patberg et al 48 found a significant decrease in nuclear cAMP-responsive element binding protein (CREB) that did not occur in control dogs or in dogs treated with the I Ca,L blocker nifidipine. These observations indicate that changes in the I Ca,L current are related to modifications in the transcription of the I Ca,L channel.…”