Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium.
Although Ca(2+) channel blockers are commonly used to control both blood pressure and angina in patients with coronary artery disease, clinical trials have associated the use of L-type Ca(2+) channel blockers with increased cardiovascular mortality. Recent evidence has implicated Ca(2+) entry through the L-type Ca(2+) channel during transient ischemia as a proximal stimulus for ischemic preconditioning (IPC) in experimental animals. We therefore hypothesized that clinical L-type Ca(2+) channel blockade prevents IPC in human myocardium. Human atrial trabeculae were suspended in organ baths, field simulated at 1 Hz, and force development was recorded. Following 90 min equilibration, trabeculae from control patients and patients taking L-type Ca(2+) channel blockers were subjected to simulated ischemia/reperfusion (I/R: 45/120 min) with or without 5 min of simulated ischemia (IPC stimulus) prior to I/R. IPC increased post-ischemic developed force in control patients from 14.6+/-2.6 to 43.1+/-3.5% baseline developed force (%BDF P<0.05 I/R vs IPC). Whereas IPC failed to increase post-ischemic developed force in myocardium from patients taking L-type Ca(2+) channel blockers (15. 1+/-1.9 vs 16.6+/-1.7 %BDF, P>0.05 L-type I/R v L-type IPC). We conclude that: (1) atrial muscle can be preconditioned by transient ischemia; (2) atrial muscle from patients taking L-type Ca(2+) channel blockers cannot be preconditioned by transient ischemia; and (3) the increased cardiovascular mortality historically associated with the use of Ca(2) channel blockers in patients with coronary artery disease may be, in part, due to the pharmacological inhibition of ischemic preconditioning.
Cain
B S
BS
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Meldrum
D R
DR
Cleveland
J C
JC
Meng
X
X
Banerjee
A
A
Harken
A H
AH
D000368:Aged; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000502:physiology*; D002986:Clinical Trials as Topic; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008875:Middle Aged
D002121:Calcium Channel Blockers; D015220:Calcium Channels