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CARDIOVASCULAR |
1 Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada
Some studies report that the positive relationship between L-type Ca2+ current (ICa–L) and frequency in cardiac myocytes is mainly due to a direct negative feedback of sarcoplasmic reticulum Ca2+ release on ICa–L inactivation while others provide evidence for activation of calmodulin kinase II (CaMKII). To further elucidate the role of endogenous CaMKII activity, the CaMKII inhibitory peptides, autocamtide-2 relating inhibitory peptide (AIP) and myristoylated AIP were applied using conventional and perforated patch-clamp methods. AIP inhibited the normal adaptive increase in ICa–L in response to abrupt increase in pacing frequency from 0.05 to 2 Hz. The positive ICa–L–frequency relationship was reversed by AIP and the inhibitory effect of AIP was significantly exaggerated at fast pacing rates. The onset of inactivation of ICa–L was not altered by AIP. After thapsigargin treatment, AIP slowed recovery from inactivation of ICa–L and this effect was exaggerated during fast pacing. Buffering of [Ca2+]i by BAPTA and EGTA accelerated recovery of ICa–L from inactivation, and BAPTA partly eliminated the effect of AIP on the recovery. We conclude that: (1) [Ca2+]i directly slows ICa–L recovery from inactivation; and (2) Ca2+-dependent endogenous CaMKII activity accelerates the ICa–L recovery. Thus, at fast heart rates, elevated [Ca2+]i activates endogenous CaMKII and compensates for its direct inhibitory effect on ICa–L recovery from inactivation. Dynamic activity of endogenous CaMKII enhances the positive ICa–L–frequency relationship.
(Received 8 March 2006;
accepted after revision 19 April 2006;
first published online 20 April 2006)
Corresponding author H. J. Duff: Department of Cardiac Sciences, University of Calgary, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Email: hduff{at}ucalgary.ca
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