| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Cardiovascular Research, Eli Lilly and Company, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: vlahos_chris_j{at}lilly.com.
The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 decreased steady-statecontraction in neonatal rat ventricular myocytes (NRVM). To determine whether the effect on steady-state contraction could be due to decreased intracellular Ca2+ content, Ca2+ content was assessed with fluorescent plate reader (FLIPR) analysis, using the caffeine-releasable Ca2+ stores as an index of sarcoplasmic reticulum (SR) Ca2+ content. Caffeine-releasable Ca2+ content was diminished in a dose dependent manner with LY294002, suggesting that the decrease in steadystate contraction was due to diminished intracellular Ca2+ content. Activation of the L-type Ca2+ channel by BAY K 8644 was attenuated by LY294002, suggesting the effect of LY294002 is to reduce Ca2+ influx at this channel. To investigate whether additional proteins involved in excitation contraction (EC) coupling are likewise regulated by PI3K activity, the effects of compounds acting at SERCA-2a, the ryanodine receptor, and the Na-Ca exchanger (NCX), were compared to LY294002. Inhibition of SERCA-2a by thapsigargin increased basal Ca2+ levels in contrast to LY294002, indicating that SERCA-2a activity is sustained in the presence of LY294002. Ryanodine decreased SR Ca2+ content. The additive effect with co-administration of LY294002 could be attributed to a decrease in Ca2+ influx at the L-type Ca2+ channel. The NCX inhibitor Ni2+ was used to investigate whether the decrease in intracellular Ca2+ content with LY294002 could be due to inhibition of NCX reverse mode activity. The minimal effect of LY294002 with Ni2+ suggests that the primary effect of LY294002 on EC-coupling occurs through inhibition of PI3K mediated L-type Ca2+ channel activity.
This article has been cited by other articles:
|
|
 |
|
  M. Ifuku, K. Farber, Y. Okuno, Y. Yamakawa, T. Miyamoto, C. Nolte, V. F. Merrino, S. Kita, T. Iwamoto, I. Komuro, et al. Bradykinin-Induced Microglial Migration Mediated by B1-Bradykinin Receptors Depends on Ca2+ Influx via Reverse-Mode Activity of the Na+/Ca2+ Exchanger J. Neurosci., November 28, 2007; 27(48): 13065 - 13073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Minhas, S. A. Khan, S. V. Y. Raju, A. C. Phan, D. R. Gonzalez, M. W. Skaf, K. Lee, A. D. Tejani, A. P. Saliaris, L. A. Barouch, et al. Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy J. Physiol., June 1, 2005; 565(2): 463 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-G. Kerfant, D. Gidrewicz, H. Sun, G. Y. Oudit, J. M. Penninger, and P. H. Backx Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3K{gamma}-Deficient Mice Circ. Res., May 27, 2005; 96(10): 1079 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Le Blanc, C. Mironneau, C. Barbot, M. Henaff, T. Bondeva, R. Wetzker, and N. Macrez Regulation of Vascular L-type Ca2+ Channels by Phosphatidylinositol 3,4,5-Trisphosphate Circ. Res., August 6, 2004; 95(3): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
