Abstract
The β2-adrenergic receptor (β2-AR)-mediated increase in cardiac L-type Ca2+ current (ICa,L) has been documented in normal subjects. However, the role and mechanism of β2-AR activation on ICa,L in heart failure (HF) are unclear. Accordingly, we compared the effect of zinterol (ZIN), a highly selective β2-AR agonist, on ICa,L in isolated left ventricular cardiomyocytes obtained from normal control and age-matched rats with HF induced by left coronary artery ligation (4 months). ICa,L was measured by using the whole-cell voltage-clamp technique. In normal myocytes, superfusion of ZIN (10−5 M) caused a 21% increase in ICa,L (9.21 ± 0.24 versus 7.59 ± 0.20 pA/pF) (p < 0.05). In HF myocytes, the same concentration of ZIN produced a significantly greater increase (30%) in ICa,L (6.20 ± 0.24 versus 4.75 ± 0.17 pA/pF) (p < 0.01). This ZIN-induced increase in ICa,L was further augmented in both normal and HF myocytes (normal: 59 versus 21%; HF: 71 versus 30%) after the incubation of myocytes with pertussis toxin (PTX, 2 μg/ml, 36°C, 6 h). These effects were not modified by the incubation of myocytes with CGP-20712A (3 × 10−7 M), a β1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551 (10−7 M), a β2-AR antagonist. In addition, all of the effects induced by ZIN were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (100 μM, in the patch-pipette solution). In conclusion, β2-AR activation stimulates L-type Ca2+ channels and increases ICa,L in both normal and HF myocytes. In HF, β2-AR activation-induced augmentation of ICa,L was increased. These effects are likely to be mediated through a cAMP-dependent mechanism and coupled with both stimulatory G protein and PTX-sensitive G protein.
Footnotes
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This study was supported in part by grants from the National Institutes of Health (HL45258, HL53541, and HL12335-01A1) and the American Heart Association (9640189N). Dr. C. P. Cheng is an established investigator of the American Heart Association. An abstract of this work was presented at the 1999 American Heart Association Meeting.
- Abbreviations:
- AR
- adrenergic receptor
- ICa,L
- L-type Ca2+ current
- HF
- heart failure
- PKA
- protein kinase A
- LV
- left ventricular
- LV dp/dtmax and dp/dtmin
- maximum and minimum time derivative of LVP, respectively
- PTX
- pertussis toxin
- MI
- myocardial infarction
- ZIN
- zinterol
- CGP
- CGP-20712A
- ISO
- isoproterenol
- ICI
- ICI-118551
- Ach
- acetylcholine
- NE
- norepinephrine
- [Ca2+]i
- intracellular calcium
- Received December 26, 2000.
- Accepted March 19, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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