Premium
Increased PKA activity and its influence on isoprenaline‐stimulated L‐type Ca 2+ channels in the heart from ovariectomized rats
Author(s) -
Kam Kenneth W L,
Kravtsov Gennadi M,
Liu Jing,
Wong Tak Ming
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706123
Subject(s) - endocrinology , medicine , isoprenaline , ovariectomized rat , stimulation , protein kinase a , forskolin , chemistry , estrogen , intracellular , basal (medicine) , phospholamban , cardioprotection , kinase , calcium , biochemistry , insulin , ischemia
1 We previously showed that oestrogen confers cardioprotection by downregulating the cardiac β 1 ‐adrenoceptor ( β 1 ‐AR). The present study examined the effect of oestrogen on the post β 1 ‐AR signalling cascade, with particular emphasis on the activity of protein kinase A (PKA) and its influence on the L‐type Ca 2+ channel. 2 Three groups of adult female Sprague–Dawley rats were used: sham‐operated controls, bilaterally ovariectomized (Ovx) rats, and Ovx rats with oestrogen replacement (Ovx+E 2 ), which restored the oestrogen concentration to normal. 3 The electrically induced intracellular Ca 2+ transient (E[Ca 2+ ] i ), 45 Ca 2+ ‐uptake through cardiac L‐type Ca 2+ channels (Ca 2+ channels), heart rate and force of contraction in response to β ‐AR stimulation with 10 n M isoprenaline (Iso) in hearts from Ovx rats were significantly greater than those of control and Ovx+E 2 rats. The basal and Iso‐induced PKA activities were also higher in hearts from Ovx rats. KT5720, a selective PKA inhibitor, completely inhibited its potentiating effect on basal Ca 2+ channel activity in the Ovx rat heart. On the other hand, expression of G proteins (G α s and G α i1−3 ), basal and forskolin‐stimulated cAMP accumulation, and responsiveness of PKA to cAMP, were not altered by Ovx. 4 Interestingly, the PKA inhibitor at the same concentration significantly reduced the increases in PKA activity and Ca 2+ channel activity upon β ‐AR stimulation in all three groups of rats and the inhibitions were significantly greater in the Ovx rat than in the other two groups of rats. 5 This study provides the first evidence that, in addition to downregulation of β 1 ‐AR shown previously, suppression of PKA activity, which is partly responsible for the suppressed Ca 2+ channel activity, also determines the E[Ca 2+ ] i and cardiac contractility following β ‐AR stimulation in the female rat.British Journal of Pharmacology (2005) 144 , 972–981. doi: 10.1038/sj.bjp.0706123