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CARDIOVASCULAR

Protein Kinase A-Mediated Phosphorylation Contributes to Enhanced Contraction Observed in Mice That Overexpress -Adrenergic Receptor Kinase-1

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

Transgenic mice with cardiac specific overexpression of -adrenergic receptor kinase-1 (ARK-1) exhibit reduced contractility in the presence of adrenergic stimulation. However, whether contractility is altered in the absence of exogenous agonist is not clear. Effects of ARK-1 overexpression on contraction were examined in mouse ventricular myocytes, studied at 37°C, in the absence of adrenergic stimulation. In myocytes voltage-clamped with microelectrodes (18–26 M; 2.7 M KCl) to minimize intracellular dialysis, contractions were significantly larger in ARK-1 cells than in wild-type myocytes. In contrast, when cells were dialyzed with patch pipette solution (1–3 M; 0 mM NaCl, 70 mM KCl, 70 mM potassium aspartate, 4 mM MgATP, 1 mM MgCl₂, 2.5 mM KH₂PO₄, 0.12 mM CaCl₂, 0.5 mM EGTA, and 10 mM HEPES), the extent of cell shortening was similar in wild-type and ARK-1 myocytes. Furthermore, when cells were dialyzed with solutions that contained phosphodiesterase-sensitive sodium-cAMP (50 µM), the extent of cell shortening was similar in wild-type and ARK-1 myocytes. However, when patch solutions were supplemented with phosphodiesterase-resistant 8-bromo-cAMP (50 µM), contractions were larger in ARK-1 than wild-type cells. This difference was eliminated by the protein kinase A inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89). Interestingly, Ca²⁺ current amplitudes and inactivation rates were similar in ARK-1 and wild-type cells in all experiments. These results suggest components of the adenylyl cyclase-protein kinase A pathway are sensitized by chronically increased ARK-1 activity, which may augment contractile function in the absence of exogenous agonist. Thus, changes in contractile function in myocytes from failing hearts may reflect, in part, effects of chronic up-regulation of ARK-1 on the cAMP-protein kinase A pathway.

Address correspondence to: Dr. Susan Ellen Howlett, Department of Pharmacology, Sir Charles Tupper Medical Bldg., 5850 College St., Halifax, NS B3H 1X5, Canada. E-mail: susan.howlett{at}dal.ca

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