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(Circulation Research. 1996;79:184-193.)
© 1996 American Heart Association, Inc.

Articles

₁-Adrenergic Activation Inhibits ß-Adrenergic–Stimulated Unitary Ca²⁺ Currents in Cardiac Ventricular Myocytes

Long Chen, Nabil El-Sherif, Mohamed Boutjdir

the Cardiology Division, Department of Medicine, Veterans Administration Medical Center and State University of New York, Health Science Center, Brooklyn.

Correspondence to Dr Mohamed Boutjdir, Cardiology Division (IIIA), VA Medical Center, 800 Poly Place, Brooklyn, NY 11209. E-mail boutjdir.mohamed@brooklyn.va.gov.

We have previously shown that whole-cell L-type Ca²⁺ current that was stimulated through ß-adrenergic receptors was negatively modulated by ₁-adrenergic activation. In the present study, we investigated the kinetic basis of this modulation at the single-channel level in adult rat ventricular myocytes using Ba²⁺ as the charge carrier. Unitary current sweeps were evoked by 300-ms depolarizing pulses to 0 mV, from a holding potential of -50 mV at 0.5 Hz. During control conditions, the ensemble-averaged current amplitude was 0.18±0.01 pA (n=7). To achieve ß-adrenergic stimulation (ß effect), cells were superfused with norepinephrine (10 µmol/L) in the presence of prazosin (10 µmol/L), an ₁-adrenergic blocker. ß-Adrenergic stimulation enhanced ensemble-averaged current (from 0.18±0.01 to 0.75±0.04 pA, P<.05, n=7), increased the open-time constants, and decreased the closed-time constants. To activate ₁-receptors while maintaining the ß-adrenergic stimulation, cells were superfused with norepinephrine alone (₁+ß effects). ₁-Adrenergic activation reduced ensemble-averaged current (from 0.75±0.04 to 0.41±0.03 pA, P<.05, n=7), decreased open-time constants, and increased closed-time constants. ₁-Adrenergic activation also inhibited ensemble-averaged currents stimulated by a low concentration (10 µmol/L) of 8-bromo-cAMP but not by (-)Bay K 8644 (1 µmol/L). Calphostin C (1 µmol/L), a specific inhibitor of protein kinase C, attenuated ₁-adrenergic inhibition on ß-adrenergic–stimulated unitary currents. We conclude that ₁-adrenergic activation exerts an inhibitory effect on ß-adrenergic–stimulated unitary Ba²⁺ current at the single-channel level. The shortening of the open-time and the lengthening of the closed-time constants and the increase in blank sweeps may explain the inhibition of the Ca²⁺-channel activity and the reduction in whole-cell Ca²⁺ current previously reported. This inhibition is in part mediated through the protein kinase C pathway.

Key Words: receptor • norepinephrine • phosphorylation • prazosin • protein kinase C

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