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Alpha 1-adrenergic activation inhibits beta-adrenergic-stimulated unitary Ca2+ currents in cardiac ventricular myocytes

Alpha 1-adrenergic activation inhibits beta-adrenergic-stimulated unitary Ca2+ currents in cardiac ventricular myocytes

Circulation Research 79(2): 184-193

We have previously shown that whole-cell L-type Ca2+ current that was stimulated through beta-adrenergic receptors was negatively modulated by alpha 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 beta-adrenergic stimulation (beta effect), cells were superfused with norepinephrine (10 mumol/L) in the presence of prazosin (10 mumol/L), an alpha 1-adrenergic blocker. beta-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 alpha 1-receptors while maintaining the beta-adrenergic stimulation, cells were superfused with norepinephrine alone (alpha 1 + beta effects). alpha 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. alpha 1-adrenergic activation also inhibited ensemble-averaged currents stimulated by a low concentration (10 mumol/L) of 8-bromo-cAMP but not by (-)Bay K 8644 (1 mumol/L). Calphostin C (1 mumol/L), a specific inhibitor of protein kinase C, attenuated alpha 1-adrenergic inhibition on beta-adrenergic-stimulated unitary currents. We conclude that alpha 1-adrenergic activation exerts an inhibitory effect on beta-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 Ca(2+)-channel activity and the reduction in whole-cell Ca2+ current previously reported. This inhibition is in part mediated through the protein kinase C pathway.

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Accession: 045203760

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PMID: 8755994

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