Role of β₁- and β₂-adrenergic receptors in regulation of Cl^- and Ca²⁺ channels in guinea pig ventricular myocytes

The role of β₁- and β₂-adrenergic receptor stimulation in modulating adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl^- and Ca²⁺ currents was investigated with use of guinea pig ventricular myocytes. Activation of the Cl^- current by the nonselective β-receptor agonist isoproterenol (Iso) was not affected by the β₂-receptor antagonist ICI- 118,551 (ICI), but it was blocked by the β₁-receptor antagonist atenolol. The inability of β₂-receptor stimulation to activate the Cl^- current was confirmed by the lack of response to the selective β₂-receptor agonists salbutamol and zinterol. Responses to β₂-adrenergic receptor stimulation were also looked for in pertussis toxin (PTX)-treated myocytes because PTX increases the sensitivity of responses to Iso, and PTX has been reported to increase the responsiveness to β₂- but not β₁-receptor stimulation. PTX treatment increased the sensitivity of the Cl^- current to activation by Iso in the presence of ICI, indicating that PTX increases β₁-receptor responsiveness. PTX treatment also resulted in the ability of salbutamol to activate the Cl^- current. However, the response to salbutamol was blocked by atenolol but not by appropriate concentrations of ICI, suggesting that salbutamol was activating β₁-receptors. These results indicate that PTX treatment increases the sensitivity to β₁-receptor stimulation, without affecting β₂-responsiveness. To verify that the lack of response to β₂- receptor stimulation was not unique to the Cl^-current, the effects of β₂- receptor agonists on the L-type Ca²⁺ current were also examined. The Ca²⁺ current was only affected by high concentrations of zinterol or salbutamol, and such responses were blocked by atenolol, but not by ICI, suggesting that activation of β₁-receptors was involved. These results indicate that β₁- but not β₂-adrenergic receptor stimulation plays an important role in modulating the cAMP-regulated Cl^- and Ca²⁺ currents in guinea pig ventricular myocytes.