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(Circulation Research. 1995;77:565-574.)
© 1995 American Heart Association, Inc.

Articles

ß-Adrenergic Stimulation Induces Acetylcholine to Activate ATP-Sensitive K⁺ Current in Cat Atrial Myocytes

Presented in part in abstract form (Biophys J. 1995;68:12).

Yong Gao Wang, Stephen L. Lipsius

From the Department of Physiology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Ill.

Correspondence to Stephen L. Lipsius, PhD, Department of Physiology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153.

Abstract Our previous work on atrial myocytes suggested that the effect of acetylcholine (ACh) to increase K⁺ conductance can be potentiated by prior loading of the sarcoplasmic reticulum (SR) with Ca²⁺. The present study, therefore, sought to determine whether prior exposure to isoproterenol (ISO) potentiates ACh-induced increases in K⁺ conductance and the underlying mechanisms. A nystatin–perforated patch whole-cell configuration was used to record from cat atrial myocytes. Voltage-clamp ramps (40 mV/s) were used to assess total membrane conductance. The experimental protocol consisted of two consecutive 30-second ACh exposures (ACh₁ and ACh₂) separated by a 6-minute recovery period in ACh-free solution. In general, experimental interventions, such as exposure to ISO, were imposed during the period between ACh₁ and ACh₂ to determine their effects on the response to ACh₂ in relation to ACh₁. Under control conditions, K⁺ conductances induced by ACh₁ and ACh₂ were not different from one another with or without activation of L-type Ca²⁺ current (I_Ca,L) during the recovery period. When 1 µmol/L ISO plus I_Ca,L activation was imposed during the recovery period, ACh₂ induced a significantly larger increase in K⁺ conductance than ACh₁. The ACh₂-induced K⁺ current potentiated by ISO was time independent and selectively blocked by 10 µmol/L glibenclamide and therefore identified as ATP-sensitive K⁺ current (I_K,ATP). The effect of ISO to induce ACh₂-activated I_K,ATP was mimicked by 1 µmol/L forskolin or 200 µmol/L 8-(4-chlorophenylthio)-cAMP, but not by 0.5 µmol/L BAY K 8644, and was selectively abolished by (1) 5 µmol/L thapsigargin or 1 µmol/L ryanodine, agents that prevent accumulation of SR Ca²⁺, (2) inhibition of L-type Ca²⁺ current (I_Ca,L) by 1 µmol/L nisoldipine or zero external Ca²⁺, (3) 50 µmol/L Rp-cAMPs, an inhibitor of cAMP-dependent protein kinase A, or (4) 2 µmol/L propranolol. Atropine (1 µmol/L) abolished all ACh-induced currents. Moreover, ACh₂-activated I_K,ATP was selectively blocked by 0.2 µmol/L pirenzepine, an M₁ muscarinic receptor antagonist, or 0.1 µmol/L calphostin C, a selective inhibitor of protein kinase C. AFDX116 (100 µmol/L), an M₂ muscarinic receptor antagonist, blocked the conventional ACh-activated K⁺ current and revealed ACh₂-activated I_K,ATP. These results indicate that prior exposure to ISO potentiates ACh-induced increases in K⁺ current via ACh-activated I_K,ATP. ISO acts via ß-adrenergic receptors and cAMP to enhance both Ca²⁺ influx via I_Ca,L and SR Ca²⁺ uptake. By loading SR Ca²⁺, ISO facilitates ACh-induced stimulation of the M₁ receptor/phosphoinositol signaling pathway to activate I_K,ATP. These findings suggest that prior ß-adrenergic stimulation accentuates subsequent cholinergic inhibition of atrial function via ACh-induced activation of ATP-sensitive K⁺ channels.

Key Words: perforated patch • muscarinic receptors • cAMP • forskolin • phosphoinositol • calcium

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