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(Circulation Research. 1999;84:1032-1042.)
© 1999 American Heart Association, Inc.

Original Contributions

Local Ca²⁺ Entry Through L-Type Ca²⁺ Channels Activates Ca²⁺-Dependent K⁺ Channels in Rabbit Coronary Myocytes

Antonio Guia, Xiaodong Wan, Marc Courtemanche, Normand Leblanc

From the Research Center, Montreal Heart Institute, Montréal, Québec, Canada.

Correspondence to Normand Leblanc, Research Center, Montreal Heart Institute, 5000 Bélanger St E, Montréal, Québec, Canada H1T 1C8. E-mail leblancn{at}alize.ere.umontreal.ca

Abstract—Large-conductance Ca²⁺-dependent K⁺ channels (K_Ca), which are abundant on the sarcolemma of vascular myocytes, provide negative feedback via membrane hyperpolarization that limits Ca²⁺ entry through L-type Ca²⁺ channels (I_CaL). We hypothesize that local accumulation of subsarcolemmal Ca²⁺ during I_CaL openings amplifies this feedback. Our goal was to demonstrate that Ca²⁺ entry through voltage-gated I_CaL channels can stimulate adjacent K_Ca channels by a localized interaction in enzymatically isolated rabbit coronary arterial myocytes voltage clamped in whole-cell or in cell-attached patch clamp mode. During slow-voltage-ramp protocols, we identified an outward K_Ca current that is activated by a subsarcolemmal Ca²⁺ pool dissociated from bulk cytosolic Ca²⁺ pool (measured with indo 1) and is dependent on L-type Ca²⁺ channel activity. Transient activation of unitary K_Ca channels in cell-attached patches could be detected during long step depolarizations to +40 mV (holding potential, -40 mV; 219 pS in near-symmetrical K⁺). This local interaction between the channels required the presence of Ca²⁺ in the pipette solution, was enhanced by the I_CaL agonist Bay K 8644, and persisted after impairment of the sarcoplasmic reticulum by incubation with 10 µmol/L ryanodine and 30 µmol/L cyclopiazonic acid for at least 60 minutes. Furthermore, we provide the first direct evidence of simultaneous openings of single K_Ca (67 pS) and I_CaL (3.9 pS) channels in near-physiological conditions, near resting membrane potential. Our data imply a novel sensitive mechanism for regulating resting membrane potential and tone in vascular smooth muscle.

Key Words: local channel regulation • subsarcolemmal Ca²⁺ • vascular smooth muscle • feedback regulation • indo 1 fluorescence

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