Time- and voltage-dependent interaction of antiarrhythmic agents with target cardiac ion channels is termed the modulated receptor hypothesis. Actuaily class I agents suppress the maximum upstroke rate (V
max) of intracellular potential (V
ic) depending on the pacing cycle length (PCL) and external potassium concentration ([K
+]
e). We examined this concept from the aspect of interstitial potential (V
is), since V
is reflects the second time derivative of V
ic. V
ic. and V
is were recorded sequentially using standard microelectrode applied to the paced and superfused guinea pig papillary muscles. In the steady state, the greatest negative deflection of V
is (V
min) was suppressed by qumldine (10 μM) In both PCL and [K
+]
e-dependent manner just like V
max. However, quinidine-induced greater inhibition of V
min than V
max was evident at shorter PCL and greater [K
+]
e. Based on the sequential alteration of PCL and exposure to ouabain (10 μM), different quinidine sensitivity between V
min and V
max is most likely accounted for by the activity-dependent K
+ efflux and Na
+-K
+ pump-mediated K
+ uptake (i. e., [K
+]
e fluctuation). Thus, the modulated receptor hypothesis is concluded to be valid in terms of V
is.
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