RESPONSES TO NOREPINEPHRINE OF NORMAL AND ISCHEMIC CANINE PURKINJE-FIBERS ARE CONSISTENT WITH ACTIVATION OF DIFFERENT ALPHA(1)-RECEPTOR SUBTYPES

Introduction: Previously we found that WB4101 (WB) 10(-7) M competitiv ely blocks three alpha(1)-adrenergic receptor-effector responses: the increase in normal automaticity occurring in Purkinje fibers (PF) at h igh membrane potentials; the increase in abnormal automaticity occurri ng in PF at depolarized membrane potentials; and the prolongation of P F action potential duration, These observations are consistent with tw o different hypotheses: (1) WB blocks a single alpha(1)-receptor subty pe, which subserves different effector pathways; and (2) WB blocks dif ferent receptor subtypes, each of which subserves an independent pathw ay, The aim of this study was to test both hypotheses. Methods and Res ults: We used standard microelectrode techniques to study the concentr ation-dependent actions of three alpha(1)-adrenoreceptor blockers (WB [alpha(1A) greater than or equal to alpha(10)], 5-methylurapidil [5-MU ] [alpha(1A) much greater than alpha(1D)], and UK52,046 [nonselective] ) on norepinephrine (NE) effects in normal PF and in PF depolarized wi th a simulated ischemic solution ([K+](o) = 10 mM; pO(2) < 20 mmHg; pH 6.8; maximum diastolic potential -60 +/- 1 mV. In normally polarized PF, concentration-dependent actions of all blockers on both the positi ve chronotropic response and the prolongation of action potential dura tion completely coincide. In contrast, the response to NE of abnormal automaticity in ''ischemic'' PF differs from normals: there is a high sensitivity to WB and 5-MU and no response to UK52,046. Conclusions: ( 1) A single receptor subtype appears responsible for both the alpha(1) -induced prolongation of repolarization and the positive chronotropic effect in normal PF. (2) Two different receptor subtypes may be respon sible for the alpha(1)-induced effects an automaticity in normal and i schemic fibers, It is likely that the latter one is alpha(1A), and tha t consideration of antiarrhythmic therapy with alpha(1)-adrenergic blo ckers should focus on this subtype as a potential target.