Responses to norepinephrine of normal and "ischemic" canine Purkinje fibers are consistent with activation of different alpha 1-receptor subtypes.
BACKGROUND
Previously we found that WB4101 (WB) 10(-7) M competitively blocks three alpha 1-adrenergic receptor-effector responses: the increase in normal automaticity occurring in Purkinje fibers (PF) at high membrane potentials; the increase in abnormal automaticity occurring in PF at depolarized membrane potentials; and the prolongation of PF action potential duration. These observations are consistent with two different hypotheses: (1) WB blocks a single alpha 1-receptor subtype, which subserves different effector pathways; and (2) WB blocks different receptor subtypes, each of which subserves an independent pathway. The aim of this study was to test both hypotheses.


RESULTS
We used standard microelectrode techniques to study the concentration-dependent actions of three alpha 1-adrenoreceptor blockers (WB [alpha 1A > or = alpha 1D], 5-methylurapidil [5-MU] [alpha 1A > > alpha 1D], and UK52,046 [nonselective]) or norepinephrine (NE) effects in normal PF and in PF depolarized with a simulated ischemic solution ([K+]o = 10 mM; pO2 < 20 mmHg; pH 6.8; maximum diastolic potential -60 +/- 1 mV). In normally polarized PF, concentration-dependent actions of all blockers on both the positive chronotropic response and the prolongation of action potential duration 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 responsible for the alpha 1-induced effects on automaticity in normal and ischemic fibers. It is likely that the latter one is alpha 1A, and that consideration of antiarrhythmic therapy with alpha 1-adrenergic blockers should focus on this subtype as a potential target.
Anyukhovsky
E P
EP
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Guo
S D
SD
Danilo
P
P
Rosen
M R
MR
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D066298:In Vitro Techniques; D008839:Microelectrodes; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*; D044005:Tetrahydroisoquinolines
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000634:Aminoquinolines; D004146:Dioxanes; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D044005:Tetrahydroisoquinolines; C057446:5-methylurapidil; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C058534:abanoquil; D009638:Norepinephrine