Specific alpha 1-adrenergic receptor subtypes modulate catecholamine-induced increases and decreases in ventricular automaticity.
Fifty percent of adult canine Purkinje fibers manifest a decrease in automaticity in response to alpha 1-adrenergic stimulation with 10(-10)-10(-8) M norepinephrine (NE), and 50% manifest an increase. In contrast, most neonatal Purkinje fibers show an increase in automaticity in response to these concentrations of NE. We studied the modulation of NE effects, using the subtype selective alpha 1-adrenergic antagonists chloroethylclonidine (CEC) and WB 4101. CEC selectively antagonized the decrease in automatically such that, in both age groups, all Purkinje fibers showed NE-induced increases in automaticity. In Purkinje fibers from dogs treated with pertussis toxin, NE no longer induced a CEC-sensitive decrease in automaticity. In contrast, WB 4101 selectively antagonized the NE-induced increase in automaticity in both age groups. In the presence of WB 4101, NE decreased automaticity uniformly in adult Purkinje fibers and tended to induce no change in automaticity in neonatal Purkinje fibers. In the presence of prazosin (10(-6) M) or combined CEC (10(-7) M) and WB 4101 (10(-7) M), no alpha-agonist-induced increase or decrease in rate was observed. Pretreatment of membranes from newborn and adult dog and rat ventricles with CEC resulted in a selective and irreversible inactivation of 25% of specific binding sites labeled with [125I]IBE2254. In cultured neonatal rat ventricular myocytes, exposure to CEC resulted in a 35% decrease in the density of specific binding sites labeled with [125I]IBE2254 but did not influence alpha-adrenergic stimulation of inositol phosphate accumulation. In contrast, WB 4101 inactivated NE-stimulated inositol phosphate accumulation. Our results suggest that 1) at least two distinct alpha 1-adrenergic receptor subtypes are present in neonatal and adult cardiac tissue, 2) the CEC-sensitive subtype is linked to a decrease in automaticity via a pertussis toxin-sensitive substrate, 3) the WB 4101-sensitive subtype is linked to an increase in automaticity (possibly via a mechanism related to phosphoinositide breakdown), and 4) although CEC- and WB 4101-sensitive alpha 1-adrenergic receptor subtypes are present in the neonate, only the WB 4101-sensitive subtype is expressed functionally to induce effects on ventricular automaticity.
del Balzo
U
U
Department of Pharmacology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
Rosen
M R
MR
Malfatto
G
G
Kaplan
L M
LM
Steinberg
S F
SF
D000367:Age Factors; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013268:Stimulation, Chemical; D016276:Ventricular Function
D004146:Dioxanes; D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D009638:Norepinephrine