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Specific alpha 1-adrenergic receptor subtypes modulate catecholamine-induced increases and decreases in ventricular
U del Balzo1, M R Rosen, G Malfatto
1Department of Pharmacology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
Circulation Research
|December 1, 1990
Summary
Norepinephrine affects canine Purkinje fiber automaticity differently in adults and neonates, mediated by distinct alpha 1-adrenergic receptor subtypes. Chloroethylclonidine and WB 4101 selectively block these effects, revealing age-dependent functional expression.
Area of Science:
- Cardiovascular Physiology
- Adrenergic Receptor Pharmacology
- Cardiac Electrophysiology
Background:
- Norepinephrine (NE) exhibits differential effects on adult and neonatal canine Purkinje fiber automaticity.
- Adult Purkinje fibers show a mixed response to NE, with 50% increasing and 50% decreasing automaticity.
- Neonatal Purkinje fibers predominantly show increased automaticity in response to NE.
Purpose of the Study:
- To investigate the specific alpha 1-adrenergic receptor subtypes mediating NE's effects on cardiac automaticity.
- To elucidate the age-dependent functional expression of these receptor subtypes in canine cardiac tissue.
- To characterize the signaling pathways linked to distinct alpha 1-adrenergic receptor subtypes.
Main Methods:
- Selective alpha 1-adrenergic antagonists, chloroethylclonidine (CEC) and WB 4101, were used to modulate NE effects.
- Experiments involved Purkinje fibers from adult and neonatal dogs, including those treated with pertussis toxin.
- Radioligand binding assays ([125I]IBE2254) and inositol phosphate accumulation assays were performed on cardiac membranes and cultured myocytes.
Main Results:
- CEC antagonized the NE-induced decrease in automaticity, revealing NE-induced increases in both age groups.
- WB 4101 selectively antagonized the NE-induced increase in automaticity, unmasking a decrease in adult fibers.
- CEC-sensitive receptors are linked to decreased automaticity via a pertussis toxin-sensitive pathway, while WB 4101-sensitive receptors are linked to increased automaticity.
Conclusions:
- At least two distinct alpha 1-adrenergic receptor subtypes exist in neonatal and adult cardiac tissue.
- The CEC-sensitive subtype mediates decreased automaticity, while the WB 4101-sensitive subtype mediates increased automaticity.
- Neonatal cardiac tissue primarily expresses the WB 4101-sensitive subtype functionally for ventricular automaticity effects.