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Reduction of catecholamine-induced cardiovascular malformations in the chick embryo with metoprolol
Insights
Sympathomimetic amines, including dopamine, cause cardiovascular malformations in embryonic chicks by stimulating beta 1-adrenergic receptors. A beta 1-blocker significantly reduced these defects, confirming the receptor
Area of Science:
- Developmental biology
- Cardiovascular research
- Pharmacology
Background:
- Beta 1-adrenergic receptor activation is linked to cardiovascular malformations in embryonic chicks.
- Adrenergic receptors are functional in early embryonic chick hearts.
Purpose of the Study:
- To investigate the effects of four sympathomimetic cardioactive amines on chick cardiovascular morphogenesis.
- To specifically examine dopamine's teratogenicity.
- To determine if beta 1-adrenergic receptor blockade can prevent these malformations.
Main Methods:
- Exposure of Hamburger and Hamilton stage 24 chick embryos to dopamine, isoproterenol, epinephrine, and norepinephrine.
- Administration of a selective beta 1-adrenergic antagonist, metoprolol tartrate, as a pretreatment.
- Assessment of aortic arch anomalies and ventricular septal defects (VSD).
Main Results:
- All tested amines, in decreasing order of teratogenic potency (dopamine > isoproterenol > epinephrine > norepinephrine), induced aortic arch anomalies and VSD.
- Dopamine demonstrated the highest teratogenic potency.
- Metoprolol tartrate pretreatment significantly decreased the incidence of malformations in amine-treated groups.
Conclusions:
- Dopamine and other sympathomimetic amines are potent teratogens causing cardiovascular malformations in embryonic chicks.
- These malformations are primarily mediated through the stimulation of beta 1-adrenoreceptors.
- Selective beta 1-adrenergic blockade can prevent drug-induced cardiovascular teratogenicity.
Abstract:
It has been documented that activation of the beta 1-adrenergic receptor mechanism is directly related to cardiovascular malformations associated with the heart and great vessels of the embryonic chick. These adrenergic receptors are believed to be present and functional in the innervated and noninnervated embryonic heart at early stages of development. The present study examined the effects of four sympathomimetic cardioactive amines on chick cardiovascular morphogenesis at Hamburger and Hamilton stage 24. Special attention was directed toward understanding dopamine teratogenicity. In order of decreasing potency at the maximum teratogenic dose (dopamine greater than isoproterenol greater than epinephrine greater than norepinephrine) each drug was found capable of producing aortic arch anomalies of the third, fourth, and sixth aortic arches and ventricular septal defects (VSD). A new specific beta 1-adrenergic antagonist, metoprolol tartrate, was employed in an attempt to lower the incidence of these cardiovascular malformations. Pretreatment with this selective beta 1-blocker profoundly reduced the incidence of malformations within any amine-treated group. These experiments demonstrate that dopamine, as well as the other sympathomimetic amines, is a potent teratogen and most likely produces these cardiovascular malformations by primarily stimulating the beta 1-adrenoreceptor in the embryonic chick.