January 1, 1995Journal of Cardiovascular Pharmacology
Are There Different ETB Receptors Mediating Constriction and Relaxation?
Key result
In rat tracheal rings, blockade of ETB receptors is insufficient to inhibit ET-1-mediated responses due to cross-talk allowing ETA receptors to compensate, suggesting a common ETB receptor subtype.
Population
Rat tracheal rings denuded of epithelium
Design
Preclinical
Authors
Discussion
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Member takes
Implication
ETA compensation may blunt ETB-selective blockade in airways; leaves open dual antagonism strategies for human vascular disease.
Key Points
- To determine whether distinct ETB receptor subtypes mediate constriction versus relaxation by evaluating the functional antagonism of ETB-mediated constriction in rat airway smooth muscle.
- Evaluated contractile responses to endothelin-1 (ET-1) and sarafotoxin S6c in epithelium-denuded rat tracheal rings.
- Assessed functional antagonism using the selective ETB antagonist Ro 46-8443 in the absence or presence of the ETA receptor antagonist BQ-123 (10⁻⁵ M).
- Investigated receptor desensitization effects by preincubating tracheal tissue with sarafotoxin S6c with or without ETA receptor blockade.
- Ro 46-8443 selectively antagonized sarafotoxin S6c contractions but failed to shift the ET-1 concentration-response curve in the absence of ETA blockade.
- Preincubation with BQ-123 unmasked an inhibitory effect of Ro 46-8443 against ET-1-induced contractions.
- Sarafotoxin S6c desensitization reduced ET-1 contractile responses only when tissues were concurrently exposed to BQ-123, confirming ETA and ETB cross-talk.
Structured PICO
P
Population
Rat tracheal rings denuded of epithelium
I
Intervention
Selective ETB receptor antagonist (Ro 46-8443) and/or ETA receptor antagonist (BQ-123) with ET-1 or sarafotoxin S6c
O
Outcome
Contractile responses to ET-1 and sarafotoxin S6csurrogate
Endothelial ETB receptors mediating dilatation and smooth muscle cell ETB receptors mediating constriction likely represent a common receptor subtype, with ETA receptors compensating when ETB is blocked.
Cite This Study
Clozel et al. (1995) studied this question. Ro 46-8443 and BQ-123 was evaluated on Contractions induced by ET-1 and sarafotoxin S6c. In rat tracheal rings, blockade of ETB receptors is insufficient to inhibit ET-1-mediated responses due to cross-talk allowing ETA receptors to compensate, suggesting a common ETB receptor subtype.