Intra-arterial injection of the TxA2-R antagonist daltroban reduced the peak mean arterial pressure response to muscle contraction in HF-rEF rats (from 22 ± 3 to 14 ± 2 mmHg; p=0.01).
Does the TxA2-R antagonist daltroban reduce the exaggerated exercise pressor reflex in a rat model of HF-rEF?
Thromboxane A2 receptors on thin fiber muscle afferents contribute to the exaggerated exercise pressor reflex in HF-rEF, suggesting a potential mechanism for reduced exercise capacity.
Absolute Event Rate: 14% vs 22%
p-value: p=0.01
Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fiber muscle afferents and produce reflex increases in sympathetic nerve activity and blood pressure during exercise (i.e., the exercise pressor reflex; EPR). The EPR is exaggerated in patients and animals with heart failure with reduced ejection fraction (HF-rEF) and its activation contributes to reduced exercise capacity within this patient population. Accumulating evidence suggests that the exaggerated EPR in HF-rEF is partially attributable to a sensitization of mechanically activated channels produced by thromboxane A2 receptors (TxA2-Rs) on those sensory endings; however, this has not been investigated. Accordingly, the purpose of this investigation was to determine the role played by TxA2-Rs on the sensory endings of thin fiber muscle afferents in the exaggerated EPR in rats with HF-rEF induced by coronary artery ligation. In decerebrate, unanesthetized rats, we found that injection of the TxA2-R antagonist daltroban (80 μg) into the arterial supply of the hindlimb reduced the pressor response to 30 s of electrically induced 1 Hz dynamic hindlimb muscle contraction in HF-rEF (n = 8, peak ∆MAP pre: 22 ± 3; post: 14 ± 2 mmHg; p = 0.01) but not sham (n = 10, peak ∆MAP pre: 13 ± 3; post: 11 ± 2 mmHg; p = 0.68) rats. In a separate group of HF-rEF rats (n = 4), we found that the systemic (intravenous) injection of daltroban had no effect on the EPR (peak ΔMAP pre: 26 ± 7; post: 25 ± 7 mmHg; p = 0.50). Our data suggest that TxA2-Rs on thin fiber muscle afferents contribute to the exaggerated EPR evoked in response to dynamic muscle contraction in HF-rEF.
Butenas et al. (2021) studied Heart failure with reduced ejection fraction (HF-rEF) (n=22). Daltroban vs. Pre-injection baseline and sham rats was evaluated on Peak ∆MAP (pressor response) to 30 s of electrically induced 1 Hz dynamic hindlimb muscle contraction (p=0.01). Intra-arterial injection of the TxA2-R antagonist daltroban reduced the peak mean arterial pressure response to muscle contraction in HF-rEF rats (from 22 ± 3 to 14 ± 2 mmHg; p=0.01).