The thromboxane A₂ mimetic U-46619 inhibits somatomotor activity via a vagal reflex from the lung

Abstract

Vagal reflexes from the heart and lungs elicit autonomic as well as somatomotor responses. The purpose of the present investigation was to determine whether the inflammatory mediator thromboxane A2 inhibits the knee-jerk reflex via a vagally mediated reflex from either the heart or the lung. The thromboxane A2 mimetic U-46619 (0.8 ± 0.08 μg/kg) was injected through a catheter placed near the right atrium ( n = 11), near the aortic arch ( n = 7), or into the pericardial sac ( n = 4) in 11 chloralose-anesthetized cats. The knee-jerk reflex, elicited by striking the patellar tendon with a solenoid-driven hammer, was used to evaluate somatomotor activity. The mean maximum tension produced by the knee-jerk reflex was 306 ± 21 g (range 154–471 g). Intravenous U-46619 injection inhibited the knee-jerk reflex by 25 ± 6% and increased peak systolic pressure 53 ± 7 mmHg on average. Bilateral cervical vagotomy abolished the somatomotor inhibition but did not reduce the pressor response. Intra-arterial U-46619 injection inhibited the knee-jerk reflex in two of seven cats and increased peak systolic pressure by 41 ± 11 mmHg. Vagotomy abolished the inhibition in one of the two cats but did not reduce the pressor response. Intrapericardial U-46619 injection did not affect the knee-jerk reflex nor blood pressure. The results indicate that U-46619 inhibited the knee-jerk reflex via a vagal reflex from the lung because the inhibition predominated after intravenous injection and was abolished by vagotomy. Speculation is made that the inflammatory mediator thromboxane A2 may contribute via a vagal reflex to the depression of motor activity associated with sickness behavior.

Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A2?

“…Our observation that intrapericardial application of U-46619 evokes sympathoexcitatory reflex responses, including increases in arterial pressure and RSNA in sinoaortic denervated and vagotomized animal, contrasts with the results of earlier studies (41,53), which have suggested that intrapericardial U-46619 does not alter peak systolic BP of anesthetized cats, either before or after vagotomy. Although the discrepancies between these earlier studies and our current observation are unclear, it is possible that baroreflex activation may have limited the excitatory cardiovascular response to epicardial U-46619, since these previous investigations did not perform sinoaortic denervation.…”

“…For example, exogenous TxA 2 stimulates hindlimb group III and IV afferent nerves (25). Also, the TxA 2 mimetic U-46619 inhibits the knee-jerk reflex through a vagal pathway originating in the lung (41). U-46619 also evokes tachypnea and a depressor reflex response, including bradycardia and hypotension through stimulation of the vagus nerve (7,41,53).…”

“…Also, the TxA 2 mimetic U-46619 inhibits the knee-jerk reflex through a vagal pathway originating in the lung (41). U-46619 also evokes tachypnea and a depressor reflex response, including bradycardia and hypotension through stimulation of the vagus nerve (7,41,53). In addition, infusion of U-46619 into the inferior vena cava of cats causes vagally mediated, rapid, shallow breathing and airway hyperresponsiveness (1,24,42).…”

Mechanisms of Cancer-Related Fatigue

“…The earliest report of such an effect was by Schweitzer and Wright [109], who showed that electrical stimulation of the central terminus of the vagal nerve in cats was associated with a reduction in the knee-jerk reflex. Subsequent animal studies showed that activation of vagal afferent nerves to the lungs or to the abdomen caused reflex inhibition of somatomotor activity, including reflex activation of skeletal muscles and exerciseinduced electromyogram activity [110][111][112][113][114][115][116]. Other studies have shown that a variety of substances, such as 5-HT, cytokines, and prostaglandins, can stimulate vagal afferent nerves [117][118][119][120].…”

Fatigue associated with cancer and its treatment

“…More recently, activation of vagal afferents by a 5-hydroxytryptamine 3 (5HT3) receptor agonist reduced steady state exercise-induced EMG activity in conscious rats [32]. Intravenous injection of a thromboxane A2 receptor agonist can inhibit the knee-jerk reflex in anesthetized cats [100]. Other studies in the rat have shown that activation of abdominal vagal afferents reduced reflex activation of skeletal muscles [67].…”