Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion

Leal, Anna K.; McCord, Jennifer L.; Tsuchimochi, Hirotsugu; Kaufman, Marc P.

doi:10.1152/ajpheart.00403.2011

Cited by 27 publications

(54 citation statements)

References 47 publications

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“…Pharmacological blockade of thromboxane receptors in the hindlimb of decerebrated rats does not affect the HR increase in response to passive hindlimb stretch (29). This is similar to our finding in older healthy humans, as well as young healthy humans (10), that low-dose aspirin did not affect the HR increase in response to passive calf muscle stretch (Fig.…”

Section: Discussionsupporting

confidence: 89%

Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation

Drew

Blaha

Herr

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Drew RC, Blaha CA, Herr MD, Stocker SD, Sinoway LI. Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation. Am J Physiol Heart Circ Physiol 309: H1361-H1369, 2015. First published September 14, 2015 doi:10.1152/ajpheart.00444.2015.-Low-dose aspirin inhibits thromboxane production and augments the sensitivity of carotid baroreflex (CBR) control of heart rate (HR) during concurrent muscle mechanoreflex and metaboreflex activation in healthy young humans. However, it is unknown how aging affects this response. Therefore, the effect of low-dose aspirin on carotid-cardiac baroreflex sensitivity during muscle mechanoreflex with and without metaboreflex activation in healthy older humans was examined. Twelve older subjects (6 men and 6 women, mean age: 62 Ϯ 1 yr) performed two trials during two visits preceded by 7 days of low-dose aspirin (81 mg) or placebo. One trial involved 3 min of passive calf stretch (mechanoreflex) during 7.5 min of limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise (mechanoreflex and metaboreflex). HR (ECG) and mean arterial blood pressure (MAP; Finometer) were recorded. CBR function was assessed using rapid neck pressure application (ϩ40 to Ϫ80 mmHg). Aspirin significantly decreased baseline thromboxane B 2 production by 83 Ϯ 4% (P Ͻ 0.05) but did not affect 6-keto-PGF1␣. After aspirin, CBR-HR maximal gain and operating point gain were significantly higher during stretch with metabolite accumulation compared with placebo (maximal gain: Ϫ0.23 Ϯ 0.03 vs. Ϫ0.14 Ϯ 0.02 and operating point gain: Ϫ0.11 Ϯ 0.03 vs. Ϫ0.04 Ϯ 0.01 beats·min Ϫ1 ·mmHg Ϫ1 for aspirin and placebo, respectively, P Ͻ 0.05). In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in healthy older humans. This increased sensitivity appears linked to reduced thromboxane sensitization of muscle mechanoreceptors, which consequently improves CBR-HR control.age; aspirin; baroreflex; mechanoreflex; thromboxane NEW & NOTEWORTHYWe demonstrate that low-dose aspirin, which decreases the production of thromboxane B 2, augments the sensitivity of carotid baroreflex control of heart rate during concurrent muscle mechanoreflex and metaboreflex activation in healthy older humans. This finding furthers our understanding of how low-dose aspirin can affect cardiovascular control in humans.HEALTHY AGING is associated with impaired baroreflex control of heart rate (HR) in humans (11,14,18,31,34). Decreased cardiac vagal activity with increasing age is one of the possible mediators of the age-related decline in baroreflex control of HR (43). Some studies have examined the effect of healthy aging on baroreflex function during exercise, a time when blood pressure (BP) and HR are both increased. The maximal gain (G MAX ) and operating point (OP) gains (G OP )/sensitivities of ...

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Section: Discussionsupporting

confidence: 89%

Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation

Drew

Blaha

Herr

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Pharmacological blockade of those receptors was found to reduce the pressor response during static stretch in ligated rats (29,57). Whether those findings have implications for our present investigation that utilized dynamic stretch is unclear, however, because femoral artery ligation has been found to augment the pressor response during static stretch in some studies (29,30,35,56, 57) but not in others (24,25,43,(52)(53)(54). In the present investigation, the pressor response during static stretch was not different between freely perfused and ligated hindlimbs.…”

Section: Chapter 4 -Discussionmentioning

confidence: 81%

Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

Kempf

Rollins

Hopkins

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease (PAD) in which a femoral artery is chronically (~72 hours) ligated, the mechanically-sensitive component of the exercise pressor reflex during 1 Hz dynamic contraction is exaggerated compared to that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats we tested the hypothesis that the increases in mean arterial blood pressure (MAP) and renal sympathetic nerve activity (RSNA) during 1 Hz dynamic stretch are larger when evoked from a previously "ligated" hindlimb compared to those evoked from the contralateral "freely perfused" hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that replicated closely the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in MAP (freely perfused: 14±1, ligated: 23±3 mmHg, p=0.02) and RSNA were significantly greater during dynamic stretch of the ligated hindlimb compared to the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically-sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated PAD involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization.iv

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“…In particular, 72 h of femoral artery ligation elicited a higher BP response to static contraction compared with control conditions (i.e., freely perfused femoral artery), and this augmented pressor response was attenuated by daltroban, a thromboxane receptor antagonist (18). In another study, Yamauchi and colleagues (41) showed that 72 h of femoral artery ligation increased endoperoxidade 4 receptor (a receptor for PGE 2 ) protein in the dorsal root ganglia; blockade of these receptors lowered the exercise pressor reflex.…”

Section: Discussionmentioning

confidence: 90%

“…Despite this heightened cardiovascular risk during exercise in PAD, there have been very few studies evaluating the mechanisms of exercise BP regulation in PAD and/or therapies to mitigate the pressor response. Because acute limb ischemia raises thromboxane B 2 (i.e., a stable product of arachidonic acid metabolism) (22) and because animal models of PAD have suggested that the group III component of the exercise pressor reflex (predominantly muscle mechanoreceptors) is augmented in this disease (18,39), we chose to evaluate the cyclooxygenase-prostanoid pathway during mild, lower limb exercise in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…The 30-mg dose was chosen because it is effective at reducing postoperative pain (1). We suspected that stimulation of muscle afferents would occur at lower prostanoid levels compared with pain (18,39). A 30-min waiting period occurred after injection to ensure the drug was sufficiently active in the blood (26), and a blood sample was then obtained for the measurement of thromboxane B 2 (stable marker of thromboxane A2) and 6-keto-PGF1␣ (stable marker of prostacyclin, Penn State Core Endocrine Laboratory).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease

Müller

Drew

Ross

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Muller MD, Drew RC, Ross AJ, Blaha CA, Cauffman AE, Kaufman MP, Sinoway LI. Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. Am J Physiol Heart Circ Physiol 309: H523-H528, 2015. First published June 8, 2015 doi:10.1152/ajpheart.00267.2015.-Prostanoids are produced during skeletal muscle contraction and subsequently stimulate muscle afferent nerves, thereby contributing to the exercise pressor reflex. Humans with peripheral arterial disease (PAD) have an augmented exercise pressor reflex, but the metabolite(s) responsible for this augmented response is not known. We tested the hypothesis that intravenous injection of ketorolac, which blocks the activity of cyclooxygenase, would attenuate the rise in mean arterial blood pressure (MAP) and heart rate (HR) evoked by plantar flexion exercise. Seven PAD patients underwent 4 min of single-leg dynamic plantar flexion (30 contractions/min) in the supine posture (workload: 0.5-2.0 kg). MAP and HR were measured on a beat-by-beat basis; changes from baseline in response to exercise were determined. Ketorolac did not affect MAP or HR at rest. During the first 20 s of exercise with the most symptomatic leg, ⌬MAP was significantly attenuated by ketorolac (2 Ϯ 2 mmHg) compared with control (8 Ϯ 2 mmHg, P ϭ 0.005), but ⌬HR was similar (6 Ϯ 2 vs. 5 Ϯ 1 beats/min). Importantly, patients rated the exercise bout as "very light" to "fairly light," and average pain ratings were 1 of 10. Ketorolac had no effect on perceived exertion or pain ratings. Ketorolac also had no effect on MAP or HR in seven age-and sex-matched healthy subjects who performed a similar but longer plantar flexion protocol (workload: 0.5-7.0 kg). These data suggest that prostanoids contribute to the augmented exercise pressor reflex in patients with PAD. PERIPHERAL ARTERIAL DISEASE (PAD) is a form of atherosclerosis that preferentially affects the lower extremity. Because leg blood flow is impaired in PAD, it is not surprising that dynamic exercise, such as walking, provokes pain in the calf, thigh, or buttocks, termed "intermittent claudication." Clinical exercise testing (e.g., the Bruce treadmill protocol) also causes a large increase in blood pressure (BP) in PAD patients, and studies (10, 11) have linked this augmented pressor response to cardiovascular morbidity and mortality. In recent years, our laboratory has focused on BP control in patients with PAD. Specifically, we found that 1) the BP response to single-leg dynamic plantar flexion exercise was augmented in PAD patients compared with healthy control subjects; 2) the pressor response occurred at very low workloads and before the onset of pain; 3) the pressor response correlated with the anklebrachial index (ABI), suggesting that disease severity plays a role; and 4) intravenous infusion of ascorbic acid lowered the pressor response to exercise in PAD (13,28). To date, the mechanisms for these findings are largely unknown. Understanding BP regulation during exercise in PAD ...

show abstract

Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion

Cited by 27 publications

References 47 publications

Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation

Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation

Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease

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