Purinergic 2X Receptors Contribute to the Exaggerated Mechanoreflex in Rats with Heart Failure

Abstract

Skeletal muscle contraction stimulates mechanically activated channels on the sensory endings of thin fiber muscle afferents which evokes reflex increases in sympathetic nerve activity and blood pressure. This reflex is termed the mechanoreflex and its activation in healthy populations plays a key role in facilitating oxygen delivery to contracting muscles and exercise performance. However, mechanoreflex activation in patients with heart failure with reduced ejection fraction (HF-rEF) results in excessive peripheral vasoconstriction and impaired limb blood flow during exercise. Recent evidence in a rat model of HF-rEF demonstrated that hindlimb arterial injection of PPADS, an antagonist for ATP-sensitive purinergic 2X (P2X) receptors, reduced thin fiber muscle afferent responsiveness to static hindlimb muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production) to a greater extent in HF-rEF rats than in healthy counterparts. Those data suggest that, in HF-rEF, P2X receptor stimulation results in the sensitization of co-localized mechanically activated channels on the sensory endings of muscle afferents. To date, however, those electrophysiological findings have not been extended to reflex experiments investigating the cardiovascular consequences of mechanoreflex activation. Accordingly, we sought to determine the role played by P2X receptors in evoking the exaggerated blood pressure response to isolated mechanoreflex activation in HF-rEF rats. We hypothesized that hindlimb arterial injection of the P2X receptor antagonist PPADS (5mg) would reduce the integrated area under the blood pressure signal (the blood pressure index: BPI) evoked during 30 seconds of static hindlimb skeletal muscle stretch in decerebrate, unanesthetized HF-rEF rats to a greater extent than in healthy rats. Experiments were performed six to eight weeks following either a coronary artery ligation surgery to induce myocardial infarction and HF-rEF ( n=8M/2F; ejection fraction 37±6%) or a sham procedure ( n=1M/4F; ejection fraction 84±4; P<0.01versus HF-rEF). In sham rats, P2X receptor blockade had no effect on the BPI response to hindlimb muscle stretch (control: 197±67, PPADS: 211±159mmHg⋅s; p=0.46). Conversely, in HF-rEF rats P2X receptor blockade reduced the BPI response to hindlimb muscle stretch (control: 425±60, PPADS: 257±83mmHg⋅s; p=0.01). The integrated area of the muscle tension signal during the stretch maneuver (tension-time-index; TTI) was not different between control and P2X receptor blockade conditions in either sham (control: 20±2, PPADS: 21±2kg·s; P=0.31) or HF-rEF (control: 24±2, PPADS: 25±2kg·s; P=0.09) rats. The data suggest that P2X receptors on the sensory endings of thin fiber muscle afferents do not play a role in the cardiovascular responses to mechanoreflex activation in health, but contribute importantly to the cardiovascular responses to mechanoreflex activation in HF-rEF. This work was supported by the National Institutes of Health (NIH) R01HL142877 to S.W.C. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.