Neural control of the circulation during exercise in healthy rats and in those with simulated peripheral artery disease
Open Access
- Author:
- Kim, Joyce
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 19, 2020
- Committee Members:
- Marc Kaufman, Dissertation Advisor/Co-Advisor
Marc Kaufman, Committee Chair/Co-Chair
Lawrence Isaac Sinoway, Committee Member
Victor J Ruiz-Velasco, Committee Member
Charles H Lang, Outside Member
Gail Doreen Thomas, Committee Member
Ralph Lauren Keil, Program Head/Chair - Keywords:
- APETx2
exercise pressor reflex
mechanoreceptor reflex
metaboreceptor reflex
protons
diprotonated phosphate
lactic acid
peripheral artery disease
sympathetic nervous system
thin fiber muscle afferents
autonomic nervous system
static contraction
tendon stretch - Abstract:
- Cardiovascular responses to exercise increase skeletal muscle blood flow in order to match skeletal muscle oxygen consumption. Two neural mechanisms control this cardiovascular phenomenon: a feed-forward mechanism called central command, and a feedback mechanism called the exercise pressor reflex (EPR). The EPR begins from the contracting skeletal muscle. This reflex is evoked by the activation of both mechanoreceptors and metaboreceptors that are expressed on the endings of thinly myelinated group III and unmyelinated group IV afferents. The metabolic component of the reflex is activated in response to a mismatch between skeletal muscle oxygen supply and demand. The EPR feedback mechanism is altered in peripheral artery disease (PAD), which is caused by atherosclerosis and affects 8 to 12 million Americans above the age of 65. This underdiagnosed and undertreated disease puts PAD patients at a higher risk of having adverse cardiovascular events, such as heart attack or stroke. The EPR is exaggerated in patients with PAD, and it is thought this augmented pressor response contributes to an increased risk of cardiovascular mortality. Mechanical and metabolic stimuli arising from contracting skeletal muscle evoke the EPR. Metabolic by-products, namely hydrogen ions, dissociated from diprotonated phosphate and lactic acid, are believed to activate acid-sensing ion channels (ASICs) on the endings of group III and IV muscle afferents and evoke the metabolic component of the EPR. ASICs have seven different channel subtypes. ASIC1, ASIC2, and ASIC3 are expressed in the peripheral nervous system, and ASIC3 channels, in particular, have been shown to activate at pH found during exercise. My work in chapters 3 and 4 focused on how the metaboreflex contributes to evoking the EPR. I specifically focused on the role played by ASIC3 in inducing the EPR in healthy, and PAD simulated models. In the studies discussed in chapters 3 and 4, I compared the magnitude of the exercise pressor reflex evoked in ASIC3 knockout (ASIC3 KO) rats with the reflex evoked in their wild-type (WT) counterparts. In addition, I compared the magnitude of the pressor responses to 4 stimuli: tendon stretch, intra-arterial injection of diprotonated phosphate (H2PO4-; 86mM; pH6.0), 12mM lactic acid (pH2.85), 24mM lactic acid (pH2.66), and capsaicin (0.2μg; pH7.2). In rats with freely perfused femoral arteries, I found that both wild-type (WT) and ASIC knock-out (KO) rats displayed similar pressor responses to static contraction (WT, n=10, 122 mmHg; KO, n=9, 112 mmHg) and calcaneal tendon stretch (WT, n=9, 132 mmHg; KO, n=7, 112 mmHg). Similarly, both WT and ASIC KO rats displayed similar pressor responses to intra-arterial injection of H2PO-4 (WT, n=6,22±3 mmHg; KO, n=6, 32±6 mmHg), 12mM lactic acid (WT, n=9,14±3 mmHg; KO, n=8, 18±5 mmHg), 24mM lactic acid (WT, n=9,24±2 mmHg; KO, n=8, 20±5 mmHg), and capsaicin (WT, n=9,27±5 mmHg; KO, n=10, 29±5 mmHg). To simulate PAD, I ligated iliac and femoral arteries 72 h before the experiment. In ligated rats, I found that the EPR in ASIC3 KO rats was significantly lower than the EPR in their WT counterparts (p=0.0001). Similarly, the pressor responses to intra-arterial injection of H2PO-4; (p=0.0020), 12mM lactic acid (p<0.0001), and capsaicin (p=0.0051) were significantly lower in ASIC3 KO rats compared to WT. In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to tendon stretch (p=0.5533). The findings mentioned above indicate that ASIC3 plays an important role in evoking the exaggerated EPR in ligated rats. The signal transmission of the EPR begins with the stimulation of thinly myelinated group III and unmyelinated group IV afferents by both mechanical and metabolic stimuli. The reflex subsequently synapses onto interneurons in the dorsal horn. This, in turn, projects to the ventrolateral medulla and subsequently synapses onto sympathetic preganglionic neurons in the intermediolateral horn of the spinal cord to increase the sympathetic nerve discharge. Activation of both spinal and peripheral opioid receptors directly inhibits neurons, which, in turn, inhibits signal transmission and neurotransmitter release. Chapter 5 will focus on the effects of spinal -opioid receptor stimulation in attenuating the exercise pressor reflex in both healthy and PAD simulated models. In the studies covered in Chapter 5, I compared the magnitude of the pressor responses before and after intrathecal injection of [D-Pen2,5]enkephalin (DPDPE), a -opioid agonist, to 4 stimuli: static contraction, tendon stretch, intra-arterial injection of 12mM lactic acid (pH2.85) and capsaicin (0.2μg; pH7.2). I found that in freely perfused rats, DPDPE significantly attenuated the pressor responses evoked by static contraction (n=7; p=0.0027) and calcaneal tendon stretch (n=9; p=0.0337). Similarly, DPDPE attenuated the pressor response to the intra-arterial injection of lactic acid (n=7; p=0.0137). In contrast, DPDPE did not attenuate the pressor response to intra-arterial injection of capsaicin (n=7; p=0.8597). In ligated rats, DPDPE significantly attenuated the pressor responses evoked by static contraction (n=6; p=0.0157) and calcaneal tendon stretch (n=6; p=0.0356). Similarly, DPDPE attenuated the pressor response to the intra-arterial injection of lactic acid (n=6; p=0.0091). However, DPDPE did not attenuate the pressor response to the intra-arterial injection of capsaicin (n=8; p=0.0753). These studies indicated that the activation of spinal -opioid receptors attenuated the exercise pressor reflex evoked by the contraction-induced stimulation of group III afferents in both freely perfused and ligated rats. In summary, this dissertation enhances our current understanding of the mechanisms regulating the EPR in freely perfused and PAD simulated rats. The findings from my study provide pieces of evidence to validate and strengthen the role played by ASIC3 in evoking the metabolic component of the EPR in freely perfused and PAD simulated rats. Also, the studies elucidate the role of spinal δ-opioid receptors as an inhibitory modulator of the EPR in freely perfused and PAD simulated rats.