Exaggerated exercise pressor reflex in adults with moderately elevated systolic blood pressure: role of purinergic receptors

Abstract

The neurocirculatory responses to exercise are exaggerated in hypertension, increasing cardiovascular risk, yet the mechanisms remain incompletely understood. The aim of this study was to examine the in vitro effectiveness of pyridoxal-5-phosphate as a purinergic (P2) receptor antagonist in isolated murine dorsal root ganglia (DRG) neurons and the in vivo contribution of P2 receptors to the neurocirculatory responses to exercise in older adults with moderately elevated systolic blood pressure (BP). In vitro, pyridoxal-5-phosphate attenuated the ATP-induced increases in [Ca 2ϩ ]i (73 Ϯ 15 vs. 11 Ϯ 3 nM; P Ͻ 0.05). In vivo, muscle sympathetic nerve activity (MSNA; peroneal microneurography) and arterial BP (Finometer) were assessed during exercise pressor reflex activation (static handgrip followed by postexercise ischemia; PEI) during a control trial (normal saline) and localized P2 receptor blockade (pyridoxal-5-phosphate). Compared with normotensive adults (63 Ϯ 2 yr, 117 Ϯ 2/70 Ϯ 2 mmHg), adults with moderately elevated systolic BP (65 Ϯ 1 yr, 138 Ϯ 5/79 Ϯ 3 mmHg) demonstrated greater increases in MSNA and BP during handgrip and PEI. Compared with the control trial, local antagonism of P2 receptors during PEI partially attenuated MSNA (39 Ϯ 4 vs. 34 Ϯ 5 bursts/min; P Ͻ 0.05) in adults with moderately elevated systolic BP. In conclusion, these data demonstrate pyridoxal-5-phosphate is an effective P2 receptor antagonist in isolated DRG neurons, which are of particular relevance to the exercise pressor reflex. Furthermore, these findings indicate that exercise pressor reflex function is exaggerated in older adults with moderately elevated systolic BP and further suggest a modest role of purinergic receptors in evoking the abnormally large reflex-mediated increases in sympathetic activity during exercise in this clinical population.hypertension; metaboreflex; muscle sympathetic nerve activity; calcium imaging; dorsal root ganglia AUGMENTED PRESSOR RESPONSES to exercise are associated with adverse cardiovascular and cerebrovascular events during and after physical activity (22,34,45). Additionally, nonhypertensive individuals with an exaggerated blood pressure (BP) response to exercise are more likely to develop clinical hypertension (12, 53) and are at higher risk of cardiovascular death compared with those with a normal BP response (57, 61). This risk is further modified by baseline hypertension status (61), making exaggerated BP responses to acute exercise especially problematic in adults with chronically elevated resting BP. Resting systolic BP increases with advancing age, such that ϳ65% of older adults have a resting systolic BP in the high-normal or stage I hypertensive range (i.e., 130 -159 mmHg) (5, 16, 40). Therefore, examining neurocirculatory regulation during exercise in this population is clinically relevant.Muscle contraction causes intensity-dependent increases in arterial BP, heart rate (HR), and sympathetic nerve activity (SNA). Afferent feedback from the exercising skeletal muscle is an import...

Why Not to Use the Handgrip Test in the Assessment of Cardiovascular Autonomic Neuropathy Among Patients with Diabetes Mellitus?

“…Patients with hypertension were shown to produce exaggerated BP elevation and enhanced muscle sympathetic nerve activation during isometric handgrip exercise compared with age-related healthy controls [23,24]. Increased muscle metaboreflex activation leading to augmented pressor responses was demonstrated in older moderately hypertensive adults [25] and in pre-hypertensive state [26]. The exercise pressor reflex might occur promptly: BP elevation and heart rate increased within 30-60 sec during static contraction in an experimental study [27].…”

Differences in hemodynamic response to metaboreflex activation between obese patients with metabolic syndrome and healthy subjects with obese phenotype

“…In this case, the blood pressure response is achieved mainly by a SVR-mediated mechanism rather than by a flow-mediated mechanism (11,42). This scenario has been proposed especially for heart failure, and hypertension and it has been ascribed to excessive sympathetic activation with exaggerated vasoconstriction (7,11,16,22,46,47), although this is not a universal finding (37,50). Results of the present investigation suggest that a similar phenomenon occurs during the metaboreflex in subjects with OMS, with a functional shift from a flow-mediated mechanism to a vasoconstrict-mediated mechanism through which the target blood pressure level is reached.…”

Dynamic exercise training prevents exercise pressor reflex overactivity in spontaneously hypertensive rats

“…As such, it is tempting to suggest that improvements in metaboreflex function were induced by exercise training in the current study and may be due, in part, to a downregulation of TRPv1 expression to more normal levels. Alternatively, it has been reported that pyridoxal-5-phosphate, a purinergic P2 receptor (P2) antagonist, partially attenuates muscle SNA during postexercise muscle ischemia in moderately hypertensive adults (16). This finding suggests a role for P2 receptors in evoking the exaggerated sympathetic response to activation of chemically sensitive afferent fibers in hypertension (16).…”

“…Alternatively, it has been reported that pyridoxal-5-phosphate, a purinergic P2 receptor (P2) antagonist, partially attenuates muscle SNA during postexercise muscle ischemia in moderately hypertensive adults (16). This finding suggests a role for P2 receptors in evoking the exaggerated sympathetic response to activation of chemically sensitive afferent fibers in hypertension (16). Like the possibility suggested for TRPv1, exercise training may normalize P2 expression reducing metaboreflex overactivity in hypertension.…”