Functional sympatholysis is impaired in hypertensive humans

Abstract

Non-technical summary In healthy individuals, blunting of the vasoconstriction caused by activation of the sympathetic nervous system is thought to be an important mechanism that optimizes blood flow to the working muscles. We show for the first time that this protective mechanism, called functional sympatholysis, is impaired in middle-aged patients with high blood pressure. We also show that this impairment can be reversed by treatment with an angiotensin receptor blocker, but not with a thiazide-type diuretic. These findings indicate that angiotensin II may augment sympathetic vasoconstriction in the active muscles of hypertensive humans, which may explain the exaggerated rise in blood pressure and blunted decline in systemic vascular resistance during exercise in this population.Abstract In healthy individuals, sympathetic vasoconstriction is markedly blunted in exercising muscles to optimize blood flow to the metabolically active muscle fibres. This protective mechanism, termed functional sympatholysis, is impaired in rat models of angiotensin-dependent hypertension. However, the relevance of these findings to human hypertension is unknown. Therefore, in 13 hypertensive and 17 normotensive subjects we measured muscle oxygenation and forearm blood flow (FBF) responses to reflex increases in sympathetic nerve activity (SNA) evoked by lower body negative pressure (LBNP) at rest and during moderate-intensity rhythmic handgrip exercise. In the normotensives, LBNP caused decreases in oxygenation and FBF (−16 ± 2% and −23 ± 4%, respectively) in resting forearm but not in exercising forearm (−1 ± 2% and −1 ± 3%, respectively; P < 0.05 vs. rest). In the hypertensives, LBNP evoked decreases in oxygenation and FBF that were similar in the resting and exercising forearm (−14 ± 2% vs. −12 ± 2% and −20 ± 3% vs. −13 ± 2%, respectively; P > 0.05), indicating impaired functional sympatholysis. In the hypertensives, SNA was unexpectedly increased by 54 ± 11% during handgrip alone. However, when SNA was experimentally increased during exercise in the normotensives, sympatholysis was unaffected. Treatment for 4 weeks with the angiotensin receptor blocker irbesartan, but not with the thiazide-type diuretic chlorthalidone, restored sympatholysis in the hypertensives. These data provide the first evidence that functional sympatholysis is impaired in hypertensive humans by a mechanism that appears to involve an angiotensin-dependent increase in sympathetic vasoconstriction in the exercising muscles.

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy

“…While angiotensin-converting enzyme inhibitors (lisinopril) and angiotensin receptor blockers (losartan) are being used increasingly in boys with DMD as preemptive therapy to delay onset of heart failure, 1,18,20,21 our data show that chronic treatment with neither lisinopril nor losartan restores sympatholysis in DMD, even though these drugs can reduce reactive oxygen species that destroy NO and thereby rescue sympatholysis in common acquired adult cardiovascular diseases such as hypertension and heart failure. [22][23][24][25][26] In contrast, the seminal finding of this study is that tadalafil rescues sympatholysis in boys with DMD, providing added putative benefit beyond that afforded by the current standard of care. The effect is marked, immediate, and dose-dependent.…”

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

“…Adults with hypertension have abnormal pressor responses to exercise (11,28,58) that are mediated, in part, by EPR dysfunction (11,52). In the current study, we confirm and extend these previous findings and demonstrate that impaired EPR function contributes to exaggerated neurocirculatory responses to muscle contraction in a group of older adults with moderately elevated resting systolic BP in the combined highnormal and stage I hypertensive ranges.…”

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

“…To date, exogenous administration of ATP does mimic the sympatholytic effects of contraction on sympathetic vasoconstriction (252,387,388), and this is also one of the primary arguments favoring ATP as a major player in exercise hyperemia. Fourth, in conditions like hypertension, aging, and perhaps congestive heart failure, there is evidence that sympatholysis is attenuated (130,156,251,494). In other words, the blood vessels in contracting muscles under these conditions remain subject to substantial sympathetic control.…”

“…When this balance is lost, as in autonomic failure, blood pressure falls during large muscle mass exercise. When it is excessive, there can be a hypertensive response to exercise, limited skeletal muscle blood flow, and exercise intolerance (494).…”