Jody L. Greaney

Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN (n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip (P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip (P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.

High Dietary Sodium Intake Impairs Endothelium-Dependent Dilation in Healthy Salt-Resistant Humans

Background: Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure. Method: Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300–350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ± 1 mmHg; high-sodium: 85 ± 2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet. Results: Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ± 0.9%, high: 7.3 ± 0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05). Conclusion: These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Dietary sodium loading impairs microvascular function independent of blood pressure in humans: role of oxidative stress.

•  Pre‐clinical studies suggest that acute dietary sodium loading impairs vascular function without alterations in blood pressure; however, human data are lacking. •  In this study, normotensive salt‐resistant adults participated in a controlled feeding study, in which they consumed a low‐sodium diet for 1 week and a high‐sodium diet for 1 week, in random order. During each diet, microvascular function was assessed. •  Here we report the novel finding of sodium‐induced impairments in microvascular function independent of blood pressure in healthy adults. •  We additionally show that function was improved by the administration of the anti‐oxidant ascorbic acid. •  Therefore, in addition to its well‐known importance for blood pressure control, lowering sodium intake may have beneficial effects on microvascular function in healthy normotensive adults.

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

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(2+)](i) (73 ± 15 vs. 11 ± 3 nM; P < 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 ± 2 yr, 117 ± 2/70 ± 2 mmHg), adults with moderately elevated systolic BP (65 ± 1 yr, 138 ± 5/79 ± 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 ± 4 vs. 34 ± 5 bursts/min; P < 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.

Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature.

Hydrogen sulphide (H2S) is vasoprotective, attenuates inflammation and modulates blood pressure in animal models; however, its specific mechanistic role in the human vasculature remains unclear. In the present study, we report the novel finding that the enzymes responsible for endogenous H2S production, cystathionine‐γ‐lyase and 3‐mercaptopyruvate sulphurtransferase, are expressed in the human cutaneous circulation. Functionally, we show that H2S‐induced cutaneous vasodilatation is mediated, in part, by tetraethylammonium‐sensitive calcium‐dependent potassium channels and not by ATP‐sensitive potassium channels. In addition, nitric oxide and cyclo‐oxygenase‐derived byproducts are required for full expression of exogenous H2S‐mediated cutaneous vasodilatation. Future investigations of the potential role for H2S with respect to modulating vascular function in humans may have important clinical implications for understanding the mechanisms underlying vascular dysfunction characteristic of multiple cardiovascular pathologies.

Impaired increases in skin sympathetic nerve activity contribute to age-related decrements in reflex cutaneous vasoconstriction.

The reduction in skin blood flow during whole‐body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole‐body cooling in human ageing remain unclear. We report that the SSNA response to whole‐body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non‐thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal‐cardiovascular integration in healthy ageing.

Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults

Cardiovascular mortality increases in cold weather in older adults, and physical activity may impart even greater cardiovascular risk than cold exposure alone. Human aging is associated with exaggerated pressor responses to whole body cooling; however, the sympathetic response to cold stress alone and in combination with isometric exercise is unknown. We hypothesized that cold stress would 1) increase muscle sympathetic nerve activity (MSNA) and 2) augment the MSNA response to isometric handgrip in older adults. Whole body cooling (water-perfused suit) was conducted in 11 young (23 ± 1 yr) and 12 healthy older adults (60 ± 2 yr). Blood pressure (BP; Finometer) and MSNA (microneurography) were measured throughout cooling and during isometric handgrip at 30% maximal voluntary contraction performed at a mean skin temperature (Tsk) of 34 and 30.5°C. MSNA was greater in older adults at Tsk = 34.0°C and throughout cooling (P < 0.05). MSNA increased during cooling in older, but not young, adults (young: Δ0 ± 1 vs. older: Δ8 ± 1 bursts/min; P < 0.05). The cooling-induced increase in BP was greater in older adults (P < 0.05). During handgrip, the increases in MSNA and BP were not different between conditions in either young (Δ14 ± 2 Tsk 34°C vs. Δ12 ± 3 Tsk 30.5°C bursts/min; Δ20 ± 3 Tsk 34°C vs. Δ19 ± 3 Tsk 30.5°C mmHg; both P > 0.05) or older adults (Δ12 ± 1 Tsk 34°C vs. Δ8 ± 1 Tsk 30.5°C bursts/min; Δ18 ± 3 Tsk 34°C vs. Δ17 ± 2 Tsk 30.5°C mmHg; both P > 0.05). In summary, MSNA increased during cold stress in older, but not young, adults. Furthermore, concomitant cold stress did not alter the sympathetic responses to isometric exercise in either age group, suggesting preserved sympathetic responsiveness during exercise in the cold in healthy aging.

Lack of limb or sex differences in the cutaneous vascular responses to exogenous norepinephrine

The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women (protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women (protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10(-12) to 10(-2) M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10(-12) to 10(-2) M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10(-12) to 10(-10) M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE.

The neural interaction between the arterial baroreflex and muscle metaboreflex is preserved in older men.

•  What is the central question of this study? Sympathetic baroreflex sensitivity increases during isolated skeletal muscle metaboreflex activation in young adults, but whether this neural interaction between the arterial baroreflex and the muscle metaboreflex is altered in healthy ageing remains unclear. •  What is the main finding and its importance? The collective findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of muscle sympathetic nerve activity is preserved in healthy ageing. This has potential implications for the regulation of blood pressure during exercise in older adults.

Influence of increased plasma osmolality on sympathetic outflow during apnea

Animal models have shown that peripheral chemoreceptors alter their firing patterns in response to changes in plasma osmolality, which, in turn, may modulate sympathetic outflow. The purpose of this study was to test the hypothesis that increases in plasma osmolality augment muscle sympathetic nerve activity (MSNA) responses to chemoreceptor activation. MSNA was recorded from the peroneal nerve (microneurography) during a 23-min intravenous hypertonic saline infusion (3% NaCl; HSI). Chemoreceptor activation was elicited by voluntary end-expiratory apnea. MSNA responses to end-expiratory apnea were calculated as the absolute increase from the preceding baseline period. Plasma osmolality significantly increased from pre- to post-HSI (284 ± 1 to 290 ± 1 mOsm/kg H(2)O; P < 0.01). There was a significant overall effect of osmolality on sympathetic activity (P < 0.01). Duration of the voluntary end-expiratory apnea was not different after HSI (pre = 40 ± 5 s; post = 41 ± 4 s). MSNA responses to end-expiratory apnea were not different after HSI, expressed as an absolute change in burst frequency (n = 11; pre = 8 ± 2; post = 11 ± 1 burst/min) and as a percent increase in total activity (pre = 51 ± 4% AU; post = 53 ± 4% AU). A second group of subjects (n = 8) participated in 23-min volume/time-control intravenous isotonic saline infusions (0.9% NaCl). Isotonic saline volume-control infusions yielded no change in plasma osmolality or MSNA at rest. Furthermore, MSNA responses to apnea following isotonic saline infusion were not different. In summary, elevated plasma osmolality increased MSNA at rest and during apnea, but contrary to the hypothesis, MSNA responsiveness to apnea was not augmented. Therefore, this study does not support a neural interaction between plasma osmolality and chemoreceptor stimulation.