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ABSTRACT: In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.
Hypertension 04/2013; · 6.21 Impact Factor
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ABSTRACT: Recent studies from our laboratory indicate that chlorthalidone triggers persistent activation of the sympathetic nervous system and promotes insulin resistance in hypertensive patients, independent of serum potassium. Mechanisms underlying these adverse effects of chlorthalidone remain unknown, but increasing evidence in rodents suggests the role of angiotensin and aldosterone excess in inducing both sympathetic overactivity and insulin resistance. Accordingly, we conducted studies in 17 subjects with untreated stage 1 hypertension, measuring sympathetic nerve activity at baseline and after 12 weeks of chlorthalidone alone (25 mg/d), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory blood pressure from 135±3/84±2 to 124±2/78±2 mm Hg and significantly increased sympathetic nerve activity from baseline (from 41±3 versus 49±4 bursts per minute; P<0.01). The addition of spironolactone to chlorthalidone returned sympathetic nerve activity value to baseline (42±3 bursts per minute; P>0.05), whereas the addition of irbesartan failed to alter the sympathetic nerve activity response to chlorthalidone in the same subjects (52±2 bursts per minute; P<0.01) despite a similar reduction in ambulatory blood pressure (121±2/75±2 and 121±2/75±2 mm Hg, respectively). Chlorthalidone alone also increased indices of insulin resistance, which was not observed when used in combination with spironolactone. In conclusion, our study demonstrates beneficial effects of spironolactone in attenuating both chlorthalidone-induced sympathetic activation and insulin resistance in humans, independent of blood pressure reduction. Because sympathetic overactivity and insulin resistance contribute to the poor prognosis in patients with cardiovascular disease, combination therapy of chlorthalidone with mineralocorticoid receptor antagonists may constitute a preferable regimen than chlorthalidone alone in hypertensive patients.
Hypertension 06/2012; 60(2):319-25. · 6.21 Impact Factor
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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.
The Journal of Physiology 01/2011; 589(Pt 5):1209-20. · 4.72 Impact Factor
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ABSTRACT: Aldosterone has been shown to exert a central sympathoexcitatory action in multiple animal models, but evidence in humans is still lacking.
Our objective was to determine whether hyperaldosteronism causes reversible sympathetic activation in humans.
We performed a cross-sectional comparison of muscle sympathetic nerve activity (SNA, intraneural microelectrodes) in 14 hypertensive patients with biochemically proven primary aldosteronism (PA) with 20 patients with essential hypertension (EH) and 18 age-matched normotensive (NT) controls. Seven patients with aldosterone-producing adenoma (APA) were restudied 1 month after unilateral adrenalectomy.
Mean blood pressure values in patients with PA and EH and NT controls was 145 ± 4/88 ± 2, 150 ± 4/90 ± 2, and 119 ± 2/76 ± 2 mm Hg, respectively. The major new findings are 2-fold: 1) baseline SNA was significantly higher in the PA than the NT group (40 ± 3 vs. 30 ± 2 bursts/min, P = 0.014) but similar to the EH group (41 ± 3 bursts/min) and 2) after unilateral adrenalectomy for APA, SNA decreased significantly from 38 ± 5 to 27 ± 4 bursts/min (P = 0.01), plasma aldosterone levels fell from 72.4 ± 20.3 to 11.4 ± 2.3 ng/dl (P < 0.01), and blood pressure decreased from 155 ± 8/94 ± 3 to 117 ± 4/77 ± 2 mm Hg (P < 0.01).
These data provide the first evidence in humans that APA is accompanied by reversible sympathetic overactivity, which may contribute to the accelerated hypertensive target organ disease in this condition.
The Journal of clinical endocrinology and metabolism 10/2010; 95(10):4756-61. · 6.50 Impact Factor
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ABSTRACT: Obesity is thought to lead to sympathetic overactivity as a compensatory adjustment to weight gain. However, most of the experimental support for the hypothesis has been derived from white cohorts. Our previous study in blacks indicated that sympathetic nerve activity (SNA) is closely correlated with body mass index only in women, whereas, in black men, SNA is elevated and dissociated from adiposity (Abate et al., Hypertension 38: 379-383, 2001). To further determine whether total and regional adiposity are determinants of SNA in blacks, we performed a prospective weight loss study in 12 normotensive obese black men and 9 obese black women. SNA, body mass index, and abdominal fat mass were measured before and 16 wk after hypocaloric diet. The major new findings are that, in obese black men, the dietary-induced weight loss of 11.3+/-0.8 kg resulted in reduction in plasma leptin, insulin, and visceral abdominal fat but had no effect on SNA (from baseline of 26+/-4 to 28+/-3 bursts/min, P=not significant). In contrast, in black women, weight loss of 8.0+/-0.9 kg caused similar reductions in plasma leptin, insulin, and visceral abdominal fat and led to a reduction in SNA by 40% (from baseline of 22+/-2 to 13+/-3 bursts/min, P<0.05). In conclusion, these new data from this prospective study provide strong support for a major adiposity-independent sympathetic activity in black men and adiposity-related sympathetic activity in black women.
Journal of Applied Physiology 03/2010; 108(6):1613-8. · 3.75 Impact Factor
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ABSTRACT: Previous studies in rats indicated that thiazide-type diuretics reduced blood pressure (BP) and triggered baroreflex-mediated increase in sympathetic nerve activity (SNA), whereas spironolactone exerted central sympathoinhibitory action in addition to diuretic effects.
The objectives were to determine effects of spironolactone and chlorthalidone on SNA and the role of SNA on diuretic-induced insulin resistance in human hypertension.
We conducted a randomized crossover study in 23 untreated hypertensive patients in which we measured muscle SNA at baseline, after 1 and 3 months of chlorthalidone (12.5-25 mg/d), and after 1 and 3 months of spironolactone (50-75 mg/d). Ambulatory BP, baroreflex sensitivity, and indices of insulin resistance were also assessed at baseline and after 3 months of each drug treatment.
Chlorthalidone caused a similar reduction in ambulatory BP from baseline when compared with spironolactone (11 +/- 2/4 +/- 2 and 10 +/- 2/4 +/- 2 mm Hg, respectively). However, chlorthalidone increased SNA by 23% (P < 0.01) within 1 month of treatment, whereas spironolactone had no effect in the same subjects. SNA continued to be elevated after 3 months of chlorthalidone when compared with baseline and spironolactone. Baroreflex control of SNA was unaffected by either drug. Chlorthalidone increased indices of insulin resistance, which were significantly correlated with increases in SNA from baseline, whereas spironolactone had no effect in the same subjects.
Our data suggest that chlorthalidone, the first-line drug therapy for hypertension, causes persistent activation of sympathetic nervous system and insulin resistance in hypertensive patients. These side effects, however, are avoided by spironolactone despite similar reduction in BP.
The Journal of clinical endocrinology and metabolism 01/2009; 94(4):1361-6. · 6.50 Impact Factor
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RN 10/2008; 71(9):28-32; quiz 33.
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ABSTRACT: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 adrenergic receptor (AR) agonist (dexmedetomidine).
We recently showed that cocaine stimulates the human cardiovascular system primarily by acting in the brain to increase sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release. Thus, SNA constitutes a putative new drug target to block cocaine's adverse cardiovascular effects at their origin.
In 22 healthy cocaine-naïve humans, we measured skin SNA (microneurography) and skin blood flow (laser Doppler velocimetry) as well as heart rate and blood pressure before and after intranasal cocaine (2 mg/kg) alone and in combination with dexmedetomidine or saline.
During intranasal cocaine alone, SNA increased by 2-fold and skin vascular resistance increased from 13.2 +/- 2.3 to 20.1 +/- 2.2 resistance units while mean arterial pressure increased by 14 +/- 3 mm Hg and heart rate by 18 +/- 3 beats/min (p < 0.01). Dexmedetomidine abolished these increases, whereas intravenous saline was without effect. Dexmedetomidine was effective in blocking these sympathomimetic actions of cocaine even in all 7 subjects who were homozygous for the Del322-325 polymorphism in the alpha2C AR, a loss-of-function mutation that is highly enriched in blacks.
The data advance the novel hypothesis that central sympatholysis with dexmedetomidine constitutes a highly effective countermeasure for cocaine's sympathomimetic actions on the human cardiovascular system, even in individuals carrying the alpha2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).
Journal of the American College of Cardiology 08/2007; 50(7):626-33. · 14.16 Impact Factor
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ABSTRACT: Sympathetic vasoconstriction is normally attenuated in exercising muscles of young men and women. Recent evidence indicates that such modulation, termed functional sympatholysis, may be impaired in older men. Whether a similar impairment occurs in older women, and what role oestrogen deficiency might play in this impairment, are not known. Based on the strong positive correlation between circulating oestrogen levels and functional sympatholysis previously reported in female rats, we hypothesized that sympatholysis would be impaired in oestrogen-deficient postmenopausal women, and that this impairment would be reversed by oestrogen replacement. To test these hypotheses, we measured vasoconstrictor responses in the forearms of pre- and postmenopausal women using near infrared spectroscopy to detect decreases in muscle oxygenation in response to reflex activation of sympathetic nerves evoked by lower body negative pressure (LBNP). In eight premenopausal women, LBNP decreased muscle oxygenation by 20 +/- 1% in resting forearm, but only by 3 +/- 2% in exercising forearm (P < 0.05). In contrast, in eight postmenopausal women, LBNP decreased muscle oxygenation by 15 +/- 3% in resting forearm, and by 12 +/- 4% in exercising forearm (P > 0.05). After 1 month of transdermal oestradiol replacement in these women, the normal effect of exercise to blunt sympathetic vasoconstriction was restored (rest, -19 +/- 3%; exercise, -2 +/- 3%; P < 0.05). These data indicate that functional sympatholysis is impaired in oestrogen-deficient postmenopausal women. The effect of short-term unopposed oestrogen replacement to correct this impairment implicates a role for oestrogen in the sympathetic neural control of muscle haemodynamics during exercise.
The Journal of Physiology 01/2005; 561(Pt 3):893-901. · 4.72 Impact Factor
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ABSTRACT: Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women.
In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 microg per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women.
Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes.
Arteriosclerosis Thrombosis and Vascular Biology 11/2004; 24(10):e164-7. · 6.37 Impact Factor
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ABSTRACT: During static exercise, metabolites accumulate in the muscle interstitium where they stimulate chemosensitive afferent nerves that reflexly increase efferent muscle sympathetic nerve activity (MSNA) and blood pressure. In experimental animals, lactic acid potently stimulates the muscle metaboreflex, but its role in humans is more controversial. To determine if lactic acid is a critical mediator of metaboreflex activation in humans, we performed microelectrode recordings of MSNA in eight patients with myophosphorylase deficiency (McArdle's disease) who cannot metabolize intramuscular glycogen and do not generate lactic acid in exercising muscles. Each patient was matched with three healthy control subjects to maximize statistical power. In controls, 2 min of static handgrip performed at 33 % or 45 % of maximal voluntary contraction (MVC) produced intensity-dependent increases in MSNA (171 +/- 22 % and 379 +/- 95 %, respectively). In the patients, MSNA responses to static handgrip were markedly attenuated (33 +/- 14 % at 33 % MVC; 32 +/- 19 % at 45 % MVC; P < 0.05 vs. controls). Likewise, when static handgrip (30 % MVC) was performed to fatigue, MSNA increased by 366 +/- 73 % in controls but only by 51 +/- 14 % in patients (P < 0.05). Pressor responses to static handgrip were also attenuated in patients compared to controls, whereas heart rate responses were identical. In contrast to exercise, the MSNA responses to other reflex stimuli (the cold pressor test or Valsalva's manoeuvre) were similar in patients and controls. Together these data indicate that appropriate activation of glycogenolytic pathways is obligatory for normal metaboreflex-mediated sympathoexcitation during static exercise in humans.
The Journal of Physiology 05/2003; 548(Pt 3):983-93. · 4.72 Impact Factor
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ABSTRACT: We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women.
Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism.
In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured.
Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis.
In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.
Journal of the American College of Cardiology 04/2003; 41(8):1358-63. · 14.16 Impact Factor
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ABSTRACT: Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy ((1)H MRS) as an in vivo tool to measure myocardial lipid content. Complementary studies in rat tissue ex vivo and in 15 healthy humans in vivo provided evidence that (1)H MRS constitutes a reproducible technique for the measurement of myocardial triglyceride. In myocardial tissue from Zucker rats, the (1)H MRS measurement of triglyceride matched that obtained by biochemical measurement (P < 0.001). In human subjects triglyceride was evident in the hearts of even the very lean individuals and was elevated in overweight and obese subjects. Increased myocardial triglyceride content was accompanied by elevated LV mass and suppressed septal wall thickening as measured by cardiac imaging.
Magnetic Resonance in Medicine 03/2003; 49(3):417-23. · 2.96 Impact Factor
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ABSTRACT: Am J Hypertens (2002) 15, 190A–190A; doi:10.1016/S0895-7061(02)02787-5
P-436: Fatty heart disease - myocardial steatosis in humans
Lidia S. Szczepaniak1, Robert L. Dobbins1, Gregory J. Metzker1, Greta S. D'Ambrosia1, Debbie Arbique1, Wanpen Vongpatanasin1, Roger Unger1, Ronald G. Victor1 and Donald W. Reynolds11Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX USA
American Journal of Hypertension 03/2002; · 3.18 Impact Factor
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ABSTRACT: Although the sympathomimetic actions and cardiovascular complications of cocaine are ascribed to inhibition of norepinephrine (NE) reuptake, this hypothesis has not been tested in humans. We asked (a) whether cocaine can inhibit NE reuptake in the human peripheral circulation and (b) whether the NE-mediated peripheral vasoconstriction is the main mechanism mediating blood pressure-raising effect of cocaine.
In 15 healthy cocaine-naive subjects, we measured blood pressure, forearm blood flow, and forearm venous NE concentration during administration of (a) intrabrachial cocaine (0.15 and 15 mg), which produced no systemic neurohormonal effects, and (b) intranasal cocaine (2 mg/kg). Intrabrachial cocaine (0.15 mg) increased venous forearm NE concentration by 82% and vascular resistance by 71% (P<0.01). Increasing the intrabrachial cocaine dose by 100-fold to match the venous cocaine level of massive cocaine overdose caused a small additional increase in venous forearm NE concentration without causing significant additional vasoconstriction. Although intranasal cocaine (2 mg/kg) matched the venous cocaine concentrations caused by 0.15 mg of intrabrachial cocaine, venous NE concentration was unchanged as sympathetic nerve activity (SNA) decreased reflexively as the result of an increase in blood pressure. When SNA was restored to baseline by blunting the cocaine-induced rise in blood pressure (baroreflex activation) with nitroprusside, venous NE concentration increased to the same level caused by intrabrachial cocaine.
In healthy cocaine-naive individuals, cocaine can inhibit NE reuptake in the human peripheral circulation. However, this mechanism does not contribute importantly to the blood pressure-raising effect of cocaine because activation of baroreceptor reflexes decreases SNA, the neural stimulus for NE release.
Circulation 03/2002; 105(9):1054-9. · 14.74 Impact Factor
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ABSTRACT: Am J Hypertens (2001) 14, 23A–23A; doi:10.1016/S0895-7061(01)01366-8
O-49: Inhibition of the human peripheral norepinephrine transporter does not explain the blood pressure-raising effect of cocaine
Meryem Tuncel1, Zhongyun Wang1, Debbie Arbique1, Ronald G. Victor1 and Wanpen Vongpatanasin11Internal Medicine/Hypertension UT Southwestern Medical Center, Dallas, TX, USA
American Journal of Hypertension 03/2001; · 3.18 Impact Factor
