Zhongyun Wang

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women

OBJECTIVES We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy

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.

Functional sympatholysis is impaired in hypertensive humans.

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.

Spironolactone Prevents Chlorthalidone-Induced Sympathetic Activation and Insulin Resistance in Hypertensive Patients

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.

Differential Effects of Chlorthalidone Versus Spironolactone on Muscle Sympathetic Nerve Activity in Hypertensive Patients

CONTEXT 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. OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism

CONTEXT Aldosterone has been shown to exert a central sympathoexcitatory action in multiple animal models, but evidence in humans is still lacking. OBJECTIVES Our objective was to determine whether hyperaldosteronism causes reversible sympathetic activation in humans. METHODS 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. RESULTS 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). CONCLUSION 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.

Oxidative stress and enhanced sympathetic vasoconstriction in contracting muscles of nitrate-tolerant rats and humans

Non‐technical summary  Activation of sympathetic nerves decreases blood flow to resting skeletal muscle, but this vasoconstrictor effect normally is blunted during exercise so that blood flow can increase to the working muscles. In rats and humans treated with nitroglycerin for 1 week, we show that overproduction of reactive oxygen species prevents the usual attenuation of sympathetic vasoconstriction in the working muscles, resulting in muscle ischaemia during exercise. Improved knowledge about the effect that reactive oxygen species has on muscle blood flow regulation may help us to better understand the decreased exercise tolerance that occurs with age as well as with chronic disease.

Differential Effects of Nebivolol Versus Metoprolol on Functional Sympatholysis in Hypertensive Humans

&NA; 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 &bgr;1-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 &bgr;1-adrenergic receptors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

Adiposity-independent sympathetic activity in black men

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.

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans.

Use of β-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation β-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.