Central Sympatholysis as a Novel Countermeasure for Cocaine-Induced Sympathetic Activation and Vasoconstriction in Humans

ObjectivesThe aim of this study was to determine whether cocaine’s sympathomimetic actions can be reversed by a potent centrally acting α2 adrenergic receptor (AR) agonist (dexmedetomidine).BackgroundWe 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.MethodsIn 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.ResultsDuring 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 α2C AR, a loss-of-function mutation that is highly enriched in blacks.ConclusionsThe 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 α2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546

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

Differential effects of eplerenone versus amlodipine on muscle metaboreflex function in hypertensive humans

Abstract Numerous studies have demonstrated that sympathetic nervous system overactivation during exercise in hypertensive rodents and humans is due, in part, to an exaggerated reflex response known as the exercise pressor reflex. Our prior studies have implicated a key role of mineralocorticoid receptor activation in mediating an augmented exercise pressor reflex in spontaneously hypertensive rats, which is mitigated by blockade with eplerenone. However, the effect of eplerenone on exercise pressor reflex has not been assessed in human hypertension. Accordingly, the authors performed a randomized crossover study to compare the effects of eplerenone to another antihypertensive drug from a different class amlodipine on sympathetic nerve activity (SNA) in 14 patients with uncomplicated hypertension. The authors found that amlodipine unexpectedly augmented the increase in SNA during the second minute of isometric handgrip, which persisted into the post‐exercise circulatory arrest period (∆ SNA, from rest of 15 ± 2 vs. 9 ± 2 vs. 10 ± 2 bursts/min, amlodipine vs. baseline vs. eplerenone, respectively, p < .01), suggesting an exaggerated muscle metaboreflex function. Eplerenone did not alter sympathetic responses to exercise or post‐exercise circulatory arrest in the same hypertensive individuals. In conclusions, our studies provide the first direct evidence for a potentially unfavorable potentiation of muscle metaboreflex by amlodipine during isometric handgrip exercise in hypertensive patients whereas eplerenone has no significant effect. Our study may have clinical implications in terms of selection of antihypertensive agents that have the least detrimental effects on sympathetic neural responses to isometric exercise

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

Functional sympatholysis is impaired in hypertensive humans

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