Jeanie Park

Adverse Effects of Cigarette and Noncigarette Smoke Exposure on the Autonomic Nervous System: Mechanisms and Implications for Cardiovascular Risk

This review summarizes the detrimental effects of cigarette and noncigarette emission exposure on autonomic function, with particular emphasis on the mechanisms of acute and chronic modulation of the sympathetic nervous system. We propose that the nicotine and fine particulate matter in tobacco smoke lead to increased sympathetic nerve activity, which becomes persistent via a positive feedback loop between sympathetic nerve activity and reactive oxidative species. Furthermore, we propose that baroreflex suppression of sympathetic activation is attenuated in habitual smokers; that is, the baroreflex plays a permissive role, allowing sympathoexcitation to occur without restraint in the setting of increased pressor response. This model is also applicable to other nontobacco cigarette emission exposures (e.g., marijuana, waterpipes [hookahs], electronic cigarettes, and even air pollution). Fortunately, emerging data suggest that baroreflex sensitivity and autonomic function may be restored after smoking cessation, providing further evidence in support of the health benefits of smoking cessation.

Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease

End-stage renal disease (ESRD) is characterized by resting sympathetic overactivity. Baseline muscle sympathetic nerve activity (MSNA), which is governed by baroreflexes and chemoreflexes, is elevated in ESRD. Whether resting skin sympathetic nerve activity (SSNA), which is independent from baroreflex and chemoreflex control, is also elevated has never been reported in renal failure. The purpose of this study was to determine whether sympathetic overactivity of ESRD is generalized to include the skin distribution. We measured sympathetic nerve activity to both muscle and skin using microneurography in eight ESRD patients and eight controls. MSNA was significantly (P = 0.025) greater in ESRD (37.3 +/- 3.6 bursts/min) when compared with controls (23.1 +/- 4.4 bursts/min). However, SSNA was not elevated in ESRD (ESRD vs. controls, 17.6 +/- 2.2 vs. 16.1 +/- 1.7 bustst/min, P = 0.61). Similar results were obtained when MSNA was quantified as bursts per 100 heartbeats. We report the novel finding that although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD. The differential distribution of sympathetic outflow to the muscle vs. skin in ESRD is similar to the pattern seen in other disease states characterized by sympathetic overactivity such as heart failure and obesity.

Sympathetic Renal Innervation and Resistant Hypertension

Hypertension in chronic renal disease and renovascular disease is often resistant to therapy. Understanding the pathogenic mechanisms responsible for hypertension in these conditions may lead to improved and more targeted therapeutic interventions. Several factors have been implicated in the pathogenesis of hypertension associated with renal disease and/or renal failure. Although the role of sodium retention, total body volume expansion, and hyperactivity of the renin-angiotensin-aldosterone system (RAAS) are well recognized, increasing evidence suggests that afferent impulses from the injured kidney may increase sympathetic nervous system activity in areas of the brain involved in noradrenergic regulation of blood pressure and contribute to the development and maintenance of hypertension associated with kidney disease. Recognition of this important pathogenic factor suggests that antiadrenergic drugs should be an essential component to the management of hypertension in patients with kidney disease, particularly those who are resistant to other modalities of therapy.

Altered pattern of sympathetic activity with the ovarian cycle in female smokers

Smoking increases cardiovascular risk in young women and eliminates the protective effect of the premenopausal state. Increased sympathetic nervous system (SNS) activity is associated with increased cardiovascular risk. One potential mechanism by which smoking increases risk is through chronic SNS activation. It has been reported that premenopausal women have high SNS activity during the midluteal (ML) phase, which falls to low levels during the early follicular (EF) phase. We tested the hypothesis that smoking disrupts this fall in SNS activity during the EF phase. We measured blood pressure and muscle sympathetic nerve activity (MSNA) using microneurography in 11 premenopausal female smokers and 11 age-matched nonsmoking controls at two separate times during the ovarian cycle: ML phase (8-10 days after the luteinizing hormone surge) and EF phase (days 1-4 of the menstrual cycle). The change in MSNA from the EF phase to the ML phase was significantly different between the smoking and nonsmoking groups (P = 0.036). Whereas there was a significant decrease in MSNA from the ML phase to the EF phase among nonsmoking controls (22.7 +/- 3.3 vs. 17.9 +/- 2.8 bursts/min, P = 0.012), MSNA remained elevated during the EF phase in smokers (22.5 +/- 3.8 vs. 26.8 +/- 4.0 bursts/min, P = 0.28). Surprisingly, mean arterial pressure (MAP) was significantly lower during the ML phase than in the EF phase in both nonsmokers (P = 0.0080) and smokers (P = 0.0094). We conclude that smoking disrupts the ovarian pattern of SNS activity by preventing the normal fall in MSNA during the EF phase of the ovarian cycle. Such chronic alterations may contribute to the pathogenesis of cardiovascular risk in young smoking females.

Exercise Pressor Reflex in Humans with End-Stage Renal Disease

Previous work has suggested that end-stage renal disease (ESRD) patients may have an exaggerated sympathetic nervous system (SNS) response during exercise. We hypothesized that ESRD patients have an exaggerated blood pressure (BP) response during moderate static handgrip exercise (SHG 30%) and that the exaggerated BP response is mediated by SNS overactivation, characterized by augmented mechanoreceptor activation and blunted metaboreceptor control, as has been described in other chronic diseases. We measured hemodynamics and muscle sympathetic nerve activity (MSNA) in 13 ESRD and 16 controls during: 1) passive hand movement (PHM; mechanoreceptor isolation); 2) low-level rhythmic handgrip exercise (RHG 20%; central command and mechanoreceptor activation); 3) SHG 30%, followed by posthandgrip circulatory arrest (PHGCA; metaboreceptor activation); and 4) cold pressor test (CPT; nonexercise stimulus). ESRD patients had exaggerated increases in systolic BP during SHG 30%; however, the absolute and relative increase in MSNA was not augmented, excluding SNS overactivation as the cause of the exaggerated BP response. Increase in MSNA was not exaggerated during RHG 20% and PHM, demonstrating that mechanoreceptor activation is not heightened in ESRD. During PHGCA, MSNA remained elevated in controls but decreased rapidly to baseline levels in ESRD, indicative of markedly blunted metaboreceptor control of MSNA. MSNA response to CPT was virtually identical in ESRD and controls, excluding a generalized sympathetic hyporeactivity in ESRD. In conclusion, ESRD patients have an exaggerated increase in SBP during SHG 30% that is not mediated by overactivation of the SNS directed to muscle. SBP responses were also exaggerated during mechanoreceptor activation and metaboreceptor activation, but without concomitant augmentation in MSNA responses. Metaboreceptor control of MSNA was blunted in ESRD, but the overall ability to mount a SNS response was not impaired. Other mechanisms besides SNS overactivation, such as impaired vasodilatation, should be explored to explain the exaggerated exercise pressor reflex in ESRD.

Tetrahydrobiopterin Lowers Muscle Sympathetic Nerve Activity and Improves Augmentation Index in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that contributes to cardiovascular risk. Decreased nitric oxide (NO) bioavailability is a major factor contributing to SNS overactivity in CKD, since reduced neuronal NO leads to increased central SNS activity. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase that increases NO bioavailability in experimental models of CKD. We conducted a randomized, double-blinded, placebo-controlled trial testing the benefits of oral sapropterin dihydrochloride (6R-BH4, a synthetic form of BH4) in CKD. 36 patients with CKD and hypertension were randomized to 12 wk of 1) 200 mg 6R-BH4 twice daily + 1 mg folic acid once daily; vs. 2) placebo + folic acid. The primary endpoint was a change in resting muscle sympathetic nerve activity (MSNA). Secondary endpoints included arterial stiffness using pulse wave velocity (PWV) and augmentation index (AIx), endothelial function using brachial artery flow-mediated dilation and endothelial progenitor cells, endothelium-independent vasodilatation (EID), microalbuminuria, and blood pressure. We observed a significant reduction in MSNA after 12 wk of 6R-BH4 (-7.5 ± 2.1 bursts/min vs. +3.2 ± 1.3 bursts/min; P = 0.003). We also observed a significant improvement in AIx (by -5.8 ± 2.0% vs. +1.8 ± 1.7 in the placebo group, P = 0.007). EID increased significantly (by +2.0 ± 0.59%; P = 0.004) in the 6R-BH4 group, but there was no change in endothelial function. There was a trend toward a reduction in diastolic blood pressure by -4 ± 3 mmHg at 12 wk with 6R-BH4 (P = 0.055). 6R-BH4 treatment may have beneficial effects on SNS activity and central pulse wave reflections in hypertensive patients with CKD.

HMG-CoA Reductase Inhibitors and Renal Function

The presence of lipids in renal cells upregulates intracellular signaling pathways involved in inflammatory and fibrogenic responses, both of which are components of progressive renal injury. Lipids activate various growth factors that cause mesangial cell proliferation. Mesangial cells bind both LDL and oxidized LDL (ox-LDL), leading to yet more cell proliferation via multiple downstream effects. LDL stimulates the expression of monocyte chemoattractant protein-1 (MCP-1) mRNA, which increases monocyte chemotactic activity (1). LDL also stimulates the expression of fibronectin mRNA, which induces proliferation of mesangial matrix cells. In the extracellular matrix, ox-LDL induces podocyte apoptosis, decreases Akt activity, depletes nephrin (an adhesion molecule specific to the glomerular slit membrane), and induces the retraction of cultured podocytes, which leads to alterations in the glomerular barrier and increased albumin diffusion (2). Both LDL and ox-LDL induce the expression of NF-κB, which has been associated with inflammation in glomerulonephritis and the progression of chronic kidney disease (CKD) (3). It has also been found to induce the expression of genes that encode other cytokines, chemokines, interferons, growth factors, cell adhesion molecules, and MHC proteins involved in inflammation and proliferation (4). Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase ( i.e. , statins) reduce renal injury in several experimental models (5–7). Statins also exert immunomodulatory and antiinflammatory effects (8–10) because mevalonate also serves as a precursor for isoprenoids—farnesylpyrophosphate (F-PP) and geranylpyrophosphate (G-PP)—that normally attach posttranslationally to intracellular signaling proteins (10). By blocking the synthesis of F-PP and G-PP, statins prevent the anchoring of growth factors to the cell membrane and cytoskeleton, thus hindering signal transduction to the nucleus, activation of transcription factors, and cell proliferation in the vascular endothelium. Among their antiinflammatory and antiproliferative effects, statins reduce levels of MCP-1, IL-1β, TNF-α, TGF-β, IL-6, PDGF, NF-κB, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, …

Exercise pressor response and arterial baroreflex unloading during exercise in chronic kidney disease

Patients with chronic kidney disease (CKD) have poor exercise capacity, which contributes to cardiovascular risk. We sought to determine whether patients with stage 2 or stage 3 CKD have an augmented blood pressure (BP) response during exercise, and if so, whether overactivation of the sympathetic nervous system (SNS) during exercise might play a role. In 13 patients with CKD and hypertension and 13 controls with hypertension, we measured hemodynamics and muscle sympathetic nerve activity (MSNA) during the following maneuvers: low-level rhythmic handgrip (RHG 20%), which primarily stimulates mechanoreceptors, and moderate static handgrip exercise (SHG 30%) followed by posthandgrip circulatory arrest (PHGCA), which isolates metaboreceptors. During baseline studies, patients with CKD had significantly greater increases in mean arterial pressure (MAP) during SHG 30% (P = 0.045), RHG 20% (P = 0.031), and PHGCA (P = 0.043); however, the MSNA response was not augmented in patients with CKD compared with controls. We hypothesized that an augmented SNS response during exercise might be revealed in CKD if arterial baroreflex constraint was equalized using nitroprusside (NTP). These exercise maneuvers were repeated in patients with CKD during NTP infusion to equalize the BP response between groups, thereby relieving baroreflex-mediated suppression of SNS activity. With NTP infusion, patients with CKD had significantly increased MSNA responses during SHG 30% (P = 0.0044), and RHG 20% (P = 0.0064), but not during PHGCA (P > 0.05), suggesting increased reflex activation of the SNS during exercise, which may be mediated by mechanoreceptors but not metaboreceptors. Patients with CKD have an exaggerated BP response during rhythmic and static exercise with underlying SNS overactivation that is revealed during arterial baroreflex unloading during exercise.

Abnormal Sympathetic Reactivity to the Cold Pressor Test in Overweight Humans

BACKGROUND Overweight individuals (body mass index (BMI) 25-29.9 kg/m²) are at higher risk for developing cardiovascular disease and hypertension when compared with lean individuals of normal weight (BMI 18.5-24.9 kg/m²). The purpose of this study was to test the hypothesis that exaggerated sympathetic nervous system responses to stressors may be one potential mechanism that predisposes overweight individuals to developing hypertension. METHODS We compared heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) using microneurography, in normotensive overweight individuals compared with age-matched lean controls, at baseline and during two sympathoexcitatory maneuvers: cold pressor test (CPT), and static handgrip exercise (SHG 30%). RESULTS During CPT, MSNA increased in both groups, but the magnitude of MSNA response was significantly greater (P = 0.03) in overweight (+18.1 ± 2.8 bursts/min) compared with lean controls (+10.8 ± 1.2 bursts/min). MSNA response to SHG at 30% maximum voluntary contraction (MVC) was similar between the two groups. There were no significant differences in systolic (SBP) or diastolic BP (DBP) responses or HR responses between the two groups during either maneuver. CONCLUSIONS Normotensive overweight individuals have an exaggerated MSNA response to the CPT. Augmented sympathetic reactivity to cold stress may contribute to increased risk of hypertension in overweight individuals.

Abnormal sympathetic nerve activity in women exposed to cigarette smoke: a potential mechanism to explain increased cardiac risk.

In women, cardiac deaths attributable to tobacco exposure have reached the same high levels as men. Normally, sympathetic nerve activity (SNA) fluctuates according to the menstrual phase, but in habitual smokers, SNA levels remain constant. Our purpose is to extend these observations to other groups of women exposed to tobacco smoke and to explore potential mechanisms. We hypothesize that women exposed to secondhand smoke, but not former smokers, have nonfluctuating SNA compared with never smokers, and that impaired baroreflex suppression of SNA, and/or heightened central SNA responses, underlie this nonfluctuating SNA. We also hypothesize that female smokers have impaired nocturnal blood pressure dipping, normally mediated by modulation of SNA. In 49 females (19 never, 12 current, 9 former, 9 passive smokers), SNA was recorded (microneurography) during high- and low-hormone ovarian phases at rest, during pharmacological baroreflex testing, and during the cold pressor test (CPT). Twenty-four hour blood pressure (BP) monitoring was performed. Current and passive smokers, but not former smokers, had a nonfluctuating pattern of SNA, unlike never smokers in whom SNA varied with the menstrual phase. Baroreflex control of SNA was significantly blunted in current smokers, independent of menstrual phase. In passive smokers, SNA response to CPT was markedly increased. Nondipping was unexpectedly high in all groups. SNA does not vary during the menstrual cycle in active and passive smokers, unlike never and former smokers. Baroreflex control of SNA is blunted in current smokers, whereas SNA response to CPT is heightened in passive smokers. Smoking cessation is associated with return of the altered SNA pattern to normal.