Hyperactivity In Hypertension Research Articles

Paying the Toll for Inflammation

Paying the Toll for Inflammation

RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity

Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca2+ balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca2+ homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.

The Cardiovascular Effect of Systemic Homocysteine Is Associated with Oxidative Stress in the Rostral Ventrolateral Medulla.

It has been demonstrated that homocysteine (HCY) is a significant risk factor of hypertension, which is characterized by overactivity of sympathetic tone. Excessive oxidative stress in the rostral ventrolateral medulla (RVLM), a key region for control of sympathetic outflow, contributes to sympathetic hyperactivity in hypertension. Therefore, the goal of the present study is to determine the effect of systemic HCY on production of reactive oxygen species (ROS) in the RVLM. In the rat model of the diet-induced hyperhomocysteinemia (L-methionine, 1 g/kg/day, 8 weeks), we found that the HCY resulted in a significant increase (≈3.7-fold, P < 0.05) in ROS production in the RVLM, which was paralleled with enhanced sympathetic tone and blood pressure (BP). Compared to the vehicle group, levels of BP and basal renal sympathetic nerve activity in the HCY group were significantly (P < 0.05, n = 5) increased by an average of 27 mmHg and 31%, respectively. Furthermore, the rats treated with L-methionine (1 g/kg/day, 8 weeks) showed an upregulation of NADPHase (NOX4) protein expression and a downregulation of superoxide dismutase protein expression in the RVLM. The current data suggest that central oxidative stress induced by systemic HCY plays an important role in hypertension-associated sympathetic overactivity.

Renal Sympathetic Hyperactivity in Hypertension: True or False?

Increased renal norepinephrine spillover, observed by using isotope-dilution method, is thought to indicate renal sympathetic hyperactivity and to play a crucial role in hypertension. However, SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension), the first randomized sham-controlled trial, failed to show a benefit of renal denervation for resistant hypertension.1 This raises the issue of whether the sympathetic hyperactivity hypothesis is true. In a recent issue of Circulation Research , Grassi et al2 have emphasized the presence and importance of sympathetic hyperactivity in hypertension, primarily based on the results of isotope-dilution studies. However, the isotope-dilution method cannot exclude the involvement of intraorgan platelet release of norepinephrine. We would argue that platelet norepinephrine release, rather than sympathetic nervous system alterations, may be the cause of increased norepinephrine spillover in hypertension for …

Response by Grassi et al to Letter Regarding Article, “The Sympathetic Nervous System Alterations in Human Hypertension”

Drs Zhou and Zhou1 write a challenging letter that aims to turn concepts of sympathetic nerve biology and norepinephrine plasma kinetics upside down. Their letter claims that there is a previously unsuspected primary importance for platelets in norepinephrine disposition after release of the transmitter from sympathetic nerves in individual organs and in clearance of norepinephrine from the circulation. Imagination is a fine thing in science, not least for overturning a dominant paradigm, but supporting quantitative analysis must buttress this. Before addressing the specific issues raised by the 2 authors in their letter,1 we would like to emphasize that, as extensively discussed in our article,2 the evidence of a sympathetic hyperactivity in hypertension is based not only on the results of the isotope-dilution studies but also, and probably to a greater extent, on other techniques assessing neuroadrenergic drive, the most important of them being represented by the microneurographic nerve traffic recording. Thus, the statement by Drs Zhou and Zhou that “the importance of sympathetic hyperactivity in hypertension is primarily based on the results of isotope-dilution studies” is not supported …

Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade

See related article, pp 319–325 Chronic sympathetic hyperactivity, characteristic of the majority of patients with hypertension or heart failure, can contribute to cardiovascular morbidity and mortality via a number of actions. Pharmacological strategies to prevent these adverse effects have had variable success. β-Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas α1-blockers or centrally acting agents have shown mixed results, and all of these classes can cause bothersome adverse effects. Device-based approaches, such as baroreflex activation therapy and renal denervation, have been shown to lower sympathetic activity in patients with hypertension, but beneficial actions on cardiovascular outcomes have yet to be demonstrated. So, where do the central nervous system (CNS) actions of angiotensin II (Ang II), aldosterone, and, hence, Ang II type 1 (AT1) receptor and mineralocorticoid receptor (MR) blockers fit in? Experimental studies have demonstrated that both circulating Ang II and aldosterone act within the CNS to cause sympatho-excitation and raise blood pressure.1,2 Ang II stimulates AT1 receptors in nuclei of the lamina terminalis and thereby activates mainly angiotensinergic pathways to the paraventricular nucleus (PVN) and rostral ventrolateral medulla. Circulating Ang II, in addition, activates an MR-endogenous ouabain pathway. This slowly acting, neuromodulatory pathway appears responsible for most of the persistent neuronal activation in, for example, the PVN, and the progressive hypertension induced by circulating Ang II. Studies using central infusions of an aldosterone synthase inhibitor suggest that the CNS MR activation by Ang II largely depends on locally produced aldosterone rather than circulation-derived aldosterone.1 However, the progressive hypertension caused by a chronic increase in circulating aldosterone can also be prevented by specific CNS blockade of either MR or AT1 receptors,2 suggesting that both circulating aldosterone and Ang II may activate …

Noradrenergic Cell Specific Gene Transfer With Neuronal Nitric Oxide Synthase Reduces Cardiac Sympathetic Neurotransmission in Hypertensive Rats

Nitric oxide-cGMP pathway can inhibit cardiac norepinephrine (NE) release. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress impairing this pathway. We tested the hypothesis that the gene transfer of neuronal NO synthase (nNOS) could restore sympathetic balance in the spontaneously hypertensive rat (SHR). An adenovirus (5x10(10) particles) constructed with a noradrenergic neuron-specific promoter (PRS x8) encoding nNOS (Ad.PRS-nNOS) or enhanced green fluorescence protein (Ad.PRS-eGFP) was targeted to the right atrial wall by percutaneous injection in age-matched male SHRs and Wistar-Kyoto (WKY) rats. Five days after transduction, right atria were removed, and evoked [(3)H] norephinephrine (NE) release, NOS activity, and cGMP were measured. In the Ad.PRS-eGFP treated group, tissue levels of cGMP were significantly lower in the SHR compared with the WKY atria. NE release was also greater in the SHR, and soluble guanylate cyclase inhibition did not alter evoked [(3)H] NE release in the Ad.PRS-eGFP-treated SHR. All atria treated with Ad.PRS-nNOS had enhanced nNOS activity when compared with Ad.PRS-eGFP atria. Ad.PRS-nNOS in WKY rats reduced NE release compared with the Ad.PRS-eGFP group. Guanylate cyclase inhibition enhanced NE release in both Ad.PRS-nNOS- and Ad.PRS-eGFP-treated WKY atria. Ad.PRS-nNOS restored cGMP levels in the SHR to those seen in the WKY atria. In the SHR, Ad.PRS-nNOS also attenuated NE release compared with Ad.PRS-eGFP group. This was reversed by guanylate cyclase inhibition. We conclude that artificial upregulation of sympathetic nNOS via gene transfer with a noradrenergic promoter may provide a novel approach for correcting peripheral sympathetic hyperactivity in hypertension.

A Cause for Central Sympathetic Hyperactivity in Hypertension

A Cause for Central Sympathetic Hyperactivity in Hypertension

Single-unit sympathetic discharge : quantitative assessment in human hypertensive disease.

Background-Reports demonstrating sympathetic hyperactivity in hypertension with the use of microneurography have been inconsistent. One possible reason is that previous studies have assessed muscle sympathetic nerve activity (MSNA) from integrated voltage waves ("bursts") recorded from multiunit discharges. We studied single units with defined vasoconstrictor properties (s-MSNA) to further characterize sympathetic output in hypertensive disease. Methods and Results-We examined 74 subjects with a wide range of arterial blood pressure that were considered to be either normal (NT), high normal (HN), or stages 1 to 3 essential hypertension (EHT-1, EHT-2/3). All had their peripheral sympathetic activity measured from both multiunit bursts and single-unit vasoconstrictor impulses. There was a significant correlation between s-MSNA and MSNA, and results of variability studies were similar. The EHT-1 and EHT-2/3 groups had greater s-MSNA and MSNA than did the matched NT group (always P<0. 01). The HN group also had greater s-MSNA and MSNA than did the NT group (mean+/-SEM; 43+/-5 vs 29+/-2 impulses/100 beats, P<0.05; 36+/-4 vs 24+/-2 bursts/100 beats, P<0.05). In addition, the EHT-1 group had significantly greater s-MSNA than did the EHT-2/3 group (63+/-6 vs 51+/-3 impulses/100 beats, P<0.05), which could not be demonstrated with MSNA bursts. Conclusions-Quantification from single vasoconstrictor units has provided additional evidence in established essential hypertension of increased central sympathetic output. Furthermore, in the mild or early stages of hypertension, this technique has provided new evidence of augmented sympathetic output compared with more severe hypertension.

Autonomic modulation of heart rate and blood pressure in hypertensive subjects with symptoms of anxiety

1. The influence of anxiety symptoms on autonomic nervous system cardiovascular control has never been studied in hypertensive subjects. This study was designed to verify the presence of sympathetic hyperactivity in hypertension associated with anxiety symptoms. 2. Neuroautonomic cardiovascular control was evaluated using short-time power spectral analysis of RR and arterial pressure variability at baseline and after the head-up tilt test. The two spectral components principally influenced by the autonomic nervous system are the low-frequency (LF) component, mainly though not exclusively due to sympathetic modulation, and the high-frequency (HF) component, due to parasympathetic activity. The ratio of LF to HF powers (LF:HF) provides an index of the sympathovagal sinus balance. 3. We studied 33 hypertensive subjects (mean age 47+/-1 years; M:F=19:14) and 37 normotensive control subjects (mean age: 47+/-2 years; M:F=20:17) divided into four subgroups: hypertensive subjects who scored 2 or more on a 5-item anxiety symptom scale, hypertensive subjects who scored 0, normotensive controls who scored 2 or more and normotensive controls who scored 0. LF:HF and LF during rest were significantly higher (P<0.05) in hypertensive and normotensive groups with an anxiety score of 2 or more compared with the two groups who scored 0. HF of systolic blood pressure was significantly lower in the hypertensive group who scored 2 or more than in the hypertensive group who scored 0 (P<0.05). Tilt in both hypertensive groups reporting anxiety symptoms left the indexes of sympathetic modulation unchanged. Tilt in hypertensive subjects reporting anxiety symptoms also induced a significant fall in arterial pressure (P<0.05). The mean left ventricular mass index was significantly higher in the hypertensive subjects who had anxiety scores of 2 or more than in those scoring 0 (144.7+/-3.0 versus 133. 4+/-2.31, P<0.05). 4. In conclusion, normotensive and hypertensive subjects reporting anxiety symptoms showed increased sympathetic modulation of heart rate at rest. Higher anxiety scores seem to be associated with the development of left ventricular hypertrophy.