Neurogenic Background for Emotional Stress-Associated Hypertension.

PURPOSE OF REVIEW: The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. RECENT FINDINGS: The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressure and even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.

Alamandine but not angiotensin-(1-7) produces cardiovascular effects at the rostral insular cortex.

Experiments aimed to evaluate the tissue distribution of Mas-related G protein-coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. To investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40 pmol/100 nL), angiotensin-(1-7), angiotensin II, angiotensin A, and Mas/MrgD antagonist d-Pro7-Ang-1-7 (50 pmol/100 nL), Mas antagonist A779 (100 pmol/100 nL), or vehicle (0.9% NaCl) were made in different rats (n = 4-6/group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ = 15 ± 2 mmHg), HR (Δ = 36 ± 4 beats/min), and RSNA (Δ = 31 ± 4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1-7) at rIC did not produce any change in MAP, HR, and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist d-Pro7-Ang-(1-7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1-7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1-7) in the brain.

Tachycardia evoked from insular stroke in rats is dependent on glutamatergic neurotransmission in the dorsomedial hypothalamus.

BACKGROUND AND PURPOSE: Damage to the insula results in cardiovascular complications. In rats, activation of N-methyl-d-aspartate receptors (NMDARs) in the intermediate region of the posterior insular cortex (iIC) results in sympathoexcitation, tachycardia and arterial pressure increases. Similarly, focal experimental hemorrhage at the iIC results in a marked sympathetic-mediated increase in baseline heart rate. The dorsomedial hypothalamic region (DMH) is critical for the integration of sympathetic-mediated tachycardic responses. Here, whether responses evoked from the iIC are dependent on a synaptic relay in the DMH was evaluated. METHODS: Wistar rats were prepared for injections into the iIC and DMH. Anatomical (tracing combined with immunofluorescence) and functional experiments (cardiovascular and sympathetic recordings) were performed. RESULTS: The iIC sends dense projections to the DMH. Approximately 50% of iIC neurons projecting to the DMH express NMDARs, NR1 subunit. Blockade of glutamatergic receptors in the DMH abolishes the cardiovascular and autonomic responses evoked by the activation of NMDARs in the iIC (change in mean arterial pressure 7 ± 1 vs. 1 ± 1 mmHg after DMH blockade; change in heart rate 28 ± 3 vs. 0 ± 3 bpm after DMH blockade; change in renal sympathetic nerve activity 23% ± 1% vs. -1% ± 4% after DMH blockade). Experimental hemorrhage at the iIC resulted in a marked tachycardia (change 89 ± 14 bpm) that was attenuated by 65% ± 5% (p = 0.0009) after glutamatergic blockade at the DMH. CONCLUSIONS: The iIC-induced tachycardia is largely dependent upon a glutamatergic relay in the DMH. Our study reveals the presence of an excitatory glutamatergic pathway from the iIC to the DMH that may be involved in the cardiovascular alterations observed after insular stroke.

Stating asymmetry in neural pathways: methodological trends in autonomic neuroscience.

Aim: Many particularities concerning interhemispheric differences still need to be explored and unveiled. Functional and anatomical differential features found between left and right brain sides are best known as asymmetries and are consequence of the unilateral neuronal recruitment or predominance that is set to organize some function. The outflow from different neural pathways involved in the autonomic control of the cardiovascular system may route through asymmetrically relayed efferences (ipsilateral/lateralized and/or contralateral). In spite of this, the literature reporting on the role of central nuclei involved in the autonomic control is not always dedicated on these interhemispheric comparisons. Considering the recent reports demonstrating that asymmetries may set differential functional responses, it is worth checking differences between right and left sides of central regions. This review aims to inspire neuroscientists with the idea that studying the interhemispheric differences may deepen the understanding on several centrally controlled responses, with special regard to the autonomic functions underlying the cardiovascular regulation. Conclusions: Thus, an avenue of knowledge may unfold from a field of research that requires further exploration.

Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex.

Cardiovascular (CV) representation has been identified within the insular cortex (IC) and a lateralization of function previously suggested. In order to further understand the role of IC on cardiovascular control, the present study compared the CV responses evoked by stimulation of N-metil-D-aspartate (NMDA) receptors in the right and left posterior IC at different rostrocaudal levels. Intracortical microinjections of NMDA were performed into the IC of male Wistar rats anaesthetized with urethane (1.4 g/kg) prepared for blood pressure, heart rate and renal sympathetic nerve activity. Gene expression of NMDA receptor subunits NR2A and NR2B in the IC was confirmed by RT-PCR. Immunofluorescence for the NMDA receptor NR1 subunit was demonstrated in the IC (coordinates anteroposterior (AP) +1.5, 0.0 and -1.5 mm). A cardiac sympathoinhibitory site was identified, more rostrally located than identified in previous studies. A site of sympathoexcitatory cardiac control was identified more caudal to this region in agreement with earlier work. Under the experimental conditions, no lateralization of cardiovascular function was identified with chemical stimulation eliciting the same responses from either left or right insular cortices. No tonic role of the insula on cardiovascular control was identified with the use of the NMDA antagonist, AP-5. Peri-insular microinjection of NMDA was without cardiovascular effect indicating the specificity of the insula as a cardiovascular regulatory site. The current study reveals a functional topography for autonomic cardiovascular control along the rostrocaudal axis of the posterior IC.

Autonomic and cardiovascular consequences resulting from experimental hemorrhagic stroke in the left or right intermediate insular cortex in rats.

Damage to the insular cortex (IC) results in serious cardiovascular consequences and evidence indicates that the characteristics are lateralized. However, a study comparing the effects of focal experimental hemorrhage between IC sides was never performed. We compared the cardiovascular, autonomic and cardiac changes produced by focal experimental hemorrhage (ICH) into the left (L) or right (R) IC. Wistar rats were submitted to microinjection of autologous blood (ICH) or saline (n = 6 each side/group) into the R or L IC. Blood pressure (BP), heart rate (HR) and renal sympathetic activity (RSNA) were recorded. Measurements of calcium transient and sarcoplasmic Ca2+ ATPase expression in cardiomyocytes were performed. ICH increased baseline HR (Δ:L-ICH 452 ± 13 vs saline 407 ± 11 bpm; R-ICH 450 ± 7 vs saline 406 ± 8 bpm, P < 0.05) without changing BP. HR was restored to baseline levels after i.v. atenolol. Strikingly, ICH rats presented a reduced baseline RSNA (Δ:L-ICH 122 ± 4 vs saline 148 ± 11 spikes/s; R-ICH 112 ± 5 vs saline 148 ± 7 spikes/s, P < 0.05). After 24 h of ICH we observed a marked increase in cardiac ectopies and this number was greater after ICH R-IC. Heart weight, calcium amplitude and SERCA expression were reduced only in ICH R-IC. Focal stroke into IC can alter the cardiac and renal autonomic control. Damage to the R-IC produces a greater number of arrhythmias and changes in calcium dynamics in cardiac cells indicating that the cardiovascular consequences are hemisphere-dependent. These findings confirm asymmetry for cardiac autonomic control at the IC and help to understand the cardiac and renal implications observed after specific side cortical damage.

Asymmetric sympathetic output: The dorsomedial hypothalamus as a potential link between emotional stress and cardiac arrhythmias.

The autonomic response to emotional stress, while involving several target organs, includes an important increase in sympathetic drive to the heart. There is ample evidence that cardiac sympathetic innervation is lateralized, and asymmetric autonomic output to the heart during stress is postulated to be a causal factor that precipitates cardiac arrhythmias. Recent animal studies provided a new picture of the central pathways involved in the cardiac sympathetic response evoked by emotional stress, pointing out a key role for the region of dorsomedial hypothalamus. However, how much of this information can be extrapolated to humans? Analysis of human functional imaging data at rest or during emotional stress shows some consistency with the components that integrate these pathways, and attention must be given to the asymmetric activation of subcortical sites. In this short review, we will discuss related findings in humans and animals, aiming to understand the neurogenic background for the origin of emotional stress-induced cardiac arrhythmias.

Emotional stress and sympathetic activity: contribution of dorsomedial hypothalamus to cardiac arrhythmias.

Maintenance of homeostasis in normal or stressful situations depends upon mechanisms controlling autonomic activity. Central requirement for changes in sympathetic output resulting from emotional stress must be adjusted to the input signals from visceral sensory afferent (feedback response) for an optimum cardiovascular performance. There is a large body of evidence indicating that emotional stress can lead to cardiovascular disease. Reviewing the descending pathways from dorsomedial hypothalamus, a key region involved in the cardiovascular response to emotional stress, we discuss the interactions between mechanisms controlling the sympathetic output to the cardiovascular system and the possible implications in cardiovascular disease.

Excitatory amino acid receptors mediate asymmetry and lateralization in the descending cardiovascular pathways from the dorsomedial hypothalamus.

The dorsomedial hypothalamus (DMH) and lateral/dorsolateral periaqueductal gray (PAG) are anatomically and functionally connected. Both the DMH and PAG depend on glutamatergic inputs for activation. We recently reported that removal of GABA-ergic tone in the unilateral DMH produces: asymmetry, that is, a right- (R-) sided predominance in cardiac chronotropism, and lateralization, that is, a greater increase in ipsilateral renal sympathetic activity (RSNA). In the current study, we investigated whether excitatory amino acid (EAA) receptors in the DMH-PAG pathway contribute to the functional interhemispheric difference. In urethane (1.2 to 1.4 g/kg, i.p.) anesthetized rats, we observed that: (i) nanoinjections of N-methyl D-aspartate (NMDA 100 pmol/100 nl) into the unilateral DMH produced the same right-sided predominance in the control of cardiac chronotropy, (ii) nanoinjections of NMDA into the ipsilateral DMH or PAG evoked lateralized RSNA responses, and (iii) blockade of EAA receptors in the unilateral DMH attenuated the cardiovascular responses evoked by injection of NMDA into either the R- or left- (L-) PAG. In awake rats, nanoinjection of kynurenic acid (1 nmol/100 nL) into the L-DMH or R- or L-PAG attenuated the tachycardia evoked by air stress. However, the magnitude of stress-evoked tachycardia was smallest when the EAA receptors of the R-DMH were blocked. We conclude that EAA receptors contribute to the right-sided predominance in cardiac chronotropism. This interhemispheric difference that involves EAA receptors was observed in the DMH but not in the PAG.