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This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI. Methods: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0%CO2) and normoxic-hypercapnia (21%O2, 5%CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. Results: Therewere no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1mth post-bleo. However, at D7 post-bleo, themale rats exhibited a higher AHI than female rats. Bothmale and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes. Conclusion: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders. [ABSTRACT FROM AUTHOR]

Skeletal muscle contraction evokes numerous biochemical alterations that underpin exercise benefits. This present study aimed to elucidate the mechanism for electrical pulse stimulation (EPS)-induced antioxidant adaptation in C2C12 myotubes. We found that EPS significantly upregulated Nrf2 and a broad array of downstream antioxidant enzymes involved in multiple antioxidant systems. These effects were completely abolished by pretreatment with a ROS scavenger, N-acetylcysteine. MitoSOX-Red, CM-H2DCFDA, and EPR spectroscopy revealed a significantly higher ROS level in mitochondria and cytosol in EPS cells compared to non-stimulated cells. Seahorse and Oroboros revealed that EPS significantly increased the maximal mitochondrial oxygen consumption rate, along with an upregulated protein expression of mitochondrial complexes I/V, mitofusin-1, and mitochondrial fission factor. A post-stimulation time-course experiment demonstrated that upregulated NQO1 and GSTA2 last at least 24 h following the cessation of EPS, whereas elevated ROS declines immediately. These findings suggest an antioxidant preconditioning effect in the EPS cells. A cell viability study suggested that the EPS cells displayed 11- and 36-fold higher survival rates compared to the control cells in response to 2 and 4 mM H2O2 treatment, respectively. In summary, we found that EPS upregulated a large group of antioxidant enzymes in C2C12 myotubes via a contraction-mitochondrial-ROS-Nrf2 pathway. This antioxidant adaptation protects cells against oxidative stress-associated cytotoxicity. [ABSTRACT FROM AUTHOR]

It has been clearly established that increased circulating angiotensin II (ANG II) with concurrent upregulation of brain and peripheral ANG II type 1 receptors ([AT.sub.1]R) are important mediators in the pathophysiology of several diseases characterized by sympatho-excitation. In an effort to further understand the regulation of [AT.sub.1]R expression in neurons, we determined the role of sequential activation of the transcription factors nuclear factor-[kappa]B (NF-[kappa]B) and Ets-like protein 1 (Elk-1) in [AT.sub.1]R upregulation. We used CATH.a neurons as our neuronal cell model. Cells were treated with ANG II (100 nM) over a preset time course. Following ANG II activation, there was a temporal increase in the p65 subunit of NF-[kappa]B that was observed at 30 min, peaked at 1 h, and was sustained up to 24 h. There was a concomitant decrease of I[kappa]B and increased I[kappa]K expression. We also observed an increase in [AT.sub.1]R expression which followed the temporal increase of NF-[kappa]B. The activation of NF-[kappa]B was blocked by using the inhibitors parthenolide or p65 small interfering RNA (siRNA) which both led to a decrease in [AT.sub.1]R expression. The expression of Elk-1 was upregulated over a time period following ANG II activation and was decreased following NF-[kappa]B inhibition, p65-DNA binding was assessed using electrophoretic mobility shift assay, and it was shown that there was a time-dependent increased binding that was inhibited by means of parthenolide pretreatment or siRNA-mediated p65 gene silencing. Therefore, our results suggest a combined role for the transcription factors NF-[kappa]B and Elk-1 in the upregulation of [AT.sub.1]R in the CATH.a cell neuronal model. These data imply a positive feedback mechanism that may impact neuronal discharge sensitivity in response to ANG II. CATH.a; cell culture; G protein-coupled receptors; small interfering RNA; angiotensin II type 1 receptor doi: 10.1152/ajpcell.00127.2010.

Angiotensin type 1 receptors ([AT.sub.1]Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which [AT.sub.1]Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of [AT.sub.1]R regulation in the setting of chronic heart failure (CHF). There is now good evidence that [AT.sub.1]R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in [AT.sub.1]R expression and transcription factor activation can be blocked by the [AT.sub.1]R antagonist losartan, a positive feedback mechanism of [AT.sub.1]R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of [AT.sub.1]R expression by altering the balance between the octapeptide ANG II and ANG(1-7). Finally, exercise training reduces both central oxidative stress and [AT.sub.1]R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter [AT.sub.1]R expression in CHF. sympathetic nerve activity; neuronal signaling; oxidative stress doi: 10.1152/ajpheart.00073.2009.

Several sympathoexcitatory reflexes, such as the cardiac sympathetic afferent reflex (CSAR) and arterial chemoreflex, are significantly augmented and contribute to elevated sympathetic outflow in chronic heart failure (CHF). This study was undertaken to investigate the interaction between the CSAR and the chemoreflex in CHF and to further identify the involvement of angiotensin II type 1 receptors (AT1 Rs) in the nucleus of the tractus solitarius (NTS) in this interaction. CHF was induced in rats by coronary ligation. Acute experiments were performed in anesthetized rats. The chemoreflex-induced increase in cardiovascular responses was significantly greater in CHF than in sham-operated rats after either chemical or electrical activation of the CSAR. The inhibition of the CSAR by epicardial lidocaine reduced the chemoreflex-induced effects in CHF rats but not in sham-operated rats. Bilateral NTS injection of the [AT.sub.1]R antagonist losartan (10 and 100 pmol) dose-dependently decreased basal sympathetic nerve activity in CHF but not in sham-operated rats. This procedure also abolished the CSAR-induced enhancement of the chemoreflex. The discharge and chemosensitivity of NTS chemosensitive neurons were significantly increased following the stimulation of the CSAR in sham-operated and CHF rats, whereas CSAR inhibition by epicardial lidocaine significantly attenuated chemosensitivity of NTS neurons in CHF but not in sham-operated rats. Finally, the protein expression of [AT.sub.1]R in the NTS was significantly higher in CHF than in sham-operated rats. These results demonstrate that the enhanced cardiac sympathetic afferent input contributes to an excitatory effect of chemoreflex function in CHF, which is mediated by an NTS-[AT.sub.1]R-dependent mechanism. sympathoexcitatory reflexes; sympathetic activity; angiotensin II type 1 receptor; microinjection; extracellular recording; nucleus of tractus solitarius

The present study tested the hypothesis that nitric oxide (NO) contributes to impaired baroreflex gain of pregnancy and that this action is enhanced by angiotensin II. To test these hypotheses, we quantified baroreflex control of heart rate in nonpregnant and pregnant conscious rabbits before and after: 1) blockade of NO synthase (NOS) with [N.sup.[omega]]-nitro-L-arginine (20 mg/kg iv); 2) blockade of the angiotensin II A[T.sub.1] receptor with L-158,809 (5 [micro]g x [kg.sup.-1] x [min.sup.-1] iv); 3) infusion of angiotensin 1I (1 ng x [kg.sup.-1] x [min.sup.-1] nonpregnant, 1.6-4 ng x [kg.sup.-1] x [min.sup.-1] pregnant iv); 4) combined blockade of angiotensin II A[T.sub.1] receptors and NOS; and 5) combined infusion of angiotensin II and blockade of NOS. To determine the potential role of brain neuronal NOS (nNOS), mRNA and protein levels were measured in the paraventricular nucleus, nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla in pregnant and nonpregnant rabbits. The decrease in baroreflex gain observed in pregnant rabbits (from 23.3 [+ or -] 3.6 to 7.1 [+ or -] 0.9 beats x [min.sup.-1] x mm[Hg.sup.-1], P < 0.05) was not reversed by NOS blockade (to 8.3 [+ or -] 2.5 beats x [min.sup.-1] x mm[Hg.sup.-1]), angiotensin II blockade (to 5.0 [+ or -] 1.1 beats x [min.sup.-1] x mm[Hg.sup.-1]), or combined blockade (to 12.3 [+ or -] 4.8 beats x [min.sup.-1] x mm[Hg.sup.-1]). Angiotensin II infusion with (to 5.7 [+ or -] 1.0 beats x [min.sup.-1] x mm[Hg.sup.-1]) or without (to 8.4 [+ or -] 2.4 beats x [min.sup.-1] x mm[Hg.sup.-1]) NOS blockade also failed to improve baroreflex gain in pregnant or nonpregnant rabbits. In addition, nNOS mRNA and protein levels in cardiovascular brain regions were not different between nonpregnant and pregnant rabbits. Therefore, we conclude that NO, either alone or via an interaction with angiotensin H, is not responsible for decrease in baroreflex gain during pregnancy. conscious rabbits; L-158,809; neuronal nitric oxide synthase; [N.sup.[omega]]-nitro-L-arginine; A[T.sub.1]-receptor blockade doi: 10.1152/ajpregu.00026.2007

The cardiac 'sympathetic afferent' reflex (CSAR) has been reported to increase sympathetic outflow and depress baroreflex function via a central angiotensin II (ANG II) mechanism. In the present study, we examined the role of ANG II type 1 (ATe) receptors in the nucleus tractus solitarii (NTS) in mediating the interaction between the CSAR and the baroreflex in anesthetized rats. We examined the effects of bilateral microinjection of [AT.sub.1] receptor antagonist losartan (100 pmol) into the NTS on baroreflex control of renal sympathetic nerve activity (RSNA) before and after CSAR activation by epicardial application of capsaicin (0.4 [micro]g). Using single-unit extracellular recording, we further examined the effects of CSAR activation on the barosensitivity of barosensitive NTS neurons and the effects of intravenous losartan (2 mg/kg) on CSAR-induced changes in activity of NTS barosensitive neurons. Bilateral NTS microinjection of losartan significantly attenuated the increases in arterial pressure, heart rate, and RSNA evoked by capsaicin but also markedly (P < 0.01) reversed the CSAR-induced blunted baroreflex control of RSNA ([Gain.sub.max] from 1.65 [+ or -] 0.10 to 2.22 [+ or -] 0.11%/mmHg). In 17 of 24 (70.8%) NTS barosensitive neurons, CSAR activation significantly (P < 0.01) inhibited the baseline neuronal activity and attenuated the neuronal barosensitivity. In 11 NTS barosensitive neurons, intravenous losartan effectively (P < 0.01) normalized the decreased neuronal barosensitivity induced by CSAR activation. In conclusion, blockade of NTS [AT.sub.1] receptors improved the blunted baroreflex during CSAR activation, suggesting that the NTS plays an important role in processing the interaction between the baroreflex and the CSAR via an [AT.sub.1] receptor-dependent mechanism. cardiovascular reflexes; losartan; renal sympathetic nerve activity; microinjection; extracellular recording; barosensitivity