Increases in conscious cardiac interoception explain the ability of some individuals with anxiety to feel their heartbeat without taking their pulse. Subconscious cardiac interoception is the detection of heart signals from baroreceptors without subjective awareness. We tested our hypothesis that contrasting sensitivity of PIEZO 1 stretch channels mediates both forms of cardiac interoception and feelings of anxiety. In healthy volunteers, we found conscious cardiac interoception assessed by measuring heartbeat detection accuracy was increased with lower heart rates and greater stroke volumes and cardiac stretch but not associated with anxiety. Disruption of Piezo 1 in cardiac sensory neurons enhanced anxiety in rodents. Accordingly, we used an ex vivo assay of PIEZO 1 sensitivity to correlate subconscious cardiac interoception with anxiety in men and women. When compared to healthy individuals with lower PIEZO 1 sensitivity, men and women with higher PIEZO 1 activity had marked diminution in state anxiety. Those with lower anxiety also had enhanced variability in their instantaneous baroreceptor sensitivity at rest and reduced cardiac rate pressure products following stress. We propose that a reduction in PIEZO 1 sensitivity causes errors in predictive coding; the imbalance between expected and actual heart rate responses to changes in blood pressure leads to anxiety and increased cardiac workloads. We also report testosterone, which is anxiolytic, enhanced, whereas the stress hormone corticosterone, decreased Piezo 1 gene transcription. Selectively enhancing subconscious interoception by increasing PIEZO 1 sensitivity may improve predictive coding, cardiovascular outcomes, and ameliorate the subjective manifestations of anxiety.

Physical trauma, psychosocial stress, and oxidative stress increase the neuronal transcription ratio of genes encoding the sodium-potassium chloride cotransporter (Nkcc1, Slc12a2) and the potassium chloride cotransporter (Kcc2, Slc12a5), which leads to neuronal depolarization and excitability. We hypothesized that increases in the Nkcc1:Kcc2 ratio of gene transcription in these injuries would be countered with downregulation of the gene encoding the cardiac and neuronal isoform of the chloride/bicarbonate exchanger (Ae3, Slc4a3). We found a reflex decrease in cardiac and neuronal Ae3 transcription that was associated with diminished traumatic brain injury (TBI)-induced increases in systolic blood pressure and decrements in heart rate and posttraumatic stress disorder (PTSD)-induced anxiety. We also observed pronounced sex differences in Nkcc1:Kcc2 expression, with female control and Ae3 knockout mice exhibiting significantly higher brain Nkcc1:Kcc2 ratios compared with males. Administration of testosterone after injury reduced the excessive cardiovascular reactivity induced by TBI. We suggest that pharmacologic antagonism of the cardiac/neuronal isoform of Ae3, perhaps with testosterone supplementation, may prove salutary in reducing the adverse cardiovascular and behavioral sequelae of TBI or psychological stress.NEW & NOTEWORTHY Our findings may lead to a new way to effectively treat the chronic stress, anxiety, and excessive cardiovascular reactivity that frequently follow head injuries, such as sports concussion.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.

Introduction: Many of the receptors for the exteroceptive senses (e.g. vision, hearing, smell, touch, pain, etc.) are known. Interoception allows us to sense threats to our “milieu interior.” The mechanisms by which threats induce a feeling of anxiety manifested by heart palpitations, shortness of breath (dyspnea), and gastric awareness (queasiness) are unknown. Using photoplethysmography, we reported that individual variation in cardiac interoception, i.e. the ability to feel a change in one’s heartbeat without taking one’s pulse, correlated with contrasts in heart rate and stroke volumes among the population. Hypothesis: Because increases in heart rate and stroke volume raise cardiac contractility, we postulated that stretch activated piezo channels in the heart are responsible for cardiac interoception. Methods: Interoceptive awareness was determined with a ten point Likert scale in which volunteers rated their ability to feel their heartbeat. Interoceptive accuracy was measured by asking subjects to count their heartbeats without taking their pulse over four time intervals in random order. Simultaneously, heart rates were surreptitiously recorded with a two lead electrocardiogram (EKG). Cardiac interoceptive accuracy was calculated using the formula 1/4 Σ [1 − (|EKG measured heartbeats − subjectively reported heartbeats|) / EKG measured heartbeats]. We used 2D speckle tracking ultrasound to measure the relationship between cardiac strain patterns, normalized for heart rate (HR) and body surface area (BSA), and cardiac interoception in 12 resting men and women. We also measured gastric interoception by determining the percent increase in the volume of water some subjects could drink after reporting water satiety. Results: Cardiac interoceptive awareness correlated with interoceptive accuracy ( r = 0.73, p = 0.009). Speckle tracking of cardiac chambers with echocardiography demonstrated that global longitudinal left ventricular (LV) strain correlated with total left ventricular preload (atrial reservoir strain, r = 0.83, p = 0.0009) and early diastolic filling (atrial conduit strain, r = 0.88, p = 0.0002). LV strain also correlated with interoceptive awareness ( r = 0.58, p = 0.046). When stratified, individuals with the highest interoceptive accuracy (n = 6), compared to those with the lowest interoceptive accuracy (n = 6), had less LV strain, [values expressed as (percent change/BSA)*HR ± S.E.M., 828 ± 81 vs. 582 ± 47, p = 0.026]. Cardiac interoceptive awareness also correlated with gastric interoception accuracy, (n = 6) r = 0.90, p = 0.015. Conclusions: Changes in the activation of cardiac stretch receptors by cardiac filling and contractility could modify interoceptive awareness in men and women at rest. Contrasts in stretch receptor activation in other contractile organs (e.g. stomach) could explain variation in interoceptive awareness in the population. Henry M. Jackson Foundation for the Advancement of Military Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Introduction: We demonstrated traumatic brain injury (TBI)-dependent increases in cardiovascular reactivity are associated with increased transcription ratio of the genes controlling intraneuronal chloride concentrations, the sodium chloride cotransporter-1 (Nkcc1) and the potassium chloride cotransporter-2 (Kcc2). We also found that in an effort to maintain constant intraneuronal chloride concentrations, greater Nkcc1:Kcc2 ratios are inversely correlated with the expression of the neuronal chloride/bicarbonate exchanger (Ae3). Hypothesis: Enhancement of Nkcc1:Kcc2 represents a generalized response to hazards confronting the milieu interior, and other challenges such as post-traumatic stress (PTS) would similarly increase Nkcc1:Kcc2 and correspondingly diminish Ae3 expression. Conversely, reductions in the expression of neuronal Ae3 could raise the Nkcc1:Kcc2 ratio and alter cardiovascular reactivity after TBI. Methods: PTS was induced in C57Bl/6 mice with intermittent, unpredictable foot shocks and noise exposure, and mRNA from brain tissue was extracted and quantified for Nkcc1, Kcc2, and Ae3 with RT-PCR. In a separate cohort of FVB/N mice, blood pressure (SBP) and heart rates (HR) were assessed noninvasively in awake, control mice and those with targeted disruption of Ae3 after TBI was induced with mild cortical impact; transcription levels of Nkcc1 and Kcc2 were measured similarly. Results: Compared to control mice, PTS increased the Nkcc1:Kcc2 ratio from (values in percent ± SEM), 1.70 ± 0.14 vs. 4.79 ± 0.53, p < 0.0001, n ≥ 10, and decreased the expression of Ae3 (values expressed as 2^[-Ct] ± SEM) from 5.78 x 10−8 2.21 x 10−8, p < 0.0001. However, the Nkcc1:Kcc2 ratio correlated significantly with Ae3 expression only in the mice without PTS, r = -0.41, p = 0.026. In our cohort of mice with targeted disruption of Ae3, Nkcc1:Kcc2 ratios were unchanged between our inbred FVB/N control mice and knockout animals on an FVB/N background (0.51 ± 0.02 vs. 0.63 ± 0.02, p = n.s.) before surgery, but these values were much lower than the ratios from commercially obtained FVB/N inbred mice (1.03 ± 0.07, p < 0.0001). After TBI, mice with targeted disruption of the Ae3 did not have different HR or blood pressure when compared to our inbred FVB/N mice. TBI increased HR only in the commercially obtained FVB/N mice compared to the knockout mice, but this is likely due to lower resting HR of the commercially obtained FVB/N mice. Conclusions: Similarly to what is found after the stress of TBI, mice with PTS had an increased Nkcc1:Kcc2 ratio, but the relationship between the Nkcc1:Kcc2 ratio and the chloride/bicarbonate exchanger is lost. When compared to commercially inbred FVB/N mice, loss of Ae3 increases HR after TBI, however, whether this relationship will be confirmed with truly inbred FVB/N mice remains to be determined. Henry M. Jackson Foundation for the Advancement of Military Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: The ADA recommends 150 minutes/week of physical activity for patients with diabetes mellitus (DM). Training-induced reductions in autonomic reactivity could impair awareness of hypoglycemia (IAH) in some patients with DM unless there are compensatory signals of low blood glucose not dependent upon the autonomic nervous system. The receptors for exteroceptive senses (e.g. temperature, pain, vision, hearing) are known, interoceptive signal transduction is unexplored. This mechanism allows us to detect the cardiac, respiratory, and gastric sensations from stress (“My heart is pounding,” and “I can’t breathe,” and I feel queasy”). Hypothesis: We posit cardiac interoceptive accuracy (IA) is impaired in patients with DM, but exercise training could enhance IA and reduce IAH. We assessed IA in healthy, fit subjects, and also, untrained men and women with DM. Methods: IA was determined by comparing the number of heartbeats a subject could count without taking their pulse while their EKG was surreptitiously recorded. Heart rate variability (HRV) was assessed by measuring the root mean square of successive differences of the interval between sequential heartbeats. Results: Although MAP was not significantly different between these two cohorts, when compared to DM (N=8), the fit subjects (N=9) had (all values in mean ± SEM) lower resting HR (63±3 vs. 85±4 bpm, p<0.001) and greater HRV (85±4 vs. 69±11 ms, p=0.01) and IA (82±7 vs. 50±12 in percent, p=0.02). Furthermore, HR was highly correlated with both HRV (r=−0.63, p=0.007) and IA (r=−0.72, p=0.001). Conclusion: Untrained DM have diminished IA which may be improved by fitness training without fear of worsening IAH; resting HR should be used to track changes in HRV and IA as DM subjects undergo fitness training. Disclosure J.Summers: None. Z.Miklja: None. W.Lockette: None.

BACKGROUND:Hypertensive individuals with higher heart rates and anxiety have greater cardiovascular morbidity and mortality. Despite the correlation between hypertension, heart rate, and anxiety, scant attention has been paid to the effect of hypertension drug therapy on behavioral outcomes in cardiovascular disease. Ivabradine, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated funny channels (HCNs), has been used clinically to reduce heart rates and has been shown to improve quality of life in patients with angina and heart failure. We postulated that in addition to lowering heart rate, ivabradine could reduce anxiety in mice exposed to a significant stress paradigm.METHODS:Mice underwent a stress induction protocol, subsequently they received either vehicle or ivabradine (10 mg/kg) via osmotic minipumps. Blood pressure and heart rates were measured with tail cuff photoplethysmography. Anxiety was assessed quantitatively through the open field test (OFT) and the elevated plus maze (EPM). Cognition was assessed with an object recognition test (ORT). Pain tolerance was measured by the hot plate test or subcutaneous injection of formalin. HCN gene expression was measured with RT-PCR.RESULTS:Ivabradine reduced resting heart rate in the stressed mice by 22%. Stressed mice treated with ivabradine displayed significantly greater exploratory behavior in the OFT, EPM, and ORT. The expression of central HCN channels was significantly reduced following stress.CONCLUSION:It is suggested from our findings that ivabradine can reduce anxiety following significant psychological stress. Reductions in heart rate may directly improve quality of life by reducing anxiety in patients with hypertension and high heart rates.

Introduction: Concussion, a form of mild traumatic brain injury (TBI), has an estimated annual incidence of 1-4 million cases in the US alone. Studies have documented impairments in cerebral vascular function following concussion which often coincide with other neurocognitive symptoms but, in some cases, persist despite symptom resolution. However, the majority of these studies were performed 3 months or less post-concussion. Therefore, we tested the hypothesis that cerebral vasodilator function is impaired in adults who had a concussion 6 months prior and are asymptomatic relative to healthy age- and sex- matched controls with no known history of concussion. Methods: Six adults (3 Male/3 Female, 26 ± 5 years) with a history of diagnosed concussion ~6 months prior to the study visit (average, 6 ± 1 months) and six controls (3 Male/3 Female, 28 ± 5 years) without a known history of concussion were recruited. Beat-to-beat blood pressure (finger photoplethysomography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound) and partial pressure of end-tidal carbon dioxide (P ET CO 2 ; capnography) were measured continuously during two-minutes of quiet supine rest and throughout a rebreathing protocol designed to increase P ET CO 2 up to +15mmHg. Cerebral vascular conductance index (CVCi) was calculated as mean MCAv divided by mean arterial pressure (MAP) on a beat-to-beat basis. Cerebrovascular reactivity was assessed as the percent change in MCAv or CVCi at increasing levels of P ET CO 2 (Δ3,6,9,12,15 mmHg P ET CO 2 ) and the gain of the relationship between MCAv or CVCi and P ET CO 2 . Results: Resting MAP (P=0.33), MCAv (control: 76 ± 6 cm/sec; TBI: 74 ± 8 cm/sec, P=0.82), and CVCi (control: 0.91 ± 0.08 cm/sec/mmHg; TBI: 0.86 ± 0.11 cm/sec/mmHg, P=0.72) were not different between groups. The CO2 rebreathing protocol increased MCAv and CVCi in both groups (main effect of time; P<0.001 for both). However, the percent change in MCAv and CVCi did not differ between control and TBI participants throughout the rebreathing protocol (Interaction, P=0.13 and P=0.26, respectively). Likewise, the MCAv (control: 3.5 ± 0.4 cm/sec/mmHg; TBI: 4.0 ± 0.6 cm/sec/mmHg, P=0.51) and CVCi (P=0.72) gains were not different between groups. Conclusion: These preliminary findings suggest that individuals six-months post-concussion who are asymptomatic do not exhibit impaired cerebral vasodilator function. This project was supported by the Henry M Jackson Foundation HU0001-18-2-0016. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Introduction: Concussion is a form of traumatic brain injury (TBI) which temporarily disrupts normal brain function. It is well established that cardiac autonomic function is impaired immediately following concussion. However, studies investigating cardiac autonomic function as measures of spontaneous cardiac baroreflex sensitivity (BRS) and heart rate variability (HRV) beyond three months from the event are limited, and the results are inconsistent. Therefore, the purpose of this study was to investigate the lasting impact of concussion on cardiac BRS and HRV in participants who are beyond 3 months from their last concussion. We hypothesized that cardiac BRS and HRV would be impaired in adults who previously had a concussion compared to healthy controls with no known history of concussion. Methods: Five adults (3 females, 27 ± 6 years; mean ± standard error) with a diagnosed concussion prior to assessment (6.2 ± 0.5 months) and six controls (3 females, 27 ± 5 years) without a known history of concussion were studied. Heart rate (HR; ECG) and beat-to-beat blood pressure (BP; finger photoplethysmography) were recorded continuously during a five-minute supine rest period. Spontaneous cardiac BRS was estimated using the Sequence Method for overall BRS gains, then separately for up gains (increase systolic BP: increase R-R interval) and down gains (decrease systolic BP: decrease R-R interval). HRV was measured in the time-domain using the root mean square of successive differences between normal heartbeats (RMSSD), and in the frequency-domain using normalized low frequency (LF) and high frequency (HF) power, and as the LF/HF ratio. Results: There were no differences in resting BP or HR between groups (P > 0.050 for both). Overall cardiac BRS gains was also not different between controls (20.3 ± 4.3 ms/mmHg) and participants with TBI (28.6 ± 9.3 ms/mmHg, P = 0.4116). Likewise, we found no group differences for up and down gains (P > 0.050 for both). For HRV measures, no differences between groups were observed for RMSSD (control: 63 ± 20 ms; TBI: 63 ± 21 ms, P = 0.890), LF power (control: 40 ± 9 n.u.; TBI: 40 ± 14 n.u.; P > 0.999), HF power (control: 56 ± 9 n.u.; TBI: 57 ± 14 n.u.; P = 0.940), or the LF/HF ratio (control: 1.08 ± 0.50; TBI: 1.49 ± 0.85; P = 0.792). Conclusion: These preliminary findings suggest that, in contrast to our hypothesis, adults at six months post-concussion do not demonstrate impairments in any indices of cardiac autonomic function. This project was supported by the Henry M. Jackson Foundation HU0001-18-2-0016. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We demonstrate that inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) improves cardiovascular and behavioral outcomes following TBI. BACKGROUND Increased catecholamines contribute to heightened cardiovascular reactivity and behavioral deficits after traumatic brain injury (TBI); adrenergic receptor blockade has limited success in reducing adverse sequelae of TBI. Injury-induced increases in the synthesis of catecholamines could contribute to adverse outcomes in TBI. Inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) could offer a benefit after TBI. METHODS Original research trial in mice randomized to αMT (50 mg·kg−1·d−1) or vehicle for 1 week after TBI induced by controlled cortical impact. Primary outcomes of cardiovascular reactivity and behavioral deficits were assessed after 1 week. Secondary outcomes included blood brain barrier permeability and quantification of gene transcription whose products determine intraneuronal chloride concentrations, the release of catecholamines, and activation of the sympathetic nervous system. These genes were the alpha-2 adrenergic receptor (“Adra2c”), the sodium-potassium-chloride cotransporter (“Nkcc1”), and the potassium chloride cotransporter (“Kcc2”). We also assessed the effect of TBI and αMT on the neuronal chloride/bicarbonate exchanger (“Ae3”). RESULTS Traumatic brain injury–induced increases in blood pressure and cardiac reactivity were blocked by αMT. Inhibition of catecholamine synthesis decreased blood brain barrier leakage and improved behavioral outcomes after TBI. Traumatic brain injury diminished the transcription of Adra2c and enhanced expression of Nkcc1 while reducing Kcc2 transcription; αMT prevented the induction of the Nkcc1 by TBI without reversing the effects of TBI on Kcc2 expression; αMT also diminished Ae3 transcription. CONCLUSION Traumatic brain injury acutely increases cardiovascular reactivity and induces behavioral deficits in an αMT-sensitive manner, most likely by inducing Nkcc1 gene transcription. Alpha-methyltyrosine may prove salutary in the treatment of TBI by attenuating the enhanced expression of Nkcc1, minimizing blood brain barrier leakage, and diminishing central catecholamine and sympathetic output. We also found an unreported relationship between Kcc2 and the chloride/bicarbonate exchanger, which should be considered in the design of trials planned to manipulate central intraneuronal chloride concentrations following acute brain injury.

. Many of the sensory receptors that encode touch, temperature, pain, and visual or auditory cues are well known. These exteroceptive receptors allow us to respond to external threats from the environment. The interoceptive sensory receptors that allow us to identify threats within the internal milieu, such as changes of our heart rate brought about by fright, gastric fullness with satiety, or breathing difficulty from increased respiratory resistance are not known. We postulated that the mechanosensitive piezo receptors in the heart are responsible for cardiac interoception in humans. If true, individual contrasts in cardiac contractility among the population sensed by these stretch receptors in the heart could explain the ability of some men and women to “feel” their heart rate without taking their pulse.

We review the pathways by which arginine vasopressin (AVP) and hydration influence the sequelae of the metabolic syndrome induced by high fructose consumption. AVP and inadequate hydration have been shown to worsen the severity of two phenotypes associated with metabolic syndrome induced by high fructose intake–enhanced lipogenesis and insulin resistance. These findings have implications for those who frequently consume sweeteners such as high fructose corn syrup (HFCS). Patients with metabolic syndrome are at higher risk for microalbuminuria and/or chronic kidney disease; however, it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension, impaired glucose metabolism, and obesity. It is not surprising the prevalence of chronic renal insufficiency is growing hand in hand with obesity, insulin resistance, and metabolic syndrome in those who consume large amounts of fructose. Higher AVP levels and low hydration status worsen the renal insufficiency found in patients with metabolic syndrome. This inter-relationship has public health consequences, especially among underserved populations who perform physical labor in environments that place them at risk for dehydration. MesoAmerican endemic nephropathy is a type of chronic kidney disease highly prevalent in hot ambient climates from southwest Mexico through Latin America. There is growing evidence that this public health crisis is being spurred by greater fructose consumption in the face of dehydration and increased dehydration-dependent vasopressin secretion. Work is needed at unraveling the mechanism(s) by which fructose consumption and increased AVP levels can worsen the renal disease associated with components of the metabolic syndrome.

. Increasing fitness levels and endogenous PIEZO 1 channel activity correlate with enhanced "IA." Although the individual's stroke volume may be a determinant of their "IA," this self-awareness of heart beats and other interoceptive clues are sensitive to environmental factors such as mild thermal heating.

Aldosterone is a steroid hormone that regulates blood pressure and cardiovascular function by acting on renal and vascular mineralocorticoid receptors (MRs) to promote sodium retention and modulate endothelial function. Indeed, MRs are expressed in endothelial cells, vascular smooth muscle cells, adipocytes, immune cells, skeletal muscle cells, and cardiomyocytes. Excessive aldosterone and associated MR activation impair insulin secretion, insulin metabolic signaling to promote development of diabetes, and the related cardiometabolic syndrome. These adverse effects of aldosterone are mediated, in part, via increased inflammation, oxidative stress, dyslipidemia, and ectopic fat deposition. Therefore, inhibition of MR activation may have a beneficial effect in prevention of impaired insulin metabolic signaling, type 2 diabetes, and cardiometabolic disorders. This review highlights findings from the recent surge in research regarding MR-related cardiometabolic disorders as well as our contemporary understanding of the detrimental effects of excess MR activation on insulin metabolic signaling.

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K + ) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles. We hypothesized that TBI causes widespread disruption of electrical signaling from capillaries-to-arterioles through impairment of Kir2.1 channel function. We randomized mice to TBI or control groups and allowed them to recover for 4 to 7 days post-injury. We measured in vivo cerebral hemodynamics and arteriolar responses to local stimulation of capillaries with 10 mM K + using multiphoton laser scanning microscopy through a cranial window under urethane and α-chloralose anesthesia. Capillary angio-architecture was not significantly affected following injury. However, K + -induced hyperemia was significantly impaired. Electrophysiology recordings in freshly isolated capillary endothelial cells revealed diminished Ba 2+ -sensitive Kir2.1 currents, consistent with a reduction in channel function. In pressurized cerebral arteries isolated from TBI mice, K + failed to elicit the vasodilation seen in controls. We conclude that disruption of endothelial Kir2.1 channel function impairs capillary-to-arteriole electrical signaling, contributing to altered cerebral hemodynamics after TBI.

BackgroundAlpha‐2 adrenergic receptor (α2AR) agonists, such as clonidine or dexmedetomidine, can decrease the working memory acquisition of a traumatic event, and also, blocking the post‐synaptic action of the catecholamines with a β‐adrenergic receptor (β‐AR) antagonist, propranolol, can reduce the emotional response to memories of the traumatic event. α2ARs and β‐ARs divergently regulate neuronal intracellular cyclic adenosine monophosphate (cAMP) concentrations. It is suggested that other pharmacologic mechanisms that similarly lead to reductions in neuronal cAMP could also be salutary in the treatment of post‐traumatic stress (PTSD). In the central nervous system, hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) “funny” channels are important for dendritic integration, synaptic transmission, setting membrane potential, and neuronal firing rate. These funny channels (HCN1 and HCN2) are expressed in the forebrain and pre‐frontal cortex where they are co‐located and cross talk with A2ARs that mediate intracellular cAMP concentrations and drive working memory and the emotional valence associated with memories. Also, targeted disruption of HCN gene expression, or inhibition of cyclic nucleotide binding to HCN channels in the brain, has been shown to result in antidepressant‐like behavior with improved coping in animal models of stress.HypothesisWe postulated that pharmacological inhibition of HCN channels would diminish the anxiolytic and cognitive decline that occurs in an animal model of PTSD.MethodsWe infused an HCN antagonist, ivabradine (10 mg/kg/day), subcutaneously or performed sham surgery in a mouse model of PTSD. After six days of random cued and contextual fear conditioning, mouse anxiety and cognition was assessed by their performance over five minutes on three standard behavioral challenges—Open Field Test (OFT), Elevated Plus Maze (EPM), and Object Recognition Test (ORT).ResultsDuring the OFT, ivabradine did not significantly affected the total exploratory distance traveled. However, ivabradine significantly increased the time the mice spent in the center of the field (all values expressed in sec ± SEM), from 19.0 ± 2.2 to 27.7 ± 3.2, p = 0.029. During EPM, ivabradine increased the time mice spent traversing the open arm from 66.8 ± 8.5 to 116 ± 11.5, p = 0.002, During the ORT, social isolation during PTSD reduced total exploratory time from 24.7 ± 4.9 to 13.1 ± 2.2, and the ivabradine group increased exploratory time to 30.0 ± 3.3 compared to the mice living in isolation with PTSD (p = 0.0004). Furthermore, when compared to the untreated PTSD mice living in social isolation, ivabradine significantly increased the exploratory times of both familiar (14.3 ± 1.9 vs. 5.6 ± 1.1, p=0.0008) and novel objects (15.8 ± 2.4 vs. 7.5 ± 1.6, p = 0.01).ConclusionIvabradine may offer salutary advantage to men and women who experience PTSD.Support or Funding InformationDepartment of DefenseThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.