Pressor Response Research Articles

Mineralocorticoid receptor antagonism prevents coronary microvascular dysfunction in intermittent hypoxia independent of blood pressure.

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), and is associated with increased cardiovascular mortality that may not be reduced by standard therapies. Inappropriate activation of the renin-angiotensin-aldosterone system occurs in IH, and mineralocorticoid receptor (MR) blockade has been shown to improve vascular outcomes in cardiovascular disease. Thus, we hypothesized that MR inhibition prevents coronary and renal vascular dysfunction in mice exposed to chronic IH. Human and mouse coronary vascular cells and male C57BL/6J mice were exposed to IH or room air (RA) for 12 hours/day for 3 days (in vitro) and 6 weeks with or without treatments with spironolactone (SPL) or hydrochlorothiazide (HTZ). In vitro studies demonstrated that IH increased MR gene expression in human and mouse coronary artery endothelial and smooth muscle cells. Exposure to IH in mice increased blood pressure, reduced coronary flow velocity reserve (CFVR), and attenuated endothelium-dependent dilation and enhanced vasoconstrictor responsiveness in coronary, but not renal arteries. Importantly, SPL treatment prevented altered coronary vascular function independent of blood pressure as normalization of BP with HTZ did not improve CFVR or coronary vasomotor function. These data demonstrate that chronic IH, which mimics the hypoxia-reoxygenation cycles of moderate-to-severe OSA, increases coronary vascular MR expression in vitro. It also selectively promotes coronary vascular dysfunction in mice. Importantly, this dysfunction is sensitive to MR antagonism by SPL, independent of blood pressure. These findings suggest that MR blockade could serve as an adjuvant therapy to improve long-term cardiovascular outcomes in patients with OSA.

Blunted Exercise Pressor Response to Isometric Knee Extension and Post Exercise Ischemia in Individuals with Down Syndrome.

Individuals with Down syndrome (DS) exhibit autonomic dysfunction, which contributes to reduced work capacity. The metaboreflex produces exercise-induced sympathoexcitation and can be assessed via post-exercise muscle ischemia (PEMI). Blunted sympathoexcitation is common in individuals with DS and contributes to the physiological basis for reduced work capacity observed this population, but the influence of the metaboreflex is unknown. Using unilateral isometric knee extension exercise with PEMI, we hypothesized that individuals with DS would demonstrate a reduced metaboreflex compared to individuals without DS. Twenty-four individuals with DS (M/F: 13/11; 24 ± 5 years; 30.3 ± 6.2 kg/m2) and without DS (M/F: 13/11; 25 ± 4 years; 26.5 ± 4.5 kg/m2) performed a unilateral isometric knee extension at 30% of their maximal voluntary contraction (MVC) on a leg dynamometer. Following 2-min of contraction, a thigh-cuff was rapidly inflated to 220 mmHg on the exercised leg for 3-min to isolate the activation of the muscle metaboreflex via PEMI. Beat-to-beat mean and systolic blood pressure (MAP, SBP) were assessed using finger photoplethysmography. Heart rate (HR) was collected via 3-lead electrocardiogram. Despite similar baseline values of all variables in both groups, individuals with DS demonstrated a blunted pressor response to unilateral isometric knee extension compared to individuals without DS (MAP; DS: 103 ± 14 vs. Non-DS: 125 ± 19 mmHg), and the blunted MAP response was maintained with PEMI (MAP; DS: 95 ± 13 vs. Non-DS: 106 ± 18 mmHg; groupXtime interaction, p < 0.001). Individuals with DS also exhibited reduced HR 2-min into contraction compared to individuals without DS (HR; DS: 90 ± 16 vs. Non-DS: 114 ± 22 bpm; groupXtime interaction, p < 0.001). Individuals with DS demonstrated a diminished metaboreflex response compared to their peers without DS, during a task known to induce sympathoexcitation. Our findings suggest that reduced influence of the metaboreflex contributes to the reduced exercise pressor response in individuals with DS. Such exercise-specific peripheral autonomic alterations extend beyond our previous cardiac autonomic findings demonstrating blunted sympathoexcitatory perturbations in individuals with DS, which may contribute to reduced work capacity observed in this population.

Comparative Study Between Intravenous Dexmedetomidine And Fentanyl For Attenuation Of Haemodynamic Response To Laryngoscopy And Endotracheal Intubation: A Randomized Control Trial

Background: The degree of haemodynamic changes that are observed may vary depending on a number of factors, including the level of anaesthesia, the kind of anaesthetic drug used, whether any safety measures are followed prior to airway manipulation, the duration of the laryngoscopy or intubation, and others The main mechanism generating hypertension and tachycardia, the sympathetic response, may be heightened by catecholamine activity. Pressor response has been linked to intraoperative myocardial infarction, abrupt left ventricular failure, dysrhythmias, or intracranial haemorrhage in patients with end organ decompensation. Dexmedetomidine is a highly selective and specific α-2 adrenoceptor agonist with an α2:α1 binding selectivity ratio of 20:1, whereas clonidine has a ratio of 220:1. Clonidine and dexmedetomidine bind to and activate α-1 and α-2 receptors, respectively.Additionally, a plethora of studies has shown that dexmedetomidine reduces the haemodynamic response to laryngoscopy and intubation. One of the most powerful analgesics is fentanyl, a synthetic opioid that, when given before induction, lowers the haemodynamic response to intubation. A comparative study between dexmedtomidine and fentanyl is necessary to determine whether medicine is more beneficial, as both medications have the ability to decrease the sympathetic response to endotracheal intubation and laryngoscopy. Materials and Methods: A prospective randomized, and double-blind study was conducted in 60 ASA Grade I and II patients of either gender, aged between 18 and 65 years, undergoing various surgical procedure under spinal-anesthesia and developing shivering. The patients were randomized into two groups of n = 30 each to receive either dexmedetomidine - 0.6 µg/kg (Group D) Fenatnyl- 2 µg/kg (Group F) as an intravenous just before intubation. Blood pressures (systolic, diastolic and mean) recordings. Apart from general physical and systemic examination, routine investigations, blood urea, serum creatinine, serum electrolytes, ECG and X- Ray chest was performed in all patients SPSS-20 was used for statistical analysis, unpaired t-test for numerical data and chisquare test for categorical data. Results: The mean age was between 39 to 40 years and mean BMI was around 26. Similarly, the mean duration of surgery was 70 minutes for both the groups. Total males in study were 29 and females were 31. There was statistically significant difference in Mean arterial blood pressure (MAP) in both study groups after intubation and at 1 minute. The mean MAP in F group was more than D group at all the time intervals. The mean heart rate was statistically higher in F group as compared to D group at all time after intubation. The frequency of bradycardia was nil in F group as compared to 20% in D group. Frequency of hypotension was13% in D group and nausea or vomiting was 20% in F group. Conclusion: Our research shows that a single intravenous dose of Fentanyl (2µg/kg body weight) given over 2 minutes prior to induction and Dexmedetomedine 0.6µg/kg body weight infused over 10 minutes are both effective at obstructing the hemodynamic stress response to laryngoscopic endotracheal intubation without causing any appreciable side effects. On the other hand, when it comes to reducing the hemodynamic stress response following laryngoscopic endotracheal intubation, IV Dexmedetomidine works better and more efficiently than Fentanyl

Autonomic Responses to Cold Pain: Effect of Type, Duration, and Habituation in Cryotherapy.

Cold limb immersion, a form of cryotherapy, can cause cardiovascular changes due to cold-pain induced autonomic reflexes. This cryotherapy treatment side effect has received less attention but could have direct implications for physical rehabilitation of individuals with cardiovascular comorbidities. To test hypotheses related to the pressor effects of varied limb sites and surface areas of cryotherapy, two common lower limb injury sites (ankle and knee) were immersed into cold water (15 min, 1-3 °C) and then referenced to a standard cold pressor test (CPT). Beat-by-beat arterial blood pressure (finger photoplethysmography), heart rate (ECG), systemic vascular conductance (SVC; Modelflow), and calf vascular conductance (VC; venous occlusion plethysmography) were measured in 14 healthy participants. At 2 min, CPT increased mean arterial pressure (MAP; 21 ± 4 mmHg) more than either ankle or leg immersion (15 ± 4 and 15 ± 5 mmHg, respectively; P = 0.015). SVC and calf VC decreased but were not different across treatments (P = 0.417 and P = 0.086). MAP and SVC were not different from 2 min to 15 min of immersion (P = 0.164 and P = 0.522), but calf VC decreased further by the end of immersion (3.1 ± 0.5 to 2.8 ± 0.4 and 2.7 ± 3 to 1.7 ± 0.2 units; P = 0.028). MAP increases with CPT were similar with solely CPT and when CPT followed ankle or leg immersion (27 ± 5 and 23 ± 4 mmHg, respectively; P = 0.199). These data indicate robust pressor responses without autonomic reflex habituation and that cryotherapy immersion location but not surface area appears to mediate cardiovascular responses. This cryotherapy side effect may be an important consideration for patients with cardiovascular-related comorbidities.

The blood flow and vascular responses in dynamically exercising skeletal muscles evoked by combination of cold stimulation and voluntary apnea in humans.

We evaluated (1) the combined effects of cold stimulation and voluntary breath holding (apnea) on heart rate, blood pressure, blood flow and vascular responses in dynamically exercising muscles in humans, and (2) if some interactions exist between cold stimulation and apnea on the cardiovascular responses. Nine males and 1 female performed three trials entailing a dynamic two-legged knee extension exercise at a constant workload that elicited heart rates around 100 beats min-1. During the trials the participants performed either: (1) immersed their right hand into ice water maintained at 4°C (cold pressor test; CPT); (2) performed maximal-duration apnea; and (3) performed a combination of CPT and apnea. Leg blood flow (LBF) and cardiac output (CO) were measured simultaneously using two Doppler ultrasound systems. CPT induced a rise in mean arterial pressure (MAP) (P < 0.05) but had no significant effect on CO or exercising leg vascular conductance (LVC). Apnea evoked large pressor responses, bradycardia and decreases in CO, LBF and LVC (all P < 0.05). The increase in MAP induced by combined CPT and apnea was smaller than the sum of those induced separately by CPT or apnea (P < 0.05). Combined CPT and apnea decreased LBF and LVC to a similar extent as apnea alone. Addition of local cold stimulation to apnea does not enhance pressor responses or vasoconstriction within active muscles. This suggests that maximum voluntary apnea evokes massive vasoconstriction, even within exercising muscles, which cannot be enhanced by additional sympathetic stimulation.

Sex-specific responses of central artery stiffness to cold pressor test-mediated sympathetic activation

Considerable attention has been devoted to investigating whether acute activation of the sympathetic nervous system, triggered by daily life stressors, increases central artery stiffness (CAS). Overt sex differences in sympathetic neurovascular transduction lead to distinct cardiovascular responses to sympathoexcitation in men versus women. Our study aimed to determine if the cold pressor test (CPT), chosen to simulate highly painful stressors individuals encounter daily, would induce CAS augmentation in a sex-balanced cohort of young individuals and whether any observed CAS increase would differ between sexes. Twenty-eight participants (14 men, 14 women) provided baseline and CPT measurements of carotid-femoral pulse wave velocity (cf-PWV), mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), and heart rate (HR). CPT involved immersing participants' feet in 5 °C ice-water slurry. Data were analyzed using 2-way analysis of variance and post hoc testing, where applicable. CPT significantly increased (p < 0.01) cf-PWV values in our population, with women showing lower collective CAS values compared to men across baseline and CPT conditions. CPT augmented (p < 0.01) MAP, HR, and CO without altering stroke volume (SV), but increased (p = 0.002) TPR only in men. Men collectively exhibited higher (p < 0.01) CO and SV values across baseline and CPT conditions, as well as lower (p < 0.01) TPR values compared to women. These results support the notion that CPT increases CAS in a healthy young population. Despite observed sex differences in peripheral vascular responses to CPT, these variances did not differently impact the central pressor response or central artery stiffening between sexes. Given the well-documented sex differences in cardiovascular risk and incidence, these findings deepen understanding of how cardiocirculatory responses differ between sexes under stress. These findings support sex-specific approaches in cardiovascular medicine and prevention, including tailored coping strategies for managing stress.

Cardiovascular effects of early maternal separation and escitalopram treatment in rats with depressive-like behaviour

Depression and cardiovascular diseases are two of the world's major health problems. Escitalopram (ESC) is widely used because of its safety in relation to other drugs in that class; however, it can affect the cardiovascular system. The present study evaluated the cardiovascular parameters of depressive-like male rats and the cardiovascular effects of ESC treatment on that condition. The EMS protocol consisted of separating the litter from the dam for 3 h over 13 days. Animals were anesthetized with tribromoethanol (250 mg/kg, intraperitoneally) and the catheters were inserted into the femoral and into the femoral vein. Depressive-like rats showed an increase in the pressor response to phenylephrine (Emax:depressive = 50.36 ± 2.997 mmHg; non-depressive = 39.51 ± 3.328 mmHg; p < 0.05) and a reduction in the EC50 (depressive = 0.6203 ± 0.03005 μg/kg; non-depressive = 0.7320 ± 0.03519 μg/kg; p < 0.05) with no change in the other cardiovascular parameters. After treatment with ESC, a reduction of intrinsic heart rate was observed in the depressive-like rats (control: 342 ± 6 bpm; ESC: 316 ± 5 bpm; p < 0.05). In addition, ESC treatment increased the bradycardic (control: −97.81 ± 8.3 bpm; ESC: −137.1 ± 12.31 bpm; p = 0.0236; t = 2.502) during the baroreflex response, caused by an increase in cardiac parasympathetic modulation in the heart, in depressive-like rats (p < 0.001). The findings suggest that depressive-like rats showed cardiovascular changes, and that ESC treatment was able to reverse these changes, suggesting that ESC has a good safety profile for depressive patients with cardiovascular disease due to increased parasympathetic modulation.

Vasopressinergic sexual dimorphism: Sex chromosome complement and organizational hormonal effects

This study aimed to analyze the role of the sex chromosomes (SCC: XX/XY) and the interaction with organizational hormonal effects on Avp gene expression at the supraoptic (SON) and paraventricular nuclei (PVN) due to water deprivation, as well as on the vasopressinergic sexually dimorphic antidiuretic and pressor responses. For this purpose, we used gonadectomized (GDX) transgenic mice of the "four core genotypes" model, in which the effect of gonadal sex and SCC are dissociated.A significant interaction between treatment and SCC on Avp gene expression at the SON was observed. Regardless of sex, XX mice showed higher basal expression than those with XY; however after water deprivation no changes in mRNA Avp expression were observed in the XX group, while an increase for XY was reported. At the PVN an interaction of SCC, organizational hormonal, and treatment factors was observed, revealing an increase in Avp gene expression in the XY-GDX male DEP group.Although no SCC or organizational hormonal effects were observed on the demopressin-antidiuretic response and renal Avpr2 mRNA expression, an interplay of organizational hormonal and SCC factors in short and medium-term vasopressin-blood pressure regulation were reported. XX-GDX females showed a facilitated vasopressin-bradycardic baroreflex response when compared to the other genotypes. Furthermore, although vasopressin continuous infusion resulted initially in the expected increase in the percentage change in MAP in all genotypes, in XX-GDX male and female this increase was sustained until the 30-min infusion, while in XY-GDX male and in XY-GDX female mice a decrease in MAP was observed.

Exercise Pressor Responses But Not Cold Pressor Responses Are Influenced By Fat-Free Mass

Exercise Pressor Responses But Not Cold Pressor Responses Are Influenced By Fat-Free Mass

Characteristics and Presentation of Orthostatic Hypertension in Community-Dwelling Older Adults

Abstract Background Standing poses a hemodynamic challenge for the cardiovascular system, regulated by neurohumoral reflexes. In 2023, an elevated blood pressure response upon standing was officially defined as a minimum 20 mmHg increase in systolic pressure during position changes, distinguishing Orthostatic Hypertension (OHT) as a condition where blood pressure exceeds 140 mmHg when standing. This new definition underscores the importance of understanding the implications of OHT on individuals' health and quality of life. Methods Retrospective study of the Technology Research for Independent Living (TRIL) Clinic at St. James’s Hospital, from August 2007 to May 2009. The population included healthy community-dwelling adults aged 60 and older. This study aimed to profile individuals with OHT, understand the predictors of this condition, and explore its association with biopsychosocial variables. Results In a study of 442 participants (67.7% female, mean age 72.7), we identified a prevalence rate of 12.9% for an exaggerated orthostatic pressor response and observed OHT in 6.1% of participants at the 120-second mark after standing. Additionally, significant associations were discovered between OHT and conditions such as heart failure, stroke, and the use of certain medications such as SSRI and ACE inhibitors. Conclusion The results of this study highlight the potential health consequences of OHT among older adults, particularly in those with pre-existing cardiovascular conditions. Further research is needed to explore this lesser-known but significant orthostatic disorder.

Hypertension induced by peri-pubertal protein restriction depends on renin-angiotensin system dysfunction in adult male rats

Background and aimsHypertension depends on renin-angiotensin system dysfunction; however, little is known about its implications in the outcomes of neurogenic hypertension induced by peri-pubertal insults. This study aimed to evaluate whether hypertension induced by a peri-pubertal low-protein diet is related to renin-angiotensin system dysfunction in adult male Wistar rats. Methods and resultsThirty-day-old male Wistar rats were fed a low-protein diet (4 % casein) for 30 days and subsequently fed a 20.5 % normal protein diet for a 60-day dietary recovery (LP group). Control animals (NP group) were fed a 20.5 % protein diet throughout their lives. Cardiovascular and renin–angiotensin system functions were evaluated on postnatal day 120 (6–24 animals per group). Statistical analyses were performed using the Student's t-test. Animals with LP show increased arterial blood pressure. The angiotensin 2 dose-response curve of LP animals showed an increase in the pressor response at a lower dose (50 ng/kg) and a reduction in the pressor response at a higher dose (400 ng/kg) compared with NP animals. Angiotensin 2 type 1 receptor mRNA levels were increased in the hearts of LP animals; however, angiotensin 2 type 2 receptor and MAS receptor mRNA levels were reduced. In the aorta, AT1 and AT2 mRNA levels were increased in LP animals, whereas MAS receptor mRNA levels were decreased in comparison to NP animals. ConclusionThe renin-angiotensin system is disrupted in hypertension induced by protein restriction exposure during peri-pubertal life.

P109 AMINOPEPTIDASE A: A POTENTIAL NOVEL THERAPY FOR ANGIOTENSIN-DEPENDENT HYPERTENSION?

Background: We have shown that mice with a genetic deficiency in Aminopeptidase A (APA) have elevatedblood pressure. APA is an enzyme that removes a single aspartate residue from the amino-terminus of several peptides in the renin-angiotensin systems (RAS), including angiotensin (Ang) II. In this study, we investigated the impact of a recombinant APA on the cleavage of various RAS peptides and its effect on blood pressure. Methods: An in vitro assay was used to identify Ang peptides as substrates for APA. Ang peptides identified as APA substrates using this assay were then injected to anesthetized WT and APA-deficient mice to assess their pressor effect by measuring systolic blood pressure (SBP). Subsequently, murine recombinant (r)APA was used to evaluate its action on the acute SBP elevation elicited by Ang peptides that were identified to trigger pressor response. Results: In the in vitro assay, Ang II (22427±3353, n=12), Ang I (21883±1692, n=3), Ang1-7 (15833±3395,n=3), Ang1-9 (15773±3395, n=3) and Ang1-12 (13170±220, n=3), were identified as a substrate for rAPA as indicated by a strong aspartate-driven fluorescence formation. When these five Ang peptides were administered to WT mice, only Ang I, Ang II and Ang 1-12 caused a significant increase in SBP. This effect was exaggerated in APA deficient mice. The SBP increase elicited by Ang II in WT mice was markedly reduced by the pre-administration of rAPA (Fig). Conclusion: Aminopeptidase A can cleave the N-terminal aspartate from Ang II as well as from other RASpeptides that elicit (Ang 1-12, Ang I) and do not elicit (Ang 1-9, Ang 1-7) pressor response in mice. APA deficiency is associated with an exaggerated SBP response to Ang I, Ang II and Ang 1-12 while the recombinant enzyme mitigates the acute hypertensive effect. rAPA markedly reduced the increase in SBP caused by AngII infusion suggesting that it may be used to treat hypertension caused by excess of AngII.

Abstract P173: Pivotal Role for the Kinin B1R in CB1 Receptor Mediated Neuroinflammation and Pressor Response

The cannabinoid receptors CB1R and CB2R are involved in blood pressure (BP) regulation and CB1R is implicated in the incidence of hypertension. CB1R is highly expressed in the brain but both receptors are also expressed in the heart. Prior research has demonstrated that CB1R mediates significant cardiovascular responses, including elevated BP, heightened plasma norepinephrine levels, and increased sympathetic nerve activity. Furthermore, the activation of the kinin B1 receptor (B1R) mediates similar effects when studied independently. However, the role of B1R in CB1R-mediated BP regulation and the associated signaling mechanisms remain unknown. In this study, we tested the hypothesis that B1R plays a pivotal role in CB1R-mediated pressor response, oxidative stress and neuroinflammation. To test this, we used both in vivo mouse models and in vitro primary hypothalamic neurons. Male C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) underwent surgical carotid artery and jugular vein catheterization to measure BP in conscious state. Following stabilization of BP for at least 90 minutes, the CB1R agonist WIN55,212-2 (300 ug/kg; i.v., WIN) or its vehicle was administered, and recordings continued for 45 minutes. WIN increased BP in WT mice (25±7 mmHg vs baseline), but this effect was blunted in B1RKO mice (n=3, p&lt;0.05). Moreover, administration of WIN led to an augmentation of CB1R expression in the paraventricular nucleus of WT mice, but not in B1RKO mice, thereby indicating the involvement of B1R in CB1R signaling (p&lt;0.05, n=3 mice/group). WT, but not B1RKO, mice treated with WIN displayed a significant increase in oxidative stress levels (p&lt;0.05, n=3 mice/group), as indicated by dihydroethidium staining. To further confirm the role of B1R blockade on CB1R signaling, we cultured primary hypothalamic neurons, as neurons express the highest levels of CB1R in the brain. Neurons were stimulated with WIN (1 uM) both with and without a B1R selective antagonist (SSR240612, 10uM). The results indicated that WIN incubation for 24 hours increased CB1R expression, inflammation, and oxidative stress compared to vehicle treated, and these responses were abrogated by prior B1R blockade (p&lt;0.05, n=5/group), consistent with the in vivo observations. These data provide novel evidence that B1R is implicated in CB1R-mediated proinflammatory responses and serves as a potential therapeutic target to reduce CB1R induced effects.

Abstract MP04: Brain miR-410-3p Expression Sex-dependently Reduces Ang-II-induced Hypertension

Dysregulation of microRNA (miRNA) is associated with hypertension and other diseases. We previously observed direct interaction of miR-410-3p with AT 1 R and sex-dependent downregulation of miR-410-3p in the hypothalamus of a mouse cardiometabolic disease (CMD) model, suggesting a possible involvement in the development of CMD through modulation of the renin-angiotensin system. To further investigate the role of hypothalamic miR-410-3p expression as a therapeutic target for hypertension, acute Ang-II injection and chronic infusion experiments were performed. In acute experiments, C57BL/6J mice (males and females) were injected with Lenti-miR-410-3p or a control virus (icv, 2 µl, n=5-6). After 3 weeks, mice were anesthetized and a catheter was inserted to the carotid artery for blood pressure (BP) monitoring, followed by a bolus icv injection of Ang-II (200 ng/200 nl). Changes in systolic BP (ΔSBP) were recorded. In chronic experiments, mice were fed with a high calorie diet for 2 months before icv virus injection (2 µl). Telemetry probes (DSI) were implanted for conscious BP monitoring. Three weeks following virus injection, all mice were infused with Ang-II using osmotic minipumps (sc, 600 ng/kg/min, 14 days) to induce CMD. BP was recorded weekly and 24 h average of mean arterial pressure (MAP) was calculated. Acute Ang-II injection-induced pressor responses were similar in males (ΔSBP; 22.2±4.7 mmHg) and females (20.6±6.5 mmHg) transfected with the control virus. In lenti-miR-410-3p transfected mice, the pressor responses were blunted in both males (6.7±4.8 mmHg, P &lt;0.001 vs. control) and females (10.9±4.7 mmHg, P&lt;0.05 vs. control), with a greater reduction observed in males (69.8% vs. 47%). In the HCD model, baseline MAP was not different between male control and Lenti-miR-410, or female control and Lenti-miR-410 group. Following Ang-II infusion, MAP was increased in both sexes treated with control virus. Interestingly, this increase was blunted by Lenti-miR-410-3p expression in males (137.3 ± 9.4 vs. 160.7 ± 4.3 mmHg, P =0.05) but not in females (140.4±4.6 vs. 140.5 ± 4.2 mmHg). These data are aligned with our previous findings that male mice had higher expression of hypothalamic AT 1 R than in females in CMD. In summary, miR-410-3p inhibits both acute and chronic Ang-II induced increases in BP in a sex-dependent manner, with more profound effects in males. miR-410-3p could be a new strategy for the treatment of hypertension in CMD.

Abstract MP05: A Preliminary 10X Genomics Xenium Profiler Spatial Transcriptomics Map of Renin-Angiotensin System Genes in the Mouse Subfornical Organ

The subfornical organ (SFO) is a brain region rich in angiotensin-II (ANG) AT1 receptors (AT1R) which regulates water and salt intake and communicates with other hypothalamic nuclei to regulate blood pressure (BP). Activation of the classical G protein-mediated AT1R signaling in the brain induces pressor and natri-dipsogenic responses. TRV027, a synthetic AT1R β-arrestin-biased agonist, decreases BP and increases saline avoidance. We examined the spatial transcriptomic makeup of the SFO to balanced or biased AT1R activation using 10X Genomics Xenium. We treated C57BL/6J mice with either aCSF, ANG (0.64 µg/h), or TRV027 (0.56 µg/h) through continuous ICV infusion for 11-days. Water intake was monitored on days 6-11. ANG caused an increase in water intake compared to aCSF or TRV027 groups (7.0±2.0, 3.0±0.2, and 1.9±0.6 mL/day, respectively, n=4, p&lt;0.05). On day 11, brains were perfused, collected, and fixed. Subsequently, 5 µm paraffin-embedded coronal sections were mounted on Xenium slides and tested with the 10X mouse brain set of 247 genes plus 100 custom add-on genes including all RAS genes. A third of the cells expressed AT1R, and the pattern of AT1R-expressing cells Xenium-detected was qualitatively similar to NZ44 mice, which express GFP under the control of the AT1R locus. Expression of the prorenin receptor ( Atp6ap2 ) was abundant throughout the SFO. A few cells in the SFO and more prominently in the adjacent blood vessels were angiotensinogen positive. Single cells were identified that expressed the ANG type 2 receptors (AT2R). Expression of Mas receptor was undetectable. Most of the AT1R-expressing cells were excitatory glutamatergic neurons (expressing Slc17a6 , VGLUT2) but a few were inhibitory GABAergic neurons co-expressing Slc32a1 (VGAT). Each section had cells classified as astrocytes, neurons, ependymal cells, and immune cells (e.g., microglia or macrophages). Increased numbers of immune cells were detected in the SFO of ANG-treated mice. Interestingly, although there was no evidence for expression of renin in the SFO, renin-expressing cells were identified in the choroid plexus which is consistent with highly sensitive in situ RNA hybridization data. Additional qualitative and quantitative analyses are ongoing to compare gene expression patterns in AT1R-positive cell types. Future studies will identify gene expression patterns in SFO neurons with connectivity to other brain regions controlling water/salt intake and BP.

Abstract P189: Maternal Hyperandrogenemia Programs Hypoandrogenemia and Intrarenal Activation of Histone Deacetylase in Adult Male Offspring

Polycystic ovary syndrome ( PCOS ) is the most common endocrinopathy in young women. In-utero, children of ~80% of PCOS women in the US are exposed to maternal “hyperandrogenemia and obesity”. It remains unclear whether this exposure affects their cardiovascular ( CV ) health later in life. Using a well-characterized rat model of maternal PCOS, the hyperandrogenemic obese ( HAO ) dams, we previously showed that adult male, not female, offspring ( HAO F1 ) have enhanced blood pressure ( BP ) response to chronic angiotensin ( Ang ) II compared to sex-matched control offspring ( CON F1 ), suggesting their increased risk of later CV disease. Sex steroids have the potential to modulate epigenetics. Histone deacetylase ( HDAC ) and histone acetyltransferase ( HAT ) are markers of epigenetic modifications. HDACs have been shown to promote tumor necrosis factor ( TNF )-α expression and play a role in Ang II-induced hypertension. The present study was designed to test the hypothesis that male HAO F1 have intra-renal activation of HDAC and increased TNF-α that could play a role in their Ang II BP response. Methods: At 4 weeks ( wks ) of age, female SD rats were implanted (s.c.) with either 5α-dihydrotestosterone pellets (7.5 mg/90 d; HAO) or placebo pellets (CON) and mated at 9-12 wks. Offspring were obtained and weaned at 3 wks. Serum testosterone ( T; by LC/MS-MS), renal cortical TNF-α (Bioplex) and renal cortical nuclear HDAC and HAT activities (colorimetric assays) were measured in male offspring (1/litter, 16-24 wks, n=5-9). Results: Male HAO F1 had significantly lower serum T, higher renal cortical HDAC activity and TNF-α (430.2±124 vs 120.6±14 ng/dl, 0.97±0.1 vs 4.51±0.96 OD/min/mg protein and 423.7±47 vs 579.8±47 pg/g tissue, in male CON F1 vs male HAO F1 , respectively, p&lt;0.05), and no change in their renal cortical HAT activity (vs male CON F1 ). Conclusion: Male offspring born to HAO dams develop hypoandrogenemia that is associated with intra-renal activation of HDAC that could be mediating their increased intra-renal inflammation (TNF-α expression) and mediating their exaggerated BP response to Ang II. Future studies will determine the causative relationship between hypoandrogenemia, HDAC activation and TNF-a and their role in the exaggerated pressor response to Ang II in those male offspring. Funding: AHA-24DIVSUP1273026 (JA), NIH-NIGMS P20GM121334 (JFR, NMS), R01HL135089 &amp; R01AG075963 (JFR), AHA-22CDA938320 and 2024 Dean Franklin Award (NMS).

Pathophysiologic Vasodilation in Cardiogenic Shock and Its Impact on Mortality.

Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm-5 (interquartile range, 870-1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0-0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm-5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P=0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P<0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P=0.003). Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm-5, high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.

Coronary and Systemic Vasodilator Responsiveness of Patients Receiving Conventional Intermittent or Nocturnal Hemodialysis.

Nocturnal hemodialysis (nHD) restores the attenuated brachial artery vasodilator responsiveness of patients receiving conventional intermittent hemodialysis (iHD). Its impact on coronary vasodilatation is unknown. We evaluated 25 patients on hemodialysis who fulfilled transplant criteria: 15 on iHD (4-hour sessions, 3 d/wk) and 10 on nHD (≈40 h/wk over 8-10-hour sessions) plus 6 control participants. Following diagnostic angiography, left anterior descending (LAD) coronary flow reserve and mean luminal diameter were quantified at baseline and during sequential intracoronary administration of adenosine (infusion and bolus), nitroglycerin (bolus), acetylcholine (infusion), acetylcholine coinfused with vitamin C, and, finally, sublingual nitroglycerin. Coronary flow reserve in those receiving nHD was augmented relative to iHD (3.28±0.26 versus 2.17±0.12 [mean±SEM]; P<0.03) but attenuated, relative to controls (4.80±0.63; P=0.011). Luminal dilatations induced by intracoronary adenosine and nitroglycerin were similar in nHD and controls but blunted in the iHD cohort (P<0.05 versus both). ACh elicited vasodilatation in controls but constriction in both dialysis groups (both P<0.05, versus control); vitamin C coinfusion had no effect. Sublingual nitroglycerin increased mid-left anterior descending diameter and reduced mean arterial pressure in controls (+15.2±2.68%; -16.00±1.60%) and in nHD recipients (+14.78±5.46%; -15.82±1.32%); iHD responses were markedly attenuated (+1.9±0.86%; -5.89±1.41%; P<0.05, all comparisons). Coronary and systemic vasodilator responsiveness to both adenosine and nitroglycerin is augmented in patients receiving nHD relative to those receiving iHD, whereas vasoconstrictor responsiveness to acetylcholine does not differ. By improving coronary conduit and microvascular function, nHD may reduce the cardiovascular risk of patients on dialysis.

Intracerebroventricular insulin injection acutely normalizes the augmented exercise pressor reflex in male rats with type 2 diabetes mellitus.

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2h post) intracerebroventricular (i.c.v.) insulin microinjections (500mU, 50nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36±14mmHg) vs. 1h (21±14mmHg) vs. 2h (11±6mmHg), P<0.05) and RSNA (ΔRSNA Pre (107.5±40%), vs. 1h (75.4±46%) vs. 2h (51±35%), P<0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41±0.19 vs. 0.11±0.05ng/ml, control (n=14) vs. T2DM (n=4), P<0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function.

An observational study to compare the efficacy of intravenous dexmedetomidine versus intravenous esmolol for attenuation of pressor response during laryngoscopy and endotracheal intubation

Laryngoscopy and endotracheal intubation during general anaesthesia is an invasive stimulus associated with release of circulating catecholamine leading to hemodynamic and cardiovascular responses resulting in tachycardia, hypertension and arrhythmias. Many prophylactic drugs have been used to decrease cardiovascular response to laryngoscopy &amp; intubation. Aim of this study is to compare effectiveness of Dexmedetomidine 1μg/kg and Esmolol 1 mg/kg intravenously in attenuating cardiovascular response during laryngoscopy and intubation during general anaesthesia.This randomised double blinded prospective study was conducted on 50 patients, of either gender between age group 18-60 years and American Society of Anaesthesiology (ASA) classification I &amp; II, undergoing various surgeries under General anaesthesia requiring intubation. Patients were randomly divided into 2 groups of 25 patients each. Group D patients received intravenously Inj. Dexmedetomidine 1 mcg/kg as an infusion in 100ml Normal Saline over 20 minutes before induction of general anaesthesia. Group E patients received intravenously Inj. Esmolol 1 mg/kg diluted with normal saline to volume of 10ml given just before induction of general anaesthesia.Hemodynamic parameters such as Heart rate (HR),systolic blood pressure (SBP),diastolic blood pressure (DBP) and mean arterial pressure (MAP) were recorded at baseline, after study drug administration, after induction, at laryngoscopy and intubation and 1, 3, 5 and 7 min after Endotracheal intubation.: Comparison of two groups reveals that dexmedetomidine shows less rise in heart rate (P-0.0003) and mean arterial pressure (P-0.0106) at the laryngoscopy and intubation. It also shows less rise in systolic and diastolic blood pressure after induction and after intubation (P&amp;#60; 0.05) than Esmolol. This study suggests that Dexmedetomidine 1µg/kg was more effective in attenuating the stress response to laryngoscopy and intubation as compared to Esmolol 1mg/kg.