Regulation Of Arterial Blood Pressure Research Articles

On the Regulation of Arterial Blood Pressure by an Intracranial Baroreceptor

Introduction: There is significant evidence for the existence of an intracranial baroreceptor mechanism(s) capable of sensing physiological changes in cerebral blood flow (Marina et al., 2020). However, little is known about the sensitivity of this mechanism to changes in brain perfusion and its interaction with inputs from the peripheral (arterial) baroreceptors. The aim of this study was to characterise the cardiovascular responses to physiological changes in cerebral perfusion induced by experimental manipulations of intracranial pressure (ICP). Methods: The experiments were performed in adult Sprague-Dawley rats (250–300 g), anesthetized with urethane (induction: 1.3 g kg−1, i.p.; maintenance: 10–25 mg kg−1 h−1, i.v.). The femoral artery and vein were cannulated for measurement of arterial blood pressure (ABP) and administration of anaesthetic. The trachea was cannulated, and the animal was mechanically ventilated. The lateral cerebral ventricles were cannulated and connected via saline-filled catheters to a pressure transducer to record ICP and to a “water column” to allow controlled manipulation of ICP. The experiments included the denervation of the arterial baroceptors, stimulation of the aortic depressor nerve and recording of renal sympathetic nerve activity. Results: The resting ICP in rats anesthetized with urethane was 6.2 ± 0.7 mmHg (n=8). Following a small craniotomy that reduced ICP to 0 mmHg, ABP decreased by 11.2 mmHg (n=6) within 30 min. Restoring the integrity of the intracranial space increased ABP to the baseline level. Progressive increases in ABP were observed in response to experimentally-induced increases in ICP by 5, 10, 15 and 20 mmHg, revealing a linear relationship between ICP and systemic arterial pressure within the physiological range of ICP changes. In the absence of inputs from the arterial baroceptors (bilateral sino-aortic denervation and vagotomy) the ABP responses to ICP increases were preserved. Analysis of the ABP and heart rate responses to the electrical stimulation of the aortic depressor nerve suggested baroreflex re-setting at raised ICP. Renal nerve recordings demonstrated increased sympathetic activity at raised ICP (172 ± 34.91 % at 20 mmHg ICP (p=0.003; n=7) with markedly enhanced bursts of activity during the inspiratory phase of the respiratory cycle. Conclusion: These data demonstrate that the intracranial baroceptor mechanism is highly sensitive to changes in cerebral perfusion within the physiological range and suggest that cerebral blood flow is an important determinant of systemic ABP. The data suggest that at raised ICP the baroreflex control of sympathetic vasomotor activity is reset and provides effective control of arterial blood pressure at a higher level required to compensate for reduced brain perfusion. Marina, N., Christie, I.N., Korsak, A., Doronin, M., Brazhe, A., Hosford, P.S., Wells, J.A., Sheikhbahaei, S., Humoud, I., Paton, J.F. and Lythgoe, M.F., 2020. Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow. Nature Communications, 11(1), 131. This PhD Studentship is funded by the British Heart Foundation. 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.

Role of Endothelial Nrf2 in the Regulation of Vasomotor Capacity and Arterial Blood Pressure

Introduction: Hypertension is a serious global public health issue. It is a complex disease with multiple factors contributing to its pathophysiology. One of these factors is oxidative stress, which results from an imbalance between the production and elimination of reactive oxygen species (ROS). Studies have shown that an increased ROS in endothelial cells (EC) impairs the vasodilatory capacity of blood vessels that contributes to blood pressure elevation. However, the modulation of endothelial ROS in the setting of hypertension is still not completely understood. To maintain cellular homeostasis, antioxidant enzymes continually adjust ROS levels under the orchestrating of transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of endogenous antioxidant responses. Modulation of endothelial Nrf2 expression may be a potential therapeutic option in hypertension. Therefore, the major objective of this study was to evaluate the role of Nrf2 in the modulation of endothelium associated vascular function and how it regulates vascular tone and blood pressure (BP). Methods: BP was measured in the conscious state using radiotelemetry transducers implanted into EC-specific Nrf2-knockout mice (Tie2-Cre-Nrf2 Floxed), EC specific Keap1 knockout mice (Tie2-Cre-Keap1 Floxed) and Wildtype (WT), all on the C57B6J background. After baseline BP recordings, mice were implanted with subcutaneous osmotic minipumps (7 days) for Angiotensin II (Ang II) (600ng/Kg/min) infusion or in a separate group L-nitroarginine methyl ester (L-NAME) (100 mg/kg/d in drinking water) for 2 weeks. For each intervention, recordings were done daily for 2 hours and one 24-hour measurement was done once per week. Endothelial specific downregulation or upregulation of Nrf2 was confirmed by immunohistochemistry on mouse aortic tissue and protein expression from mouse EC. For in-vitro studies: femoral-to-popliteal artery segments were harvested from mice of each genotype. Vasodilation was assessed in response to flow (30 uL·min−1) and acetylcholine (ACh, 10−7-10−3 M) with and without L-NAME, using video microscopy. Results: Ang II infusion significantly increased the mean arterial pressure (MAP) in each group when compared to their baseline values (Baseline: Nrf2KO = 92.6 ± 3.1, Keap1KO = 93.8 ± 4.1 and WT = 92.8 ± 1.7 mmHg; after Ang II Nrf2KO = 141.7 ± 3.8, Keap1KO = 121.9±5.4 and WT = 120.4±5.4 mmHg). The response to ANG II was significantly (p<0.05) augmented in Nrf2KO mice and stayed elevated for a longer period after emptying of the pump. The response to L-NAME was similar in both Nrf2KO and WT mice. Protein expression of Nrf2 was decreased in Nrf2KO mice in comparison to WT mice. Nrf2KO mice exhibited reduced endothelium-dependent vasodilation induced by flow (WT: 35.8± 1.3%, Nrf2KO: 24.1 ±1.7%; p<0.0001) and ACh (10−3M) (WT: 60.4±4.1%, Nrf2KO: 44.7± 2.1%; p<0.0001) compared to WT. In contrast, endothelial dependent vasodilatory responses to flow and Ach were markedly elevated in Keap1KO mice (51.3± 6.8%, p<0.0001; 71.6±11.6%, p<0.0087, respectively) compared to both WT and Nrf2KO mice. Conclusion: These results suggest that antioxidant defense mediated by Nrf2 in the endothelium plays a significant role in the modulation of blood pressure and vascular tone. Based on the L-NAME data, these effects are most likely due to an increase in the nitric oxide bioavailability and reduced ROS. University of Nebraska Theodore Hubbard foundation. 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.

PIEZO Ion Channels in Cardiovascular Functions and Diseases.

The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells and tissues. Thus, this system is primed with mechanosensory structures that respond and adapt to changes in mechanical stimuli. Since their discovery in 2010, PIEZO ion channels have dominated the field of mechanobiology. These have been proposed as the long-sought-after mechanosensitive excitatory channels involved in touch and proprioception in mammals. However, more and more pieces of evidence point to the importance of PIEZO channels in cardiovascular activities and disease development. PIEZO channel-related cardiac functions include transducing hemodynamic forces in endothelial and vascular cells, red blood cell homeostasis, platelet aggregation, and arterial blood pressure regulation, among others. PIEZO channels contribute to pathological conditions including cardiac hypertrophy and pulmonary hypertension and congenital syndromes such as generalized lymphatic dysplasia and xerocytosis. In this review, we highlight recent advances in understanding the role of PIEZO channels in cardiovascular functions and diseases. Achievements in this quickly expanding field should open a new road for efficient control of PIEZO-related diseases in cardiovascular functions.

The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway.

Human genetic and clinical trial data suggest that peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor transcription factor plays an important role in the regulation of arterial blood pressure. The examination of a series of novel animal models, coupled with transcriptomic and proteomic analysis, has revealed that PPARγ and its target genes employ diverse pathways to regulate vascular function and blood pressure. In endothelium, PPARγ target genes promote an antioxidant state, stimulating both nitric oxide (NO) synthesis and bioavailability, essential components of endothelial-smooth muscle communication. In vascular smooth muscle, PPARγ induces the expression of a number of genes that promote an antiinflammatory state and tightly control the level of cGMP, thus promoting responsiveness to endothelial-derived NO. One of the PPARγ targets in smooth muscle, Rho related BTB domain containing 1 (RhoBTB1) acts as a substrate adaptor for proteins to be ubiquitinated by the E3 ubiquitin ligase Cullin-3 and targeted for proteasomal degradation. One of these proteins, phosphodiesterase 5 (PDE5) is a target of the Cullin-3/RhoBTB1 pathway. Phosphodiesterase 5 degrades cGMP to GMP and thus regulates the smooth muscle response to NO. Moreover, expression of RhoBTB1 under condition of RhoBTB1 deficiency reverses established arterial stiffness. In conclusion, the coordinated action of PPARγ in endothelium and smooth muscle is needed to maintain NO bioavailability and activity, is an essential regulator of vasodilator/vasoconstrictor balance, and regulates blood vessel structure and stiffness.

EFFECTS OF SMOKING ON CIRCADIAN ARTERIAL BLOOD PRESSURE PROFILE IN PATIENTS WITH NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROME AND CHRONIC KIDNEY DISEASE

The paper presents the results of a study of the effects of smoking on circadian arterial blood pressure (ABP) profile in patients with Non-ST-Segment Elevation Acute Coronary Syndrome (NSTE-ACS) and Chronic Kidney Disease (CKD).
 Aim. The research aims at studying the features of circadian blood pressure monitoring (CBPM) in patients with NSTE-ACS and CKD, smoking-dependent.
 Materials and Methods. The study includes 70 patients with NSTE-ACS and CKD aged 35 to 75 years. The patients were divided into 2 groups: Group I - 35 smokers (mean age - 60.09±1.66 years), Group II - 35 individuals who have never smoked (mean age - 62.31±1.04 years). The circadian blood pressure monitoring was carried out on the second day of hospital admission after stabilization of the patient's condition. The following indicators have been determined: systolic blood pressure (SBP) - daytime, nighttime, and average daily (24 hours) (SBPd, SBPn, and SBPav); diastolic blood pressure (DBPd, DBPn, and DBPav); pulse pressure (PBPd, PBPn, and PBPav); time index (TI) for SBPd and SBPn (SBPd TI and SBPn TI) and DBP (DBPd TI and DBPn TI); heart rate (HR). To study the renal functional status in the examined patients, the urine albumin-creatinine ratio (ACR) was determined using the semi-quantitative method. The glomerular filtration rate (GFR) was calculated using the CKD-EPI Creatinine Equation.
 Results. Mean SBP, DBP, and PBP levels were significantly higher in Group I patients compared to Group II patients: SBPd - by 5.10% (p<0.05), SBPn - by 6.60% (p<0.05); DBPd - by 9.60% (p=0.01), DBPn - by 14.10% (p<0.05); PBPd - by 7% (p=0.05), PBPn - by 8.50% (p<0.05). The mean TI value also turned out to be significantly higher in the group of smokers (I) versus non-smokers (II): SBPd TI - by 55.50% (p<0.01), SBPn TI - by 58.90% (p<0.01), DBPd TI - by 57.50% (p<0.01), DBPn TI - by 46.30% (p<0.01). The HR was higher by 10.80% in Group I patients compared to Group II patients (p<0.01). The mean GFR level in smokers is 13.00% lower than in non-smokers (p<0.05). A 57% significantly higher ACR level was found in the group of smokers (Group I) compared to non-smokers (Group II) (p<0.01).
 Conclusions. Mean SBP, DBP, PBP, TI, and HR levels were significantly higher in the group of smokers with NSTE-ACS and CKD. In the same Group, more distinct signs of kidney injury were found, namely, lower GFR values and higher ACR values, which indicates the probable adverse effect of smoking on ABP regulation and renal microvasculature.

Abstract P3168: Identification Of Exosome MicroRNA In Association With Severe Calcification In Coronary Chronic Total Occlusion

Backgrounds: Coronary artery calcification (CAC) is prevalent in patients with coronary chronic total occlusion (CTO). We investigated the association between plasma miRNAs and coronary artery calcification in patients with CTO. Methods: Blood samples were collected from 18 patients who underwent percutaneous coronary intervention (PCI) of CTO. Exosomal small RNA sequencing was performed from plasma to quantify miRNA expression. Calcium volume was quantified in computed tomography (CT) in CTO. Gene ontology and functional pathway were analyzed in the miRNAs that significantly correlates with calcium volume. Results: Calcium volume was positively correlated with miR-1-3p and miR-708-3p (p <0.05), and was negatively correlated with 4 miRNAs -including let-7d-5p (p <0.05). Gene enrichment and pathway analysis showed that the target genes of the 2 positively correlated miRNAs were involved in regulation of osteoblast differentiation and osteopontin signaling pathway. In contrast, the target genes of the 4 negatively correlated miRNAs were enriched in acetylcholine-mediated vasodilation involved in regulation of systemic arterial blood pressure, blood vessel development and response to sterol. Multiple linear regression showed that miR-1-3p and let-7d-5p could be key predictors of the calcium volume of CTO (adjusted R 2 = 0.798 and p <0.001). Conclusions: We identified miR-1-3p and let-7d-5p could be related with CAC in patients with CTO.

#6050 TEMPORAL CHANGES IN PLASMA ENDOTHELIN-1 AND BLOOD PRESSURE DURING MAINTENANCE HAEMODIALYSIS

Abstract Background and Aims Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor that plays an important role in the regulation of arterial blood pressure (BP). Elevated levels of plasma ET-1 have been reported in patients with end-stage renal disease (compared with controls), patients on dialysis (compared with non-dialyzed uremic patients), and patients on haemodialysis (compared with peritoneal dialysis). It has been suggested that ET-1 plays a role in BP response to HD; however, the temporal association of changes in ET-1 with changes in BP during the course of an HD session has not been well defined. Moreover, conflicting results have been reported as to the patterns of intradialytic ET-1 changes, with different studies reporting either a decrease, an increase, or no change in ET-1 during HD. The aim of this study was to investigate temporal changes in ET-1 in patients with different intradialytic BP profiles. Methods Data was obtained from a prospective cohort study of 50 maintenance, thrice-weekly HD patients admitted to Brigham and Women's Hospital in Boston, MA, USA. BP was measured before, after, and every 15 min during dialysis using a calibrated ambulatory BP cuff. Blood samples were drawn before dialysis, at 30, 60, and 120 min into HD, and at the end of treatment. Following the exclusion of cases with missing data, shorter dialysis sessions, or very low pre-dialysis BP (below 85/55 mmHg), 42 patients were included in the analysis (17 females, median age 62 years, over 90% diagnosed with hypertension). One HD session was studied in each patient (median ultrafiltration 2.05 L, median duration 232 min). The patients were divided into three subgroups with different patterns of intradialytic systolic blood pressure (SBP): 1) patients with intradialytic hypotension (IDH) defined as: a) drop of SBP to or below 90 mmHg; or b) drop in SBP by at least 30 mmHg associated with at least two hypotension-related symptoms; or c) drop in SBP associated with multiple symptoms requiring intervention; 2) normotensive patients (NT) defined as patients in whom SBP remained between 90 and 130 mmHg for most of the HD session; 3) hypertensive patients (HT) defined as patients in whom the median intradialytic SBP was above 140 mmHg. Results 9 hypertensive patients (HT), 24 IDH patients, and 9 normotensive patients (NT) were identified. In the IDH group, at the end of HD, the median drop in SBP from the pre-HD level was 28 mmHg [25th–75th percentile 10–45 mmHg]. In HT and NT patients, SBP did not change significantly during HD. IDH patients had lower baseline ET-1 (2.2 pg/mL) compared with HT patients (3.4 pg/mL, P = 0.006) but similar compared with NT patients (2.3 pg/mL). ET-1 decreased over the course of dialysis in HT patients (P = 0.02) and NT patients (P = 0.008), whereas no change was observed in IDH patients (P = 0.30). At the end of HD, IDH patients had a similar ET-1 level (2.4 pg/mL) compared with HT patients (2.6 pg/mL) but higher compared with NT patients (1.4 pg/mL, P = 0.004). A moderate negative correlation was found between the dialysis-associated changes in ET-1 and SBP (r = –0.43, P = 0.005) as well as between the baseline ET-1 and baseline SBP in IDH patients (r = –0.42, P = 0.04). Conclusions HD patients may present various patterns of ET-1 changes during HD, which seem to be associated with BP response to HD. In particular, the patterns of ET-1 response to HD may vary among patients categorized as ‘hypertensive’ (the vast majority of patients in our study), who previously were observed to have an intradialytic increase in ET-1. Our results provide a possible explanation as to why previous studies that did not consider intradialytic BP patterns have yielded conflicting results regarding the direction of ET-1 changes during HD.

Cerebral blood flow response to cardiorespiratory oscillations in healthy humans

Dynamic cerebral autoregulation (CA) characterizes the cerebral blood flow (CBF) response to abrupt changes in arterial blood pressure (ABP). CA operates at frequencies below 0.15Hz. ABP regulation and probably CA are modified by autonomic nervous activity. We investigated the CBF response and CA dynamics to mild increase in sympathetic activity. Twelve healthy volunteers underwent oscillatory lower body negative pressure (oLBNP), which induced respiratory-related ABP oscillations at an average of 0.22Hz. We recorded blood velocity in the internal carotid artery (ICA) by Doppler ultrasound and ABP. We quantified variability and peak wavelet power of ABP and ICA blood velocity by wavelet analysis at low frequency (LF, 0.05-0.15Hz) and Mayer waves (0.08-0.12Hz), respectively. CA was quantified by calculation of the wavelet synchronization gamma index for the pair ABP-ICA blood velocity in the LF and Mayer wave band. oLBNP increased ABP peak wavelet power at the Mayer wave frequency. At the Mayer wave, ABP peak wavelet power increased by >70% from rest to oLBNP (p<0.05), while ICA blood flow velocity peak wavelet power was unchanged, and gamma index increased (from 0.49 to 0.69, p<0.05). At LF, variability in both ABP and ICA blood velocity and gamma index were unchanged from rest to oLBNP. Despite an increased gamma index at Mayer wave, ICA blood flow variability was unchanged during increased ABP variability. The increased synchronization during oLBNP did not cause less stable CBF or less active CA. Sympathetic activation seems to improve the mechanisms of CA.

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate, mediate the slow component of excitatory neurotransmission in the central nervous system (CNS), and induce long-term changes in synaptic plasticity. NMDARs are non-selective cation channels that allow the influx of extracellular Na+ and Ca2+ and control cellular activity via both membrane depolarization and an increase in intracellular Ca2+ concentration. The distribution, structure, and role of neuronal NMDARs have been extensively investigated and it is now known that they also regulate crucial functions in the non-neuronal cellular component of the CNS, i.e., astrocytes and cerebrovascular endothelial cells. In addition, NMDARs are expressed in multiple peripheral organs, including heart and systemic and pulmonary circulations. Herein, we survey the most recent information available regarding the distribution and function of NMDARs within the cardiovascular system. We describe the involvement of NMDARs in the modulation of heart rate and cardiac rhythm, in the regulation of arterial blood pressure, in the regulation of cerebral blood flow, and in the blood-brain barrier (BBB) permeability. In parallel, we describe how enhanced NMDAR activity could promote ventricular arrhythmias, heart failure, pulmonary artery hypertension (PAH), and BBB dysfunction. Targeting NMDARs could represent an unexpected pharmacological strategy to reduce the growing burden of several life-threatening cardiovascular disorders.

Arterial Blood Pressure, Neuronal Excitability, Mineral Metabolism and Cell Volume Regulation Mechanisms Revealed by Xenopus laevis oocytes.

Xenopus laevis oocytes have been an invaluable tool to discover and explore the molecular mechanisms and characteristics of many proteins, in particular integral membrane proteins. The oocytes were fundamental in many projects designed to identify the cDNA encoding a diversity of membrane proteins including receptors, transporters, channels and pores. In addition to being a powerful tool for cloning, oocytes were later used to experiment with the functional characterization of many of the identified proteins. In this review I present an overview of my personal 30-year experience using Xenopus laevis oocytes and the impact this had on a variety of fields such as arterial blood pressure, neuronal excitability, mineral metabolism and cell volume regulation.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

Chloride Ions, Vascular Function and Hypertension.

Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl−) are a type of anions accumulated by anion exchangers and the anion–proton cotransporter system, and efflux of Cl− through Cl− channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl− regulatory pathways, emerging evidence suggests that upregulation of the Ca2+-activated Cl− channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl− in vascular smooth muscle cells through the increased activity of Na+–K+–2Cl− cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension. In this review, we discuss recent findings regarding the role of Cl− in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1.

The relationship between muscle sympathetic nerve activity and systemic hemodynamics is altered in women with uterine fibroids.

Women with uterine fibroids (UF), benign tumors of the myometrium, have a higher prevalence of hypertension than women without UF. The cause for this relationship is unclear. Muscle sympathetic nerve activity (MSNA) is a regulator of arterial blood pressure, and it is possible that variations in MSNA predispose women with UF to develop hypertension. The purpose of this study was to assess baseline blood pressure and MSNA and the relationships between MSNA and systemic hemodynamics in women with and without UF. We measured blood pressure (brachial intra‐arterial line), MSNA (microneurography), and systemic hemodynamics (total peripheral resistance and cardiac output) at rest in 14 healthy, normotensive, premenopausal women with UF (42 ± 2 years old) and 9 healthy, normotensive, premenopausal women without UF (41 ± 2 years old). Baseline blood pressure and MSNA did not differ between groups (p > 0.05 for both). In women with UF, there was a positive correlation between MSNA and total peripheral resistance (r = 0.75, p = 0.02), as well as a negative correlation between MSNA and cardiac output (r = −0.73, p = 0.03). In contrast, these relationships were not seen in women without UF (p > 0.05 for both relationships). These data suggest that autonomic interactions with systemic hemodynamics, and thus blood pressure regulation, are different in healthy women with UF compared to healthy women without UF.

EFFECT OF SEVERE FOOD RESTRICTION ON BLOOD PRESSURE REGULATION IN THE FEMALE SPRAGUE DAWLEY RAT

Objective: Eating disorders have both short term and long term consequences that can be present years after recovery. However, the molecular mechanisms contributing to the increased cardiovascular risk for “recovered’’ individuals is still largely unknown. We have previously found that inbred female F344 rats have altered renin-angiotensin-aldosterone-system regulation of mean arterial blood pressure(MAP) following a 60% food restriction (to achieve a 15–20% body weight drop in F344). The purpose of this work was to see if these are robust changes that can be replicated in an outbred strain which is a better model of the human population. Design and method: Two-month-old female Sprague Dawley(SD) rats were divided into control(CON) that had access to food ad libitum and a food restricted(FR) that received a 56% food restriction (to achieve a 15–20% body weight drop in SD). After 2 weeks, CON (n = 5) and FR (n = 5) rats were sacrificed, the remaining FR (n = 4) and CON (n = 4) rats received chow ad libitum for 5 months. Prior to sacrifice, an acute MAP response to 200ng/kg Angiotensin II(ANGII) was recorded from the femoral artery under anesthesia by indwelling catheter. Results: We found that after 14 days of food restriction the FR rats had lower baseline MAP compared to CON rats (CON = 92 ± 3.0 vs. FR = 75 ± 0.4mmHG, p &lt; 0.05), however, both groups had the same absolute response in MAP to ANGII infusion (CON = 19 ± 2.8 vs. FR = 18 ± 2.0 mmHG). After 5 months of refeeding we found that there were no statistical differences in baseline MAP between the groups (CON = 86 ± 2.2 vs. FR = 91 ± 4.8mmHg), however, there was a trend towards an increase in peak MAP response to ANGII (CON = 19 ± 1.5 vs. FR = 27 ± 3.0mmHg, p = 0.056). Conclusions: When compared to F344, we found similar trends in baseline MAP immediately following food restriction and months after refeeding. We did not detect a blunting of the ANGII response immediately following food restriction as in F344. We did find similarities between F344 and SD in response to ANGII months after refeeding. Food restriction appears to create a robust change in the response to ANGII months after refeeding, that is not strain specific.

GPR18 receptor – the structure and the role in the physiology and pathophysiology

G-protein coupled receptors constitute the largest family of membrane receptors and they participate in the maintenance of the homeostasis in the body. Some of these receptors still remain orphan receptors as there is insufficient research and ambiguous evidence concerning their function and endogenous ligands. For a long time, GPR18 belonged to this group, but recently it has been classified as an endocannabinoid receptor due to its affinity to cannabinoid ligands. GPR18 receptor is expressed in the encephalon, thyroid gland, leukocytes, lungs and testicles. The modulatory role of GPR18 receptor has been proven in the regulation of intraocular pressure, neuroimmunomodulation, regulation of arterial blood pressure and in metabolic disorders. In this article we summarize the current knowledge concerning the GPR18 receptor – its expression, ligands and the in the physiological processes and the pathophysiological conditions.

The Complexity of the Arterial Blood Pressure Regulation during the Stress Test.

In this study, two categories of persons with normal and high ABP are subjected to the bicycle stress test (9 persons with normal ABP and 10 persons with high ABP). All persons are physically active men but not professional sportsmen. The mean and the standard deviation of age is 41.11 ± 10.21 years; height 178.88 ± 0.071 m; weight 80.53 ± 10.01 kg; body mass index 25.10 ± 2.06 kg/m. Machine learning algorithms are employed to build a set of rules for the classification of the performance during the stress test. The heart rate, the JT interval, and the blood pressure readings are observed during the load and the recovery phases of the exercise. Although it is obvious that the two groups of persons will behave differently throughout the bicycle stress test, with this novel study, we are able to detect subtle variations in the rate at which these changes occur. This paper proves that these differences are measurable and substantial to detect subtle differences in the self-organization of the human cardiovascular system. It is shown that the data collected during the load phase of the stress test plays a more significant role than the data collected during the recovery phase. The data collected from the two groups of persons are approximated by Gaussian distribution. The introduced classification algorithm based on the statistical analysis and the triangle coordinate system helps to determine whether the reaction of the cardiovascular system of a new candidate is more pronounced by an increased heart rate or an increased blood pressure during the stress test. The developed approach produces valuable information about the self-organization of human cardiovascular system during a physical exercise.

Spontaneous Cardiovagal Baroreflex Sensitivity in Females with Multiple Sclerosis

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system that is known to disrupt autonomic function. Females with MS are at an increased risk of cardiovascular disease partly due to altered autonomic regulation of arterial blood pressure. Longitudinal data suggest that low spontaneous cardiovagal baroreflex sensitivity is a predictor of cardiovascular disease. Therefore, the purpose of this investigation is to test the hypothesis that spontaneous cardiovagal baroreflex sensitivity (cBRS) is less in females with MS compared to healthy controls. Electrocardiogram (ECG) and beat‐to‐beat blood pressure (Finometer) were continuously recorded during 10 minutes of quiet supine rest in 3 females with relapsing‐remitting MS (Expanded Disability Scale Score &lt; 6.0) and 3 sex‐, age‐, height‐, weight‐ and race‐ matched healthy controls. Spontaneous cBRS was determined using the sequence method (CardioSeries v2.7). Spontaneous cBRS gain is calculated as the average slope of the relationship between R‐R interval and systolic blood pressure from individual sequences of 3 or more consecutive cardiac cycles where both variables are increasing (up‐up sequences) or decreasing (down‐down sequences). Females with MS had similar resting mean arterial pressures (P=0.55), systolic blood pressures (P=0.53) and heart rates (P=0.18) compared to healthy controls. Overall spontaneous cBRS gain was greater in females with MS compared to healthy controls (27.1 ± 6.3 ms/mmHg vs. 18.8 ± 1.1 ms/mmHg respectively; P=0.04). Spontaneous cBRS gain from up‐up sequences was also greater in females with MS compared to healthy controls (27.6 ± 5.1 ms/mmHg vs. 17.1 ± 2.1 ms/mmHg respectively; P=0.01). Spontaneous cBRS gain from down‐down sequences trended to be greater in females with MS compared to healthy controls but was not statistically significant (27.2 ± 7.8 ms/mmHg vs. 20.1 ± 2.4 ms/mmHg respectively; P=0.10). Counter to our hypothesis, these preliminary findings in a small sample suggest that females with MS have increased spontaneous cBRS compared to healthy controls. If this relationship continues with additional data collection, it may indicate that females with MS have enhanced cardiac responses to regulate arterial blood pressure.

Inhibition of the Hippo Pathway Prevents Arterial Stiffness and Hypertension in Vascular Smooth Muscle Cell Specific Kdm6a Knockout Mice

Arterial stiffness (AS) results from the progressive loss of elasticity of large vessels due to aging and is correlated with hypertension and other cardiovascular co‐morbidities. Increased collagen deposition and contractile protein loss are key contributors to diminished flexibility. The histone 3 lysine demethylase 6a (Kdm6a) transcriptionally activates target genes via removal of tri‐methyl residues on lysine 27 of histone 3 (H3K27me3). The Hippo signaling pathway is crucial for regulating cell proliferation, cell survival, and organ size. The relationship between H3K27me3 and the Hippo pathway in vascular smooth muscle cells (VSMCs) and their effects on arterial compliance and blood pressure (BP) regulation remains unclear. We generated VSMC‐specific Kdm6a knockout (KO) mice of C57BL/6 background and confirmed Kdm6a KO and elevation of H3K27me3 levels by Western blot. Pilot studies (unpublished) indicate that Kdm6a KO results in increased systolic BP and AS due to aortic ECM remodeling and downregulation of contractile protein expression. Further, increased activity of mammalian sterile 20‐like kinase 2 (MST2), a core kinase of the Hippo pathway, was found in Kdm6a KO VSMCs. The objectives of this study were to investigate the effects of Hippo pathway inhibition on arterial compliance and sBP in a VSMC‐specific Kdm6a KO model. Based on the increased MST2 activity noted in Kdm6a KO VSMCs, we hypothesized that Hippo inhibition would prevent the onset of Kdm6a KO‐induced AS and hypertension or blunt the severity of symptoms. Male Myh11Cre/Kdm6aLoxP and Myh11Cre controls were randomly assigned to four groups (n=7‐8): Kdm6a KO‐treated, Kdm6a KO‐vehicle, control‐treated, or control‐vehicle. Immediately after gene deletion, Kdm6a KO mice and controls were administered the MST1/2 inhibitor XMU‐MP‐1 (1mg/kg, i.p.), or vehicle (2% DMSO, i.p.), daily for 4 weeks. Pulse wave velocity (PWV), the gold‐standard method for determination of degree of arterial compliance, was measured weekly. At the study endpoint, sBPs were obtained via direct carotid artery cannulation. The aortic media were collected for further analyses. After one week of treatment, PWVs of Kdm6a KO‐treated mice (3.05 + 0.26 mm/ms) were significantly lower compared with Kdm6a KO‐vehicle (4.10 + 0.29 mm/ms; p&lt;0.01) and remained so throughout the study. The sBPs of Kdm6a KO‐treated mice (106.3 + 2.9 mmHg) were significantly less than those of the Kdm6a KO‐vehicle mice (118.0 + 6 mmHg; p&lt;0.01). Analysis of aortic media by Western blot and immunohistochemistry revealed that treatment with XMU‐MP‐1 effectively inhibits MST2 phosphorylation and activates the downstream Hippo effector protein YAP. Additionally, treated Kdm6a KO mice produced significantly less collagen (p&lt;0.05) and more Myh11 (p&lt;0.05) and calponin (p&lt;0.05) than the Kdm6a KO‐vehicle group. This study suggests that Kdm6a expression by VSMCs is essential for maintaining arterial compliance and regulating BP. Inhibiting the Hippo signaling pathway prevented Kdm6a KO‐induced vascular deregulation by lowering collagen production and rescuing contractile protein expression. These results demonstrate the therapeutic potential of the Hippo pathway in preservation of arterial compliance and BP.

Sedentary behavior is associated with reduced cardiovagal baroreflex sensitivity in healthy adults.

Sedentary behavior is an established risk factor for cardiovascular disease; however, it remains unclear whether sedentary behavior is associated with the deterioration of arterial blood pressure regulation. The purpose of this study was to determine the association between the time spent in sedentary behavior and cardiovagal baroreflex sensitivity (cBRS) in healthy adults. We investigated the cross-sectional relationship between sedentary time and cBRS in 179 adults aged 22-81 years. Sedentary time was objectively measured using a triaxial accelerometer. cBRS was evaluated by the transfer function gain of beat-by-beat changes in systolic blood pressure and the R-R interval during 5 min of spontaneous resting. Glycemic, lipidemic, and vascular risk factors were measured as potential covariates of cBRS and sedentary behavior. Men had a longer sedentary time and lower cBRS than women (p = 0.001). In a simple correlation analysis, older age was negatively associated with cBRS and positively associated with sedentary time, but sedentary time was not correlated with cBRS. However, after adjustment for age and sex, a longer sedentary time was associated with a lower cBRS. Multiple linear regression analysis showed that sedentary time was independently associated with lower cBRS with adjustment for covariates (β = -0.325, p = 0.002). A significant association was also confirmed when the analysis was performed separately in the younger and older groups. This finding suggests that high sedentary behavior may have an adverse effect on arterial blood pressure regulation.

Optimal Interval Type-2 Fuzzy Logic Control Based Closed-Loop Regulation of Mean Arterial Blood Pressure Using the Controlled Drug Administration

In pandemic times, the remote and automatic control/observation of physiological variables of the patients is the prime necessity for healthcare technologies. The closed-loop regulation of mean arterial pressure is essential for critically ill patients or post-surgery recovery patients. The physiological variables have serious issues such as parameter variations and uncertainties. In this paper, an interval type-2 fuzzy logic controller (IT2FLC) with footprints of uncertainty in the membership functions is presented in a two-layered design (TL-IT2FLC) that can efficiently deal with uncertainties and parameter variations. In this design, a pre-compensator IT2FLC is used, which deals with the uncertainties and parameter variations before the primary IT2FLC approach. The robustness analysis of the proposed method is investigated for external noise, and results are compared with traditional PID and T1-FLC techniques.