Increase In Mean Blood Pressure Research Articles

Females with a History of Spontaneous Coronary Artery Dissection Exhibit Greater Pressor Responses to Isometric Handgrip and Post-exercise Ischemia Compared to Healthy Females

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome via the sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is >80% female who typically have few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Risk of a recurrent SCAD is reported as high as 19% at 3 years after an initial SCAD. Mechanisms underlying SCAD (re)occurrence are unknown. Common triggers for SCAD include sympathoexcitatory stimuli, including heavy exercise and intense Valsalva-like activities. This study tested the hypothesis that SCAD patients exhibit greater neurocardiovascular responses (e.g., blood pressure, heart rate, muscle sympathetic nerve activity) to isometric handgrip and post-exercise ischemia compared to healthy females. Methods: Eight females with a history of SCAD (age: 56±6 yrs, BMI: 28±4 kg/m2) and 6 age- and BMI-matched healthy female controls (CON, age: 55±8 yrs, BMI: 26±5 kg/m2) participated. Continuous blood pressure (finger photoplethysmography) and heart rate (3-lead ECG) were measured during rest (1 minute), isometric handgrip at 30% maximal voluntary contraction (2 minutes), and post-exercise ischemia at 220 mmHg (2 minutes) to isolate the skeletal muscle metaboreflex. Muscle sympathetic nerve activity (MSNA, peroneal microneurography) was measured in a subset of participants (5 SCAD/4 CON). Data are presented as an absolute change from rest (mean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (SCAD: 96±8 vs CON: 91±9 mmHg, p=0.354), heart rate (SCAD: 56±11 vs CON: 59±10 bpm, p=0.666), and MSNA (SCAD: 50±19 vs CON: 43±32 bursts/100 heartbeats, p=0.697) were not different between groups. Relative to healthy controls, SCAD patients elicited greater increases in mean blood pressure during isometric handgrip (SCAD: Δ9±3 vs CON: Δ4±4 mmHg, p=0.034) and post-exercise ischemia (SCAD: Δ7±4 vs CON: Δ3±3 mmHg, p=0.046). There were no group differences regarding heart rate responses during isometric handgrip (SCAD: Δ3±4 vs CON: Δ4±4 bpm, p=0.359) and post-exercise ischemia (SCAD: Δ3±4 vs CON: Δ2±3 bpm, p=0.861). Responses in MSNA during isometric handgrip (SCAD: Δ12±8 vs CON: Δ9±8 bursts/100 heartbeats, p=0.536) and post-exercise ischemia (SCAD: Δ11±2 vs CON: Δ13±10 bursts/100 heartbeats, p=0.713) also were not different between groups. Conclusion: These preliminary data suggest that compared to healthy females, female patients who experienced a SCAD exhibit greater pressor, but not chronotropic or sympathetic, responses to isometric handgrip and post-exercise ischemia. Exaggerated pressor responses to these perturbations may be a potential risk factor for SCAD (re)occurrence. NIH K23 HL155506, NIH T32 DK07352, NIH K01 HL148144, NIH UL1 TR0022377, and AHA 898649. 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.

High altitude sojourn elicits divergent effects in aortic and carotid stiffness in healthy-young adults

High altitude exposure challenges the cardiovascular system to compensate for barometric pressure-mediated reductions in arterial oxygen content. Reductions in oxygen content elicit simultaneous increases in sympathetic nervous system activity and vasodilation that may have competing effects on changes in large artery stiffness. The objective of this study was to examine changes in aortic and carotid stiffness during high altitude sojourn in healthy, young adults. We hypothesized that short-term high-altitude sojourn would increase both aortic and carotid stiffness. 17 Generally healthy adults (23±4 yrs, 25.0±3.0 BMI, n=9 females) underwent vascular assessments in the supine position at 1400 m and after an 8-day incremental ascent to 4300 m. Aortic stiffness and carotid β-stiffness were derived from carotid-femoral pulse wave velocity (cfPWV) via applanation tonometry and right common carotid artery ultrasonography, with blood pressure assessed via oscillometry. Ascent from 1400 m to 4300 m resulted in decreased arterial oxygen saturation (-11±4 %, p<0.001) and carotid β-stiffness (-4.48±2.73 au, p<0.001), and increased cfPWV, (+54.98±78.10 cm/s, p=0.01) and mean arterial pressure (+4±7 mmHg, p=0.02). Changes in cfPWV, arterial oxygen saturation, and blood pressure were moderately to strongly correlated (r=-0.425-0.503, p=0.09-0.04). Our data suggest that short term exposure to high altitude has differential effects on carotid versus aortic stiffness despite increases in mean blood pressure. Increases in aortic stiffness appear related to hypoxia-induced reductions in arterial oxygen saturation and concomitant increases in blood pressure, while reductions in carotid stiffness may stem, in-part, from compensatory carotid artery dilation necessary to increase cerebral blood flow at high altitude. Additional research is necessary to further understand mechanisms underlying differential changes in large artery stiffness during high altitude sojourn. 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.

Mitochondrial AKAP1 Is Necessary for Obesity- and Angiotensin II-induced Hypertension

Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1−/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1−/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1−/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1−/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm2, p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1−/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1−/−). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1−/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II. Veterans Affairs NIH. 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.

Analysis of haemodynamics surrounding blood transfusions after the arterial switch operation: a pilot study utilising real-time telemetry high-frequency data capture.

Packed red blood cell transfusions occur frequently after congenital heart surgery to augment haemodynamics, with limited understanding of efficacy. The goal of this study was to analyse the hemodynamic response to packed red blood cell transfusions in a single cohort, as "proof-of-concept" utilising high-frequency data capture of real-time telemetry monitoring. Retrospective review of patients after the arterial switch operation receiving packed red blood cell transfusions from 15 July 2020 to 15 July 2021. Hemodynamic parameters were collected from a high-frequency data capture system (SickbayTM) continuously recording vital signs from bedside monitors and analysed in 5-minute intervals up to 6 hours before, 4 hours during, and 6 hours after packed red blood cell transfusions-up to 57,600 vital signs per packed red blood cell transfusions. Variables related to oxygen balance included blood gas co-oximetry, lactate levels, near-infrared spectroscopy, and ventilator settings. Analgesic, sedative, and vasoactive infusions were also collected. Six patients, at 8.5[IQR:5-22] days old and weighing 3.1[IQR:2.8-3.2]kg, received transfusions following the arterial switch operation. There were 10 packed red blood cell transfusions administered with a median dose of 10[IQR:10-15]mL/kg over 169[IQR:110-190]min; at median post-operative hour 36[IQR:10-40]. Significant increases in systolic and mean arterial blood pressures by 5-12.5% at 3 hours after packed red blood cell transfusions were observed, while renal near-infrared spectroscopy increased by 6.2% post-transfusion. No significant changes in ventilation, vasoactive support, or laboratory values related to oxygen balance were observed. Packed red blood cell transfusions given after the arterial switch operation increased arterial blood pressure by 5-12.5% for 3 hours and renal near-infrared spectroscopy by 6.2%. High-frequency data capture systems can be leveraged to provide novel insights into the hemodynamic response to commonly used therapies such as packed red blood cell transfusions after paediatric cardiac surgery.

Intravenous infusion of lidocaine as a component of opioid-free anesthesia in thoracic surgery: prospective randomized single-center observational study

BACKGROUND: The possibility of reducing doses of narcotic analgesics during the perioperative period is widely discussed in modern scientific literature. This direction is called opioid-free anesthesia and is used in abdominal surgery, oncology, gynecology, and other areas. Publications on the use of opioid-free anesthesia in thoracic surgery are scarce.
 OBJECTIVE: To evaluate the analgesic effectiveness of intravenous lidocaine infusion as a component of anesthesia in thoracic surgery.
 MATERIALS AND METHODS: Ninety patients who underwent open lobectomy or pneumonectomy were examined. Depending on the analgesic component, patients were divided into three groups: group 1 (n=30) received intravenous infusion of lidocaine, group 2 (n=30) received epidural block, and group 3 (n=30) had fentanyl infusion. Blood pressure, heart rate, cortisol, and blood serum glycemia levels were measured. The intensity of postoperative pain syndrome and the need for promedol, tramadol, and sanitation fibrobronchoscopy were assessed. Arterial hypotension and frequency of postoperative nausea and vomiting were recorded. The length of stay of the patients in the intensive care unit and hospital was recorded.
 RESULTS: Cortisol levels did not differ between groups (p=0.26). The glucose level in the epidural block group was significantly lower than that in other groups (p=0.011). A significant increase in mean blood pressure and heart rate was observed in the opioid analgesia group (p 0.001). The lowest severity of pain 6 h after surgery was observed in the epidural blockade and lidocaine groups (p 0.001). Perioperative hypotension was more common in the epidural analgesia group (p=0.045). The incidence of postoperative nausea and vomiting was higher in the opioid anesthesia group (p=0.004). In the fentanyl infusion group, sanitary fibrobronchoscopy was more often required to eliminate atelectasis (p=0.039). The number of bed days spent in the ICU was significantly higher in the opioid analgesic group (p=0.002); however, no significant differences were noted between the groups regarding the number of days spent in the hospital (p=0.228).
 CONCLUSION: Opioid-free anesthesia based on intravenous lidocaine infusion, as a component of anesthetic management in thoracic surgery, provides sufficient perioperative stability of hemodynamic and neuroendocrine status, has a pronounced analgesic effect, with less opioid consumption on the first day after surgery, and helps reduce the length of stay in the intensive care unit and hospital.

Cardiovascular Protective Effect of Lignan Glycosides of Plumeria rubra Leaves

Introduction: Cardiovascular disorders are the most prevalent and life-threatening conditions affecting human beings. Therefore, this study aimed to assess the cardioprotective effect of P. rubra leaves. Aim: Plumeria rubra L. has been used for ages in alternative/traditional systems of medicine for several conditions, such as arthritis, toothache, pruritus, asthma, dysuria, gonorrhoea, diabetes, and various types of inflammation. Methods: Acute toxicity studies were performed using OECD 423 guidelines, and cardiomyopathy was induced in Wistar albino rats through an intraperitoneal injection of doxorubicin hydrochloride. Different groups were established to study the efficacy of doxorubicin-treated P. rubra leaf extract for 7 days. Blood pressure of both systolic and diastolic was recorded with noninvasive blood pressure apparatus, and the mean was considered. Biochemical parameters were analysed for serum and tissue homogenate viz. lactate dehydrogenase (LDH), thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Results: The LD50 cut-off range for the leaf extract was found to be 2,000 mg/kg body weight. P. rubra leaf extract prevented the increase in heart rate (364.8 BPM) and mean blood pressure (122.24 mmHg) and demonstrated good results as an antihypertensive agent. The treatment with the extract was also found to revert the oxidative stress levels, as depicted by the MDA, SOD, and catalase levels in heart tissue in treated rats. Conclusion: P. rubra leaf extract at a higher dose (200 mg/kg) exerted a compelling cardioprotective action against cardiomyopathy induced by doxorubicin in Wistar rats due to the presence of lignan glycoside, liriodendrin.

Deep Parasternal Intercostal Plane Block for Intraoperative Pain Control in Cardiac Surgical Patients for Sternotomy: A Prospective Randomized Controlled Trial

Sternotomy pain is common after cardiac surgery. The deep parasternal intercostal plane (DPIP) block is a novel technique that provides analgesia to the anterior chest wall. The aim of this study was to investigate the analgesic effect of bilateral DPIP blocks on intraoperative pain control in cardiac surgery. This is a double-blinded, prospective randomized controlled trial (Oct 2020-Dec 2022). This study was conducted in a single institution, which is an academic university hospital. Eighty-six elective cardiac surgical patients with median sternotomy were recruited. Patients were randomly divided into DPIP or control group. Either 20ml 0.25% levobupivacaine or 0.9% normal saline was injected for the DPIP under ultrasound guidance after induction of general anaesthesia. The primary outcome was intraoperative opioids consumption and hemodynamic changes at sternotomy. Secondary outcomes included postoperative morphine consumption, postoperative pain and time to tracheal extubation. Intraoperative opioids requirement was reduced from a median (IQR) intravenous morphine equivalence of 21.4mg (13.8-24.3mg) in control group to 9.5mg (7.3-11.2mg) in the DPIP group (P<0.001). Hemodynamic parameters were more stable in DPIP group at sternotomy, as evidenced by lower percentage increase in systolic, diastolic and mean arterial blood pressure from baseline. No difference was observed in time to tracheal extubation, postoperative morphine consumption, postoperative pain score and spirometry. Bilateral DPIP block provides effective intraoperative analgesia and opioid-sparing. It may be included as part of the multimodal analgesia for enhanced recovery in cardiac surgery.

Comparative evaluation of propofol, thiopentone and etomidate on induction time, intubation response and recovery time during laparoscopic surgery under general Anaesthesia

: Optimal choice of inducing agent can partially modify the post induction hypotension, having a reported incidence of 9-40% in various studies. So, we compared the induction and recovery profile of the routinely available induction agents.This prospective randomized, comparative study was carried out on 120, ASA 1 and II patients undergoing routine laparoscopic cholecystectomy. Patient received either thiopentone 5 mg/kg, propofol 2.0 mg/kg or 0.3mg/kg injection etomidate at induction in group T, P and E respectively. The time taken from the administration of inducing agent to loss of eyelash reflex was noted. Heart rate, systolic, diastolic and mean arterial pressure, SpO2 was recorded at 1, 2, 3, 4, 5, 6 minutes and every five minutes after intubation. Steward score and the vitals were noted every 5 minutes after extubation till 30 minutes. It was noted that how long it took to get a Steward score of 6.The mean induction time (sec) was 49.85 ±2.54 in group T, 43.45 ±2.66 in group P and 52.675 ±2.11 in group E. (p&amp;#60;0.0001). The increase in mean heart rate from baseline upon induction and intubation was (10%, 31% in group T), (3%, 23% in group E) and (-7%, 16% in group P) (p&amp;#60;0.0001). Post induction decrease in systolic, diastolic and mean blood pressures observed in group T was (-9%, -4.5%, -6%), (-12.8%, -9.8%, -11%), in group P and (-4.6%, -1.7%, -2.9%) in group E. (p&amp;#60;0.0001). Post intubation increase in systolic, diastolic and mean blood pressures was (21.76%, 18%, 19.7%) in group T, (16%, 8.1%, 11.7%) in group E and (9.6%, 0%, 4%) in group P. Mean recovery time in min was 5.87 ±0.23 min with propofol, 6.97 ±0.28 with etomidate and 8.96 ±0.28 with thiopentone. (p&amp;#60;0.0001). : Amongst the three agents, we recommend propofol as preferred agent for induction due to faster induction, better attenuation of intubation response, faster recovery and stable hemodynamic parameters.

Lung aeration reduces blood pressure surges caused by umbilical cord milking in preterm lambs.

Umbilical cord milking (UCM) at birth causes surges in arterial blood pressure and blood flow to the brain, which may explain the high risk of intraventricular haemorrhage (IVH) in extremely preterm infants receiving UCM. This high risk of IVH has not been reported in older infants. We hypothesized that lung aeration before UCM, reduces the surge in blood pressure and blood flow induced by UCM. At 126 days' gestation, fetal lambs (N = 8) were exteriorised, intubated and instrumented to measure umbilical, pulmonary, cerebral blood flows, and arterial pressures. Prior to ventilation onset, the umbilical cord was briefly (2-3 s) occluded (8 times), which was followed by 8 consecutive UCMs when all physiological parameters had returned to baseline. Lambs were then ventilated. After diastolic pulmonary blood flow markedly increased in response to ventilation, the lambs received a further 8 consecutive UCMs. Ovine umbilical cord is shorter than the human umbilical cord, with ∼10 cm available for UCMs. Therefore, 8 UCMs/occlusions were done to match the volume reported in the human studies. Umbilical cord clamping occurred after the final milk. Both umbilical cord occlusions and UCM caused significant increases in carotid arterial blood flow and pressure. However, the increases in systolic and mean arterial blood pressure (10 ± 3 mmHg vs. 3 ± 2 mmHg, p = 0.01 and 10 ± 4 mmHg vs. 6 ± 2 mmHg, p = 0.048, respectively) and carotid artery blood flow (17 ± 6 ml/min vs. 10 ± 6 ml/min, p = 0.02) were significantly greater when UCM occurred before ventilation onset compared with UCM after ventilation. UCM after ventilation onset significantly reduces the increases in carotid blood flow and blood pressure caused by UCM.

The Relationship Between the Dipping Pattern and Coronary Artery Disease Severity Assessed by the SYNTAX Score in Patients With Hypertension.

Background The morbidity and mortality rates related to hypertension (HT) are still high despite the developments in this area. Nondipper hypertension (NDHT) is related to worse clinical outcomes. But the dipping pattern of HT is not still used for treatment targets. In this study, we investigated the effect of dipping patterns on coronary artery disease (CAD) complexity evaluated by the SYNTAX score (SS). Methodology Patients with stable CAD and HT were included in the study. All patients were monitored with 24-hour ambulatory monitoring, and dipping patterns were evaluated. Coronary artery complexity was determined by SS for all patients and compared along with different dipping patterns. Results A total of 331 patients with HT and stable CAD were evaluated in the study. The mean age of the patients was 62.6 ± 9.9 years, and 172 (52%) were male. The number and percentage of patients with dipper HT (DHT), NDHT, over-dipper HT (ODHT), and reverse-dipper HT (RDHT) were 89 (26%), 143 (43%), 11 (3%), and 88 (26%), respectively. When the groups were compared according to SS, the SS of the patients with RDHT were significantly higher (the SS were 6.33, 4.99, 3.09, and 2.7 for RDHT, ODHT, NDHT, and DHT, respectively, P = 0.003). The mean SS between the DHT group and the NDHT group (P = 0.03) and between the DHT group and the RDHT group (P = 0.01) was significantly different. The less decrease or increase in mean blood pressure (MnBP) values was significantly correlated with high SS. Conclusions NDHT, especially the reverse dipping pattern, is closely related to complex CAD. Meticulous consideration of dipping patterns can identify high-risk patients and improve clinical outcomes.

Plasma Histone Deacetylase activities, Lipid Profile, and Glycated Haemoglobin levels as indicator of Glycemic control in Type 2 Diabetes Mellitus

Background: The number of people with Diabetes mellitus (DM) is steadily rising globally and its socio-economic effects extend beyond the individual to affect their families and whole societies.Aim: This study aimed at determining the Plasma Lipid Profile, Glycated Haemoglobin (HbA1C) and Histone Deacetylase (HDAC) enzyme activities as indicator of Glycaemic control in Type 2 Diabetes mellitus.Methods: A total of 100 newly diagnosed DM patients and 50 control subjects were recruited. The weight, height, body mass index (BMI), waist circumference (WC), and blood pressure of each participant were determined. Also, fasting plasma glucose (FPG), triglycerides, total Cholesterol (TC), high density lipoprotein (HDLC) and HDAC activities were measured using standard methods. Low density lipoprotein (LDLC) was computed.Results: A significant increase in mean age, FPG, systolic and diastolic blood pressure, HbA1c total cholesterol, triglyceride, and low density lipoprotein, and HDAC activities; and a decrease in plasma HDLC were observed among the diabetics when compared with the controls. A direct but significant correlation existed between HDAC activities and FPG, WC, and duration of diabetes; and between HbA1C and FBG, TC, LDLC, HDLC, and duration of diabetes; a direct but non-significant correlation existed between HDAC and HbA1C, HDLC; an inverse and significant correlation existed between BMI and TC, Triglyceride and LDLC.Conclusion: It could be inferred from thia study that plasma HDAC activities is directly related to FPGÂ as it was found to increase with increasing FPG, indicating its likely role in metabolism.

Feasibility of a protocol for deprescribing antihypertensive medication in older patients in Dutch general practices

BackgroundOlder patients using antihypertensive medication may experience Adverse Drug Events (ADEs), and thus benefit from deprescribing. The lack of a practical protocol may hamper deprescribing. Therefore, we aimed to develop a deprescribing protocol, based on a review of literature, combined with a feasibility test in a small number of patients.MethodsA deprescribing protocol for general practitioners was drafted and tested in older patients using multiple antihypertensive medication in a single arm intervention. Patients were included if they were 75 years or older, were using two or more antihypertensives, had at least one ADE linked to antihypertensive medication and deprescribing was considered to be safe by their general practitioner. The primary outcome was the percentage of patients for whom one or more antihypertensive drugs were stopped or reduced in dose after 12 months of follow up while maintaining safe blood pressures. Secondary outcomes were the proportion of patients reporting no ADEs after 12 months and the number of deprescribed antihypertensives. Patient’s opinions on deprescribing and enablers and barriers for study participation were also collected.ResultsNine general practitioners included 14 patients to deprescribe antihypertensive medication using the deprescribing protocol. After 12 months antihypertensive drug use was lowered in 11 patients (79%). These patients had a mean systolic blood pressure increase of 16 mmHg and a mean diastolic blood pressure increase of 8 mmHg. Nine patients (64%) reported experiencing no ADEs anymore after twelve months. The mean number of deprescribed antihypertensives was 1.1 in all patients and 1.4 (range: 0.5 to 3.5) in patients who successfully lowered their medication.At baseline, being able to use less medication was the most frequently mentioned enabler to participate in this study. The most frequently mentioned positive experience at the end of the study was using less medication, which was in line with the most mentioned enabler to participate in this study.ConclusionA protocol for deprescribing antihypertensives in older patients was considered feasible, as it resulted in a substantial degree of safe deprescribing in this pilot study. Larger studies are needed to demonstrate the effect and safety of deprescribing antihypertensives in older patients.

Antihypertensive Effects of Aqueous Extract of Ricinodendron heudelotii (Baill.) Pierre (Euphorbiaceae) in Wistar Rat.

Ricinodendron heudelotii stem bark is commonly used in Cameroonian traditional medicine to treat cardiovascular diseases such as hypertension. The present study was designed to investigate the antihypertensive and antioxidant properties of the aqueous extract of Ricinodendron heudelotii in salt-induced hypertensive rats. Analysis by HPLC-ESI-Q-TOF-MS was used to identify various chemical components of the extract. A total of thirty rats were used for each test. High-salt hypertension was induced in rats by oral administration of NaCl for 12 weeks. Mean blood pressure (MBP) and heart rate (HR) were monitored by noninvasive methods. Oral administration of Ricinodendron heudelotii significantly (p < 0.01) reduced the increase of mean blood pressure (23.12%, 26.14%, and 24.34%) and heart rate (31.19%, 31.09%, and 26.98%), respectively, at the doses of 40, 20, and 6 mg/kg, compared to the hypertensive group. All the doses tested significantly reduced or/and ameliorated biochemical and oxidative stress parameters. Histological analysis showed that Ricinodendron heudelotii restored renal disorders induced by the administration of salt. The aqueous extract of Ricinodendron heudelotii exerts a cardioprotective effect, and the antihypertensive activity seems associated with an improvement in antioxidant status. Overall, the results justify and support the traditional use of Ricinodendron heudelotii.

Bi-directional relationships of arterial stiffness with hypertension and diabetes mellitus from the early pathophysiological stages: a 16-year prospective observational study

Abstract Background Hypertension and diabetes mellitus frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes mellitus. Methods In this 16-year prospective observational study, 3960 middle-aged employees of a Japanese company without hypertension/diabetes mellitus at the study baseline underwent annual repeated measurements of the blood pressure, serum glycosylated hemoglobin A1c levels (HbA1c), and brachial-ankle pulse wave velocity (baPWV). Results By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes mellitus, and prediabetes, respectively. Increased baPWV at the baseline was associated with a significant odds ratio (per 1 standard deviation increase) for new onset of prehypertension/hypertension with (2.45/3.28, P&amp;lt;0.01) or without (2.49/2.76, P&amp;lt;0.01) coexisting prediabetes/diabetes mellitus, but not for new onset of prediabetes/diabetes mellitus without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between baPWV and hypertension, but no such relationship was observed between baPWV and abnormal glucose metabolism. Moreover, after the adjustments, higher mean blood pressure at baseline accelerated the increases in the baPWV over follow-up (unstandardized coefficient [B] = 0.39, standard error [SE] = 0.05x10–1, P&amp;lt;0.01). Similarly, higher baPWV at baseline accelerated the increases in mean blood pressure over follow-up (B = 0.02x10–1, SE = 0.01x10–1, P&amp;lt;0.01) (Figure 1). On the other hands, higher HbA1c levels at baseline accelerated the increases in the baPWV over follow-up (B = 0.43, SE = 0.05x10–1, P&amp;lt;0.01), but higher baPWV at baseline did not accelerate the increases in HbA1c levels over follow-up (B &amp;lt;0.01, SE &amp;lt;0.01, P=0.52) (Figure 2). Conclusions In middle-aged employees of a Japanese company, in contrast to the bidirectional relationships that exist between arterial stiffness and hypertension, increased arterial stiffness preceding the development of diabetes mellitus may represent that associated with the development of hypertension, as it is observed only in cases of diabetes mellitus coexisting with hypertension. Therefore, arterial stiffness may be associated to a greater degree with the development of hypertension than with the development of diabetes mellitus. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Omron Health Care Company (Kyoto, Japan),Teijin Pharma Company (Tokyo, Japan)

Abstract 058: ACE2 Ubiquitination Regulates Neuronal Activity In Hypertension

ACE2 expression on GABAergic neurons could maintain the inhibitory tone over pre-sympathetic neurons in the paraventricular nucleus (PVN) and thus contribute to the regulation of blood pressure (BP). Here we investigated the role of ACE2 ubiquitination in the bed nucleus of the stria terminalis (BNST), a region containing GABAergic neurons and involved in cardiovascular responses to stress. C57BL6/J male mice were injected in the BNST with a ubiquitination-resistant human ACE2 mutant (AAV-hACE2-5R). A subset of mice was also injected with AAV-GCaMP6s-eYFP in the PVN and BNST to record intracellular Ca 2+ activity via fiber photometry. After 6 weeks, the mice were chronically infused with Ang-II (600 ng/kg/min) for 2 weeks while BP was monitored by telemetry. Ang-II-infusion resulted in a significant increase in mean BP compared to controls (152±7 vs. 123±4 mmHg, respectively; n=6, p&lt;0.05) that was blunted in mice expressing hACE2-5R (133±5 mmHg, n=6, p&lt;0.05). Injection of bicuculline (GABA A antagonist, 1 mmol/L in 100nL) in the PVN produced a blunted BP rise in Ang-II-infused mice compared to controls (AUC: 261±36 vs. 392±45, respectively; n=4, p&lt;0.05) and an enhanced pressor response in the hACE2-5R+Ang-II group (AUC: 690±81, n=5, p&lt;0.05). Acute injection of Ang-II (250 ng iv) caused an immediate increase in Ca 2+ mediated fluorescence in the PVN and a parallel reduction of neuronal activity in the BNST (ΔF/F 0 : +0.9±0.02 and -0.1±0.03; respectively). Surprisingly, hACE2-5R expression in the BNST produced a rapid and persistent inhibition of neuronal activity. Capillary Western analysis showed a 3-fold increase in NEDD4-2 (n=4, p&lt;0.05) with a parallel reduction of ACE2 levels (-50%, n=4, p&lt;0.05) in the BNST of Ang-II-infused mice, while hACE2-5R prevented NEDD4-2 upregulation and ACE2 downregulation (n=4, p&lt;0.05). Our data show that increases in peripheral Ang-II levels result in an immediate regulation of neuronal activity in the PVN and BNST. Hypertension is associated with NEDD4-2 mediated ubiquitination of ACE2 blunting GABAergic input to the PVN and potentially increasing the activity of pre-sympathetic neurons. ACE2 ubiquitination by NEDD4-2 in key brain regions is a new mechanism contributing to the development of neurogenic hypertension.

Contrast-Enhanced Ultrasonography Enables the Detection of a Cold Pressor Test-Induced Increase in Renal Microcirculation in Healthy Participants.

BackgroundRenal microcirculation is essential for regulation of the glomerular filtration rate, the reabsorption of salt and water from the interstitium, and hence the blood pressure. Renal ultrasonography coupled to Doppler analysis and contrast-enhanced ultrasound enables the study of renal perfusion. So far, physiologic interventions have rarely been performed to assess the renal perfusion. The objective of our study was to measure the renal perfusion in response to a cold pressor test (CPT).MethodsHealthy adult participants were exposed to a 2 min CPT or a sham exposure (body temperature). Systemic hemodynamics, renal resistive index (RRI) and renal perfusion index (PI) were measured before and during the CPT or the sham exposure. Renal responses were compared using a paired Student's t-test or Wilcoxon signed rank test. Pearson correlation test was used to test association of variables of interest.ResultsForty-one normotensive participants (21 women) were included in the study. Mean blood pressure and heart rate both increased with the CPT. The RRI decreased from 0.60 ± 0.05 arbitrary units (AU) to 0.58 ± 0.05 AU (p < 0.05) and the PI increased from 2,074 AU (1,358–3,346) to 3,800 AU (2,118–6,399) (p < 0.05) (+66% (24–106%)). Compared to the sham exposure, the increase in PI with the CPT was more marked. There was a negative association between the increase in heart rate and mean blood pressure with the RRI (r: −0.550, p = 0.002 and r: −0.395, P = 0.016), respectively.ConclusionDoppler Ultrasound and CEUS enable the detection of physiological changes within the macro- and microvascular renal circulation. The CPT decreases the RRI and increases the PI. Whether these changes are present in pathological states such as diabetes or hypertension will need additional studies.

Cholinergic‐mediated Circulatory Responses at the Onset of Isometric Exercise: Does Sex Matter?

IntroductionWe have shown that handgrip exercise evokes an initial decrease in systemic vascular resistance (SVR), which was abolished by cholinergic blockade (glycopyrrolate) and, thereby, augmented the blood pressure (BP) response. These findings suggest that a cholinergic mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans. Noteworthy, this previous study included men only, and was not designed to investigate the potential existence of sex‐related differences in immediate BP and circulatory responses evoked at the exercise onset. Given this, the aim of this study was to test the hypothesis that women present an attenuated fall in SVR and increased pressor response compared to men at the onset of isometric handgrip exercise due to a blunted cholinergic vasodilation.MethodsTen healthy men (aged 21 ± 1 year) and 10 women (aged 24 ± 1 year) were recruited. Women were non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. Participants performed 20s bout of isometric handgrip exercise at 40% of maximal voluntary contraction. Beat‐to‐beat heart rate (HR) (ECG) and mean BP (finger photopletysmography) were continuously measured. Beat‐to‐beat stroke volume (SV) was obtained with the Modelflow method and matched with HR to estimate cardiac output (CO) and SVR. The exercise responses were expressed as a change from 10s immediately before the onset of voluntary contraction.ResultsThe BP response pattern appeared to be different between men and women at the onset of isometric exercise. While men presented a typical exercise‐evoked biphasic BP response (3s: Δ2 ± 2 mmHg; 10s: Δ1 ± 1 mmHg; 20s: Δ5 ± 3 mmHg), women showed a progressive increase in mean BP (3s: Δ1 ± 1 mmHg; 10s; Δ3 ± 1 mmHg; 20s: Δ6 ± 1 mmHg; P=0.681). Men demonstrated a decrease in SVR at 3s (Δ‐0.9 ± 0.3 mmHg.L‐1.min), 10s (Δ ‐1.6 ± 0.4 mmHg.L‐1.min) and 20s (Δ‐1.9 ± 0.7 mmHg.L‐1.min) following the exercise onset, and these responses tended to be attenuated in women (3s: Δ‐0.3 ± 0.3 mmHg.L‐1.min; 10s: Δ‐1.2 ± 0.4 mmHg.L‐1.min; 20s: Δ‐0.6 ± 0.5 mmHg.L‐1.min; P=0.131). There were no sex differences in HR, SV and CO responses to exercise.ConclusionThese findings suggest a lack of sex differences in immediate BP and circulatory responses at the onset of isometric handgrip exercise, indicative of similar cholinergic‐mediated vasodilation in skeletal muscle between men and women.

Selective blockade of AT1R and B1R modulates the expression of ACE2 ubiquitination partners

Angiotensin Converting Enzyme 2 (ACE2) is an important compensatory enzyme in the renin‐angiotensin system (RAS), converting Angiotensin (Ang)‐II to Ang‐(1‐7). We previously reported that Ang‐II mediates ACE2 internalization through its type 1 receptor (AT1R), followed by ubiquitination and degradation in lysosomes. We recently identified UBR1 and BRCC36, as potential ubiquitinase and deubiquitinase, respectively, modulating ACE2 expression in hypertensive conditions. Here, we aimed to evaluate the role of bradykinin B1R receptor in Ang‐II‐mediated ACE2 internalization and the enzyme’s ubiquitination partners in hypertension.C57BI/6J mice (3‐month‐old, n=3/group) were divided into 3 groups: control (Ctrl), B1R antagonist SSR240612 (SSR), AT1R antagonist Losartan (Los). Mice were implanted with blood pressure (BP) probes (telemetry) and upon recovery, baseline BP was recorded for 24 hours. Mice were then implanted subcutaneously with an osmotic pump containing Ang‐II (490 ng/Kg/min/4 weeks) or saline. BP was recorded weekly, for 4 weeks. After 2weeks of Ang‐II infusion, the mice were implanted with an additional osmotic pump containing Losartan (30 mg/Kg/min) or SSR240612 (10 mg/Kg/min) for 2 weeks. Animals were sacrificed and the heart was isolated from all groups and protein expression for UBR1, BRCC36 and ACE2 was assessed using capillary western. Clinical relevance was further assessed in human heart left ventricle tissues of normal and hypertensive donors.Ang‐II infusion induced a significant increase in mean BP in Ctrl group (159.2±1.5 vs. 100.6±0.5 mmHg; one‐way ANOVA, **P&lt;0.001) after 4 weeks of infusion. This was significantly attenuated with blockade of B1R or AT1R (SSR: 98.8±0.6; Los: 99.6±0.8 mmHg; n=3: one‐way ANOVA, **P&lt;0.001). Capillary western with mouse heart tissue confirmed that Ang‐II‐induced a significant 2‐fold increase (*P&lt;0.05) in UBR1 expression and the SSR240612 treatment contributed to a significant 4‐fold increase (**P&lt;0.001). However, losartan had no effect. BRCC36 expression in Ang‐II, losartan and SSR240612 treated group was significantly decreased by 2‐3‐fold (*P&lt;0.05). However, Ang‐II induced decrease in ACE2 levels was significantly attenuated by losartan and SSR240612 (**P&lt;0.001), indicating both B1R and AT1R receptors contribute to ACE2 internalization and degradation. In human’s, the UBR1 expression was 2 folds (*P&lt;0.05) higher in hypertensive CA male and AA female and BRCC36 expression showed 2 folds decrease (*P&lt;0.05) in CA hypertensive females. However, ACE2 expression showed 3 folds decrease in hypertensive CA males, indicating elevated levels of UBR1 mediated ACE2 ubiquitination and degradation in hypertensive conditions.Our data show that Ang‐II‐mediated hypertension was attenuated with inhibition of both AT1R and B1R receptor, while B1R contributed to upregulation of UBR1 and both AT1R and B1R contributes to downregulation of BRCC36. Therefore, inhibition of both AT1R and B1R modulates the expression of ACE2 ubiquitination partners and also inhibits ACE2 internalization and degradation. Therefore, developing a treatments strategy and simultaneously targeting AT1R, B1R, UBR1 and BRCC36, involved in the regulation of ACE2 expression may be effective for the treatment of cardiovascular disorders.

Aging exacerbates hypertension related testicular injury in rats

ABSTRACT Introduction The average age of paternity is rising in developed world. Hypertension is the most common chronic disease among adult males, affecting male fertility. Aging is an important risk factor for the development of atherosclerosis and hypertension. However, involvements of aging on hypertension related testicular injury are not fully clarified. Objective In this study, we investigated the involvements of aging on testes in spontaneously hypertensive rats (SHRs). Methods Male SHRs and Wistar Kyoto rats (WKYs; normotensive control) at the age of 36, 54 or 72 weeks (wk) were used (n=6, each age). At each age, body weight, testicular weight and blood pressure were measured. Serum testosterone and testicular tissue levels of malondialdehyde (MDA: a maker of lipid peroxide) were also measured by colorimetric assay and ELISA assay. Morphological changes in the testis were evaluated by hematoxylin and eosin staining. TUNEL staining was performed to quantify the apoptosis in testis. Results SHRs at 36, 54 o 72 wk showed a significant increase in mean blood pressure compared to WKYs at each age. SHRs at 54 or 72 but not 36 wk demonstrated a significant decrease in body weight and increase in testicular weight/body weight ratio compared to WKYs at each age. Testicular tissue levels of MDA in SHRs at all ages were significantly higher than those in WKYs at all ages. Serum testosterone in SHRs at 54 or 72 but not 36 wk was lower than that in WKYs at each age. SHRs at 54 or 72 but not 36 wk demonstrated obvious morphological changes such as thickening of blood vessel wall in testis, and seminiferous tubules with degeneration compared to the WKYs at each age. Number of TUNEL positive cells in testicular seminiferous tubules in SHRs at 36 wk was significantly greater than those in WKYs at 36 wk. While number of TUNEL positive cells in testicular seminiferous tubules in SHRs at 72 wk was significantly lower than those in WKYs at 72 wk. Conclusion Aged SHRs showed significant increases in oxidative damage and vacuolation in testes, and decrease in serum testosterone compared to age matched WKYs. Aging could exacerbate hypertension related testicular injury in rats. Disclosure Work supported by industry: no.

Cardiovascular and autonomic profiles in offspring of fructose fed parents: role of anti‐inflammatory cholinergic reflex and exercise training

AimConsidering that anti‐inflammatory cholinergic reflex has been implicated in cardiovascular disorder, and spleen seems to be a critical organ in this reflex, here we evaluated the impact of aerobic exercise training on cardiovascular and autonomic profiles in offspring of rats submitted to fructose overload, as well as, the role of the splenectomy in this condition.MethodsOffspring of Wistar rats treated with fructose or placebo (water) were divided into 5 groups: Sedentary Control (OC), Sedentary Fructose (OF), Trained Fructose (OFT), Splenectomized Sedentary Fructose (OFE) and Splenectomized Trained Fructose (OFST). Fructose overload (10%) was started 30 days after weaning only for the parents and continued until the end of lactation. The offspring received standard feeding and were evaluated 30 days after weaning, at which time the spleen was removed (splenectomy) and the aerobic exercise training was realized on treadmill (1h/d, 5d/week, 4 weeks, moderate intensity). Blood pressure (BP) and heart rate (HR) signals were direct recorded, baroreflex sensitivity (BRS) was measured using increasing doses of phenylephrine and sodium nitroprusside. Oxidative stress was measured in cardiac tissue.ResultsSystolic BP, Diastolic BP and Mean BP increase in OF compared to OC, OFT, OFE and OFST groups (OC: 105±1.3, OF: 112±1.6, OFT: 104±2.4, OFE: 103±3.1, OFST: 104±2 mmHg) HR reduced in the OFT compared to the OC group. Regarding BRS, bradycardic and tachycardic responses were impaired in OF compared to OC group; and OFE, OFT and OFST groups increased these parameters compared to OF group. In the antioxidant profile in cardiac tissue, the activities of catalase and superoxide dismutase were reduced in the OF group compared to the OC group, and increased in the OFE, OFT and OFST groups compared to the OF group. Protein oxidation was increased in the OF group compared to the OC, OFE, OFT and OFST groups (OC: 5.37±0.15, OF: 6.41±0.21, OFT: 4.93±0.3, OFE: 4.94±0.23, OFST: 4.66±0.46 nmol/mg protein). The redox balance of glutathione (GSH/GSSG) was decreased in the OF group compared to the OC and OFT groups.ConclusionThese results demonstrate that fructose exposure in parents induced early changes in offspring BP, BRS and cardiac oxidative stress, that seems to be mediated, at least in part, by the anti‐inflammatory cholinergic reflex. Moreover exercise training seems to prevent/attenuate such dysfunctions.