Decrease In Total Peripheral Resistance Research Articles

The relative contribution of hemodynamic parameters to blood pressure decrease in classical orthostatic hypotension.

We studied the relative contributions of total peripheral resistance (TPR), stroke volume (SV) and heart rate (HR) to low blood pressure in classical orthostatic hypotension (cOH) on group and individual levels. We retrospectively analyzed tilt test records from cOH patients and age/sex-matched controls. We quantified relative effects of HR, SV and TPR on mean arterial pressure (MAP) with the log-ratio method. We studied relations of changes of HR, SV or TPR with the change of MAP across patients and variability of contributions of HR, SV and TPR to MAP. We also explored neurogenic vs. nonneurogenic causes. MAP responded to tilt with a decrease in patients (n = 80) and an increase in controls (n = 80). A too small TPR-increase contributed most to cOH, followed by a too large SV-decrease; both effects were partially corrected by a larger increase of HR. Only TPR changes consistently affected MAP change in patients and controls. TPR decreased almost exclusively in patients, most in those with severe cOH. Contributions of HR, SV and TPR to MAP did not differ between probable neurogenic and nonneurogenic causes. HR, SV and TPR all contributed to cOH, with a key role for TPR; a decrease of TPR was almost unique to patients and may be due to hyperventilation. The lack of differences between neurogenic and nonneurogenic causes needs further study.

Endovascular Treatment of Flow-Limiting Iliofemoral Stenosis Improves Left Ventricular Diastolic Function in Patients With HFpEF by Reducing Aortic Pulsatile Load.

Recent research indicates that there is a high prevalence of heart failure with preserved ejection fraction in patients with peripheral artery disease. We hypothesized that endovascular treatment (EVT) of flow-limiting peripheral stenosis improves left ventricular (LV) diastolic function. Thirty patients with symptomatic peripheral artery disease and heart failure with preserved ejection fraction according to Heart Failure Association-preserved ejection fraction score who were scheduled for EVT or angiography were investigated at baseline, the day after EVT (n=25) or angiography (control, n=5), and at 4 months follow-up. Peripheral hemodynamics were determined by the total peripheral resistance, common femoral artery flow, and ankle brachial index. Aortic function was measured by arterial compliance, augmentation index, and pulse wave velocity. Aortic pulsatile load was estimated as the characteristic impedance of the proximal aorta and the magnitude of wave reflection (reflection coefficient). LV mass index, LV mean wall thickness, and systolic and diastolic function were assessed using echocardiography. Patient-centered outcomes were treadmill walking distance and New York Heart Association class. After EVT, peripheral hemodynamics changed significantly with a decrease in total peripheral resistance and an increase in common femoral artery flow and ankle brachial index. Aortic function improved after EVT, with significantly reduced augmentation index and pulse wave velocity and increased compliance immediately and at follow-up, resulting in a reduction in aortic pulsatile load (characteristic impedance of the proximal aorta and reflection coefficient). Concurrently, LV diastolic function improved after EVT compared with control, acutely and at follow-up, with increased septal and lateral e´ velocities and decreased E/e´ and left atrial volume index. The LV mass index and LV mean wall thickness decreased at follow-up. The New York Heart Association class and treadmill walking distance improved post-EVT at follow-up. Augmentation index, pulse wave velocity, and arterial compliance were identified as independent contributors to E/e´. Endovascular treatment of flow-limiting iliofemoral stenosis reduces aortic pulsatile load and concurrently lowers total peripheral resistance. This beneficial effect is associated with an acute and sustained improvement of left ventricular diastolic function. URL: http://www.clinicaltrials.gov; Unique identifier: NCT02728479.

Arterial and Intracranial Hypotension During and Following Exercise

Exercise induced arterial hypertension and post-exercise arterial hypotension (PEH) are well-described phenomena with direct impact on cerebral blood flow. Cerebral perfusion pressure is given by the difference between mean arterial pressure at brain-level (MAPbrain) and intracranial pressure (ICP), however, little is known about effects of moderate aerobic exercise on ICP. We hypothesize that moderate exercise does not increase ICP thereby facilitating the augmented cerebral blood flow and that a post-exercise decrease in ICP is a contributing mechanism to maintained cerebral blood flow during PEH.Non-invasive (N=14) and invasive (N=3) ICP recordings and cardiovascular parameters were measured upright and supine before, during, and after 30 minutes of seated moderate aerobic bicycle exercise. Exercise elevated MAPbrain from 68±4 to 82±7 mmHg (mean±SEM, P<0.05) without elevating ICP, thus increasing CPP (72±3 to 87±6 mmHg, P<0.05). Compared to before exercise, we found significant PEH with a decrease in MAPbrain of 5±3% (5 mmHg; P<0.05), predominantly driven by a 26±5% (P<0.0001) decrease in total peripheral resistance (TPR). Because post-exercise ICP decreased concomitantly by 58±20% (P<0.0001) CPP remained unchanged. Recovery of ICP towards baseline was similarly correlated to TPR-recovery (R2=0.92, P<0.001), all variables returned to baseline within one hour.Here, we show for the first time ICP during and following aerobic exercise and consequences for cerebral perfusion. Periodic PEH is cardio-vascular protective and has long-term benefits for hypertensive patients, here we suggest that post-exercise decreases in ICP could similarly be cerebo-protective and in part explain the long-term beneficial effects of exercise for cerebral health and cognition. This work was supported by NASA grant no 80NSSC19K0020 and the Novo Nordic Foundation grant no NNF15OC0019196 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein.

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

Is vicarious stress functionally adaptive? Perspective-taking modulates the effects of vicarious stress on future firsthand stress.

Mere observation of others experiencing stress is often sufficient to evoke stress vicariously, especially when people try to understand the situation from the viewpoint of others. Here, we tested whether and how the experience of vicarious stress, facilitated by perspective-taking, would influence individuals' affective and motivational reactions to an upcoming experience of firsthand stress-when they themselves encounter the same stressor in the future. Participants viewed a video clip of another participant undergoing a stressful task (a speech task), after being randomly assigned to take either a first-person perspective of the person (perspective-taking condition; n = 45) or maintain a detached, third-person, observer perspective (objective condition; n = 46). Subsequently, participants were given a surprise speech task and asked to prepare for their own speech for 2 minutes, during which their cardiovascular responses were assessed to differentiate motivational states of challenge or threat. Compared to participants in the objective condition, those in the perspective-taking condition perceived higher levels of stress in anticipation of giving a speech. The heightened stress appraisals, in turn, were associated with a more adaptive pattern of cardiovascular reactivity to the firsthand (relative to vicarious) stressor, characterized as challenge responses (an increase in cardiac output and a decrease in total peripheral resistance). These results suggest that perspective-taking enhances sensitivity to vicarious stress, which in turn, may facilitate preparedness for future stressors. Discussion centers on the functional adaptiveness of vicarious stress. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

СИНДРОМ ЭЙЗЕНМЕНГЕРА И БЕРЕМЕННОСТЬ: АСПЕКТЫ ЭТИОПАТОГЕНЕЗА И ЛЕЧЕБНОЙ ТАКТИКИ

In the modern world, the problem of maintaining a woman's reproductive potential and preserving the resulting pregnancy comes to the fore. An important aspect remains the increasing number of concomitant extragenital diseases. The most common pathology of the cardiovascular and respiratory systems. A rare and often fatal complication is Eisenmenger's syndrome. Eisenmenger's syndrome is a pathological process that occurs due to bidirectional blood discharge or right-left blood discharge due to the presence of a message between the right and left parts of the heart, clinically manifested by severe pulmonary hypertension with diffuse cyanosis. It occurs against the background of an existing decompensated heart defect - a defect of the atrial septum, interventricular septum, open arterial duct, anomalies of the pulmonary veins. Previously, it was believe that the threat of developing Eisenmenger syndrome is an absolute indication for termination of pregnancy, and this pathology is not compatible with gestation. Currently, the effect of pregnancy on the cardiovascular system has been study and recommendations for the management of such patients have been develop. It found that due to an increase in the volume of circulating blood, cardiac output, a decrease in total peripheral resistance and blood pressure, there is an increase in the load on the cardiovascular system and a change in the pharmacokinetics of drugs, which leads to a revision of the treatment tactics used before pregnancy. The situation is aggravated by an increase in blood clotting factors, fibrinogen, platelet aggregation and a decrease in fibrinolysis factors, which, together with the restriction of taking low-molecular-weight heparins due to the tendency of patients with Eisenmenger syndrome to bleeding and thrombosis, causes difficulties in determining the tactics of patient management, emphasizing the importance and relevance of the problem.

ОСОБЕННОСТИ ПЕРИФЕРИЧЕСКОЙ ГЕМОДИНАМИКИ У МУЖЧИН МОЛОДОГО И СРЕДНЕГО ВОЗРАСТА С РЕЦИДИВИРУЮЩИМ ТЕЧЕНИЕМ ИНФАРКТА МИОКАРДА

Relevance. Hemodynamics changes in recidivating myocardial infarction and early postinfarction angina are not well understood. In recent years, the frequency of these complications has been increasing. Aim. To evaluate peripheral hemodynamics changes in men under 60 years old with recurrent myocardial infarction and early postinfarction angina to improve prevention and outcomes. Material and methods. The study included men aged 19-60 years old with type I myocardial infarction. Patients are divided into two age-comparable groups: I - the study group, with recurrent myocardial infarction - 102 patients; II - control, without it - 541 patients. A comparative assessment of hemodynamics changes in first 48 hours (1) and the end of third week disease (2), also risk analysis of recurrent ischemia and poor outcome in selected groups were performed. Results. The study group was distinguished by a high level of total peripheral resistance1 (2055.5±965.2 (dyn×sec×cm-5)) from the control (2055.5± 965.2 (dyn×sec×cm-5); p=0.02). In both groups, a decrease in the values of all indicators was noted (p<0.05). A more pronounced decrease in total peripheral resistance was found in the study group, and in the parameters of blood pressure and heart rate - in the control group. The values of total peripheral resistance1 ≥1600 dyne×sec×cm-5 were the markers of the risk of ischemia recurrence. Predictors of poor outcome are blood pressure levels1 (systolic <97; diastolic <70; mean <93.3 (mm Hg)); total peripheral resistance1 <1746.2 dyne×sec×cm-5 and heart rate (˃92 per min). Conclusions. Patients with recurrent ischemia are characterized by higher levels of total peripheral resistance in the first hours of myocardial infarction. For both groups, a decrease in all studied indicators is determined. The above values of hemodynamic parameters should be used in the formation of groups with a high risk of early recurrence of ischemia and an unfavorable outcome, as well as for prognostic modeling of these complications.

Effect of combination antihypertensive therapy, including renin-angiotensin-aldosterone system inhibitors, on oxidative stress and arterial remodeling in hypertensive patients with heart failure with preserved ejection fraction

Aim. To study the effect of triple combination therapy on oxidative stress and arterial remodeling in hypertensive patients with heart failure with preserved ejection fraction (HFpEF).Material and methods. The study involved 76 people with diagnosed HFpEF. After a comprehensive examination, patients were randomized into two equal groups: first group — patients who received perindopril 10 mg, indapamide 2,5mg and amlodipine 5 mg; second — patients who received losartan 100 mg, indapamide 2,5 mg, amlodipine 5 mg. Before and 16 weeks after the therapy initiation, cardiac ultrasound, assessment of endothelial function with estimating endothelium-dependent vasodilation, assessment of vascular stiffness by photoplethysmography and compression oscillometry were carried out. The plasma concentration of oxidative stress marker 8-isoprostane was studied.Results. During the follow-up period, a significant improvement in endothelial function was noted: in the first group — from 8,1% to 11,4% (p=0,001), in the second — from 5,8% to 8,3% (p=0,0007). In both groups, there was an improvement in microvessel elasticity: a significant decrease in specific peripheral vascular resistance, as well as a significant decrease in total peripheral resistance in the first group (p<0,002) and a tendency to decrease in the second one (p>0,05). There was a significant increase in the stiffness of the aorta and muscular arteries in both groupsю In the first group, a stiffness index decreased from 10,38 m/s to 8,33 m/s (p<0,0001), in the second — from 10,6 m/s to 9,3 m/s (p<0,01). In addition, resistance index in the first group decreased from 71,5% to 60% (p<0,0001), while in the second — from 68% to 60% (p=0,006). Also, both groups showed a significant decrease in the left atrial diastolic dimension and the left atrial volume index. A decrease in the 8-isoprostane plasma levels was noted, which indicates a decrease in oxidative stress.Conclusion. Oxidative stress, which develops due to chronic systemic inflammation, plays a key role in the pathogenesis of HFpEF. The results obtained show an improved endothelial function as a result of decrease in oxidative stress, which is accompanied by an improvement in vessel wall elasticity, thereby slowing down the heart failure progression.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of β-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following β-adrenergic receptor blockade. In accordance, we also reveal that insulin augments β-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of β-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Non-Invasive Hemodynamic Monitoring in TAVI-Patients Reveals More Pronounced Early in-Hospital Circulatory Recovery for Low-Gradient Aortic Stenosis

Background: Little is known about differences and changes in hemodynamic in patients with Low-gradient (LG) and Non-Low-Gradient (NLG-) Aortic valve Stenosis (AS). Our current observation reveals such specific changes using the non-invasive NICaS® electrical bio-impedance monitoring system. Aim: Primary goal was to illustrate possible differences in subgroups of LG-AS and NLG-AS patients and to discriminate post-procedural adaptive mechanisms for the two subgroups. Methods and findings: In 99 unselected patients subjected to TAVI, NICaS® measurements were performed at baseline, 6 to 8 hours after TAVI and before discharge. 46 patients had a mean pressure gradient <40 mmHg corresponding to a LG-AS. Primary endpoint was defined as the change in cardiac index between the LG-AS and NLG-AS group at discharge. Cardiac index increased in both groups as compared with baseline [from 2.52 ± 0.75 to 3.45 ± 1.15 L/min/m2 (P=0.00014) in LG-AS and form 2.70 ± 0.97 to 3.08 ± 0.94 L/min/m2 (P=0.0198) in NLG-AS]. Increase in cardiac index was more pronounced in LG-AS with a difference between the groups of 0.52 ± 0.32 L/min/m2 (P=0.041) at discharge. Additionally, LG-AS patients showed higher increase in stroke volume index, cardiac power index, and Granov-Goor index and decrease of total peripheral resistance and total peripheral resistance index as secondary parameters. One limitation of our study is the observational design in a small cohort of patients. Therefore, larger trials are warranted to confirm our findings and to show whether there is prognostic relevance for long term outcomes of the different subgroups. Conclusion: NICaS® monitoring represents an accurate non-invasive bedsidetool to discriminate adaptive circulatory changes in subgroups of aortic stenosis patients subjected to TAVI. Hemodynamic parameters recovered more effectively in LG-AS patients after procedure. Whether a measurement-guided approach might be used for tailored peri-procedural management and could have long-term prognostic influence for AS subgroups remains to be elucidated.

Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

AimsArginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short‐term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long‐term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre‐clinical HF models.Methods and resultsIn vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing‐induced HF, and (ii) conscious telemetric dogs with a non‐invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP‐induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m2, P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (−5348.6 ± 3601.3 dyn × s/cm5, P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect.ConclusionsSimultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP‐mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

Difference in cardiovascular response during orthostatic stress in Parkinson's disease and multiple system atrophy.

Although orthostatic hypotension is more prominent in multiple system atrophy (MSA) than in Parkinson's disease (PD), there is no study comparing the degree of decrease in total peripheral resistance and cardiac response during orthostatic stress between both diseases. In this study, we examined whether there is a difference in cardiovascular response between MSA and PD. We examined the results of the head-up tilt test in 68 patients with MSA, 28 patients with cardiac non-denervated PD, and 70 patients with cardiac denervated PD whose total peripheral resistance after 60° tilting was lower than the value at 0°. Differences in cardiac output and blood pressure changes were compared against the decrease in total peripheral resistance. There was no difference in the degree of decrease in total peripheral resistance among the three groups. However, the slope of the regression line revealed that the increase in cardiac output against the change in total peripheral resistance was significantly lower in the MSA group than in the cardiac non-denervated and denervated PD groups, and that the decrease in systolic blood pressure against the change in total peripheral resistance was significantly greater in the MSA group than in the cardiac non-denervated and denervated PD groups. In MSA, the cardiac response during orthostatic stress is lower than that in PD, possibly underlying the fact that orthostatic hypotension is more prominent in MSA than in PD.

The Effect of Dietary Inorganic Nitrate Supplementation on Cardiac Function during Submaximal Exercise in Men with Heart Failure with Reduced Ejection Fraction (HFrEF): A Pilot Study.

Heart failure with reduced ejection fraction (HFrEF) is a common end point for patients with coronary artery disease and it is characterized by exercise intolerance due, in part, to a reduction in cardiac output. Nitric oxide (NO) plays a vital role in cardiac function and patients with HFrEF have been identified as having reduced vascular NO. This pilot study aimed to investigate if nitrate supplementation could improve cardiac measures during acute, submaximal exercise. Five male participants (61 ± 3 years) with HFrEF (EF 32 ± 2.2%) completed this pilot study. All participants supplemented with inorganic nitrate (beetroot juice) or a nitrate-depleted placebo for ~13 days prior to testing. Participants completed a three-stage submaximal exercise protocol on a recumbent cycle ergometer with simultaneous echocardiography for calculation of cardiac output (Q), stroke volume (SV), and total peripheral resistance (TPR). Heart rate and blood pressure were measured at rest and during each stage. Both plasma nitrate (mean = ~1028%, p = 0.004) and nitrite (mean = ~109%, p = 0.01) increased following supplementation. There were no differences between interventions at rest, but the percent change in SV and Q from rest to stage two and stage three of exercise was higher following nitrate supplementation (all p > 0.05, ES > 0.8). Both interventions showed decreases in TPR during exercise, but the percent reduction TPR in stages two and three was greater following nitrate supplementation (p = 0.09, ES = 0.98 and p = 0.14, ES = 0.82, respectively). There were clinically relevant increases in cardiac function during exercise following supplementation with nitrate. The findings from this pilot study warrant further investigation in larger clinical trials.

Abstract P158: Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An In Silico Analysis

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

An increase in prefrontal oxygenation at the start of voluntary cycling exercise was observed independently of exercise effort and muscle mass.

We have reported using near-infrared spectroscopy that an increase in prefrontal oxygenated-hemoglobin concentration (Oxy-Hb) at the start of cycling exercise has relation to central command, defined as a feedforward signal descending from higher brain centers. The final output of central command evokes the exercise effort-dependent cardiovascular responses. If the prefrontal cortex may output the final signal of central command toward the autonomic nervous system, the prefrontal oxygenation should increase depending on exercise effort. To test the hypothesis, we investigated the effects of exercise intensity and muscle mass on prefrontal oxygenation in 13 subjects. The subjects performed one- or two-legged cycling at various relative intensities for 1min. The prefrontal Oxy-Hb and cardiovascular variables were simultaneously measured during exercise. The increase in cardiac output and the decrease in total peripheral resistance at the start of one- and two-legged cycling were augmented in proportion to exercise intensity and muscle mass recruitment. The prefrontal Oxy-Hb increased at the start of voluntary cycling, while such increase was not developed during passive cycling. Mental imagery of cycling also increased the prefrontal Oxy-Hb, concomitantly with peripheral muscle vasodilatation. However, the increase in prefrontal Oxy-Hb at the start of voluntary cycling seemed independent of exercise intensity and muscle mass recruitment. It is likely that the increased prefrontal activity at the start of cycling exercise is not representative of the final output signal of central command itself toward the autonomic nervous system but may trigger neuronal activity in the caudal brain responsible for the generation of central command.

Time course of compensatory physiological responses to central hypovolemia in high- and low-tolerant human subjects

Lower body negative pressure (LBNP) simulates hemorrhage in human subjects. Most subjects (67%) exhibited high tolerance (HT) to hypovolemia, while the remainder (33%) had low tolerance (LT). To investigate the mechanisms for decompensation to central hypovolemia in HT and LT subjects, we characterized the time course of total peripheral resistance (TPR), heart rate (HR), and muscle sympathetic nerve activity (MSNA) during LBNP to tolerance determined by the onset of decompensation (presyncope, PS). We hypothesized that 1) maximum (Max) TPR, HR, and MSNA would coincide, and 2) PS would result from simultaneous decreases in TPR, HR, and MSNA in LT and HT subjects but occur earlier in LT than in HT subjects. Max TPR was lower and occurred earlier in LT ( n = 59) than in HT ( n = 113) subjects (LT: 24 ± 1 mmHg·min·1-1 at 756 ± 31 s; HT: 28 ± 1 mmHg·min·1-1 at 1,265 ± 37 s, P < 0.01). Max TPR occurred several minutes before PS. During subsequent decrease in TPR, HR and MSNA continued to increase. Max HR (LT: 111 ± 2 beat/min at 923 ± 27 s; HT: 130 ± 2 beats/min at 1489 ± 23 s, P < 0.01) occurred several seconds before PS. Higher MSNA ( P < 0.01) was attained in HT ( n = 10; 51 ± 5 bursts/min at max TPR; 54 ± 5 bursts/min at max HR) than LT subjects ( n = 4; 41 ± 8 bursts/min at max TPR; 39 ± 8 bursts/min at max HR). The onset of cardiovascular decompensation is a biphasic process in which vasodilation occurs before bradycardia and sympathetic withdrawal. This pattern was similar in LT and HT but occurred earlier in LT subjects. We conclude that sudden bradycardia plays a critical role in the determination of tolerance to central hypovolemia.

An increase in prefrontal oxygenation at the start of voluntary cycling exercise was observed independently of exercise effort and muscle mass

We have reported using near‐infrared spectroscopy that an increase in prefrontal oxygenated‐hemoglobin concentration (Oxy‐Hb) at the start of cycling exercise has relation to central command, defined as a feedforward signal descending from higher brain centers. The final output of central command evokes the cardiovascular responses depending on exercise effort. If the prefrontal cortex may output the final signal of central command toward the autonomic nervous system, the prefrontal oxygenation should increase depending on exercise effort. To test the hypothesis, we investigated the effects of exercise intensity and muscle mass on prefrontal oxygenation by longitudinal comparisons in 13 subjects. The subjects performed one‐ or two‐legged cycling at various relative intensities (20%, 35%, 45%, and 60% of maximal voluntary exercise intensity) for 1 min. The prefrontal Oxy‐Hb and cardiovascular variables were simultaneously measured during exercise. The increase in cardiac output and the decrease in total peripheral resistance at the start of one‐ and two‐legged cycling were augmented (P&lt;0.05) in proportion to exercise intensity and/or muscle mass recruitment. However, the increase in prefrontal Oxy‐Hb seemed independent of exercise intensity. When the rating of perceived exertion was equal, the increase in prefrontal Oxy‐Hb was not different (P&gt;0.05) between one‐and two‐legged cycling. Furthermore, no correlations (P&gt;0.05) were found between the increase in prefrontal Oxy‐Hb and exercise intensity or rating of perceived exertion. It is likely that increased prefrontal oxygenation at the start of cycling exercise does not represent the final output of central command descending to the autonomic nervous system.Support or Funding InformationThis study was funded by Grant‐in‐Aid (15H03061) for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute exhaustive rowing exercise reduces skin microvascular dilator function in young adult rowing athletes.

The effect of acute exhaustive exercise session on skin microvascular reactivity was assessed in professional rowers and sedentary subjects. A potential involvement of altered hemodynamic parameters and/or oxidative stress level in the regulation of skin microvascular blood flow by acute exercise were determined. Anthropometric, biochemical, and hemodynamic parameters were measured in 18 young healthy sedentary men and 20 professional rowers who underwent a single acute exercise session. Post-occlusive reactive hyperemia (PORH), endothelium-dependent acetylcholine (ACh), and endothelium-independent sodium nitroprusside (SNP) microvascular responses were assessed by laser Doppler flowmetry in skin microcirculation before and after acute exercise. Serum lipid peroxidation products and plasma antioxidant capacity were measured using spectrophotometry. At baseline, rowers had significantly lower diastolic blood pressure (DBP) and heart rate (HR), and higher stroke volume (SV), PORH, and endothelium-dependent vasodilation than sedentary. Acute exercise caused a significant increase in systolic blood pressure, DBP, HR, and SV and a decrease in total peripheral resistance in both groups. Acute exercise induced a significant impairment in PORH and ACh-induced response in rowers, but not in sedentary, whereas the SNP-induced vasodilation was not affected by acute exercise in any group. Antioxidant capacity significantly increased only in sedentary after acute exercise. Single acute exercise session impaired microvascular reactivity and endothelial function in rowers but not in sedentary, possibly due to (1) more rowing grades and higher exercise intensity achieved by rowers; (2) a higher increase in arterial pressure in rowers than in sedentary men; and (3) a lower antioxidant capacity in rowers.

Placental Nano-vesicles Target to Specific Organs and Modulate Vascular Tone In Vivo

How do nano-vesicles extruded from normal first trimester human placentae affect maternal vascular function? Placental nano-vesicles affect the ability of systemic mesenteric arteries to undergo endothelium- and nitric oxide- (NO-) dependent vasodilation in vivo in pregnant mice. Dramatic cardiovascular adaptations occur during human pregnancy, including a substantial decrease in total peripheral resistance in the first trimester. The human placenta constantly extrudes extracellular vesicles that can enter the maternal circulation and these vesicles may play an important role in feto-maternal communication. Human placental nano-vesicles were administered into CD1 mice via a tail vein and their localization and vascular effects at 30 min and 24 h post-injection were investigated. Nano-vesicles from normal first trimester human placentae were collected and administered into pregnant (D12.5) or non-pregnant female mice. After either 30 min or 24 h of exposure, all major organs were dissected for imaging (n = 7 at each time point) while uterine and mesenteric arteries were dissected for wire myography (n = 6 at each time point). Additional in vitro studies using HMEC-1 endothelial cells were also conducted to investigate the kinetics of interaction between placental nano-vesicles and endothelial cells. Nano-vesicles from first trimester human placentae localized to the lungs, liver and kidneys 24 h after injection into pregnant mice (n = 7). Exposure of pregnant mice to placental nano-vesicles for 30 min in vivo increased the vasodilatory response of mesenteric arteries to acetylcholine, while exposure for 24 h had the opposite effect (P < 0.05, n = 6). These responses were prevented by L-NAME, an NO synthase inhibitor. Placental nano-vesicles did not affect the function of uterine arteries or mesenteric arteries from non-pregnant mice. Placental nano-vesicles rapidly interacted with endothelial cells via a combination of phagocytosis, endocytosis and cell surface binding in vitro. N/A. As it is not ethical to administer labelled placental nano-vesicles to pregnant women, pregnant CD1 mice were used as a model of pregnancy. This is the first study to report the localization of placental nano-vesicles and their vascular effects in vivo. This work provides new insight into how the dramatic maternal cardiovascular adaptations to pregnancy may occur and indicates that placental extracellular vesicles may be important mediators of feto-maternal communication in a healthy pregnancy. This research was supported by the Faculty of Medical and Health Science (FMHS) School of Medicine PBRF research fund to L.W.C. M.T. is a recipient of a University of Auckland Health Research Doctoral Scholarship and the Freemasons Postgraduate Scholarship. No authors have any competing interests to disclose.