Arterial Pressure Responses Research Articles

Evaluating maternal hyperglycemic exposure and fetal placental arterial dysfunction in a dual cotyledon, dual perfusion model

BackgroundGestational diabetes affects almost 1 in 10 pregnancies and is associated with adverse outcomes including fetal demise. Pregnancy complications related to diabetes are attributed to placental vascular dysfunction. With diabetes, maternal hyperglycemia is thought to promote placental vasoconstriction. However, it remains poorly understood if and how hyperglycemia leads to placental vascular dysfunction or if humoral factors related to maternal diabetes are responsible. Methods and ResultsUtilizing a human placenta dual cotyledon, dual perfusion assay we examined the arterial pressure response to the thromboxane mimetic U44619, in cotyledons exposed to normal vs. a hyperglycemic infusion into the intervillous space. Tissues were then analyzed for the activity of key signaling molecules related to vascular tone; eNOS, Akt, PKA and VEGFR2. Results indicate a significant increase in fetal vascular resistance with maternal exposure to hyperglycemia. This response corresponded with a reduction in the phosphorylation of eNOS at Ser1177 and Akt at Thr308. In contrast, VEGFR2 at Tyr1175 and PKA at Thr197 were not different with hyperglycemia. ConclusionReductions of eNOS and Akt phosphorylation at key residues implicated in nitric oxide production suggest that hyperglycemia alters the vasodilatory signaling of placental vessels. In contrast, acute hyperglycemic exposure may not alter vasoconstriction via VEGF and PKA signaling. Altogether our results link hyperglycemic exposure in human placentas to nitric oxide signaling; a mechanisms that may account for the elevations in vascular resistance commonly observed in diabetic pregnancies.

Vascular Smooth Muscle Contractile Function Declines With Age in Skeletal Muscle Feed Arteries.

Aging induces a progressive decline in vasoconstrictor responses in central and peripheral arteries. This study investigated the hypothesis that vascular smooth muscle (VSM) contractile function declines with age in soleus muscle feed arteries (SFA). Contractile function of cannulated SFA isolated from young (4 months) and old (24 months) Fischer 344 rats was assessed by measuring constrictor responses of denuded (endothelium removed) SFA to norepinephrine (NE), phenylephrine (PE), and angiotensin II (Ang II). In addition, we investigated the role of RhoA signaling in modulation of VSM contractile function. Structural and functional characteristics of VSM cells were evaluated by fluorescence imaging and atomic force microscopy (AFM). Results indicated that constrictor responses to PE and Ang II were significantly impaired in old SFA, whereas constrictor responses to NE were preserved. In the presence of a Rho-kinase inhibitor (Y27632), constrictor responses to NE, Ang II, and PE were significantly reduced in young and old SFA. In addition, the age-group difference in constrictor responses to Ang II was eliminated. ROCK1 and ROCK2 content was similar in young and old VSM cells, whereas pROCK1 and pROCK2 were significantly elevated in old VSM cells. Aging was associated with a reduction in smooth muscle α-actin stress fibers and recruitment of proteins to cell-matrix adhesions. Old VSM cells presented an increase in integrin adhesion to the matrix and smooth muscle γ-actin fibers that was associated with increased cell stiffness. In conclusion, our results indicate that VSM contractile function declined with age in SFA. The decrement in contractile function was mediated in part by RhoA/ROCK signaling. Upregulation of pROCK in old VSM cells was not able to rescue contractility in old SFA. Collectively, these results indicate that changes at the VSM cell level play a central role in the reduced contractile function of aged SFA.

Exercise-Induced Modulation of Baroreflex Control of Sympathetic Nerve Activity.

Exercise modulates arterial pressure (AP) regulation over various time spans. AP increases at the onset of exercise and this increase is then sustained during exercise. Once exercise is stopped, AP is suppressed for up to an hour afterwards. Prolonged endurance training is associated with dysfunction of the sympathetic regulation of AP in response to posture changes (orthostatic intolerance). Baroreflex control of sympathetic nerve activity (SNA) has been extensively studied to understand the mechanisms underlying exercise-induced changes in AP. We have previously presented entire baroreflex AP-SNA curves during and after exercise, and during central volume expansion, obtained using direct measurements of renal sympathetic nerve activity (RSNA) in conscious animals. In this review, we describe the modulatory effects of exercise on baroreflex control of AP based on these entire AP-RSNA baroreflex curves. We suggest that both acute and chronic exercise can have modulatory effects on the entire baroreflex curve for SNA, and that these effects differ among time periods.

Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk.

Study Objectives Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. Methods Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. Results Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (-2.1 ± 1.0 vs. -4.3 ± 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Δ21 ± 11 vs. Δ14 ± 8 mm Hg; time × group = 0.04) and total MSNA reactivity (Δ127%, 54%-208% vs. Δ52%, 30%-81%; time × group = 0.02) were augmented in chronic insomnia. Conclusions Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. Clinical Trial Registration NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878.

Ambulatory arterial stiffness index and blood pressure response to renal denervation.

Ambulatory arterial stiffness index and blood pressure response to renal denervation.

Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II.

Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. ICUs. Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). IV angiotensin II or placebo. Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.

Interaction between graviception and carotid baroreflex function in humans during parabolic flight-induced microgravity.

The aim of the present study was to assess carotid baroreflex (CBR) function during acute changes in otolithic activity in humans. To address this question, we designed a set of experiments to identify the modulatory effects of microgravity on CBR function at a tilt angle of -2°, which was identified to minimize changes in central blood volume during parabolic flight. During parabolic flight at 0 and 1 g, CBR function curves were modeled from the heart rate (HR) and mean arterial pressure (MAP) responses to rapid pulse trains of neck pressure and neck suction ranging from +40 to -80 Torr; CBR control of HR (carotid-HR) and MAP (carotid-MAP) function curves, respectively. The maximal gain of both carotid-HR and carotid-MAP baroreflex function curves were augmented during microgravity compared with 1 g (carotid-HR, -0.53 to -0.80 beats·min-1·mmHg-1, P < 0.05; carotid-MAP, -0.24 to -0.30 mmHg/mmHg, P < 0.05). These findings suggest that parabolic flight-induced acute change of otolithic activity may modify CBR function and identifies that the vestibular system contributes to blood pressure regulation under fluctuations in gravitational forces. NEW & NOTEWORTHY The effect of acute changes in vestibular activity on arterial baroreflex function remains unclear. In the present study, we assessed carotid baroreflex function without changes in central blood volume during parabolic flight, which causes acute changes in otolithic activity. The sensitivity of both carotid heart rate and carotid mean arterial pressure baroreflex function was augmented in microgravity compared with 1 g, suggesting that the vestibular system contributes to blood pressure regulation in humans on Earth.

Modulation of nesfatin-1-induced cardiovascular effects by the central cholinergic system

Nesfatin-1, a peptide whose receptor is yet to be identified, has been shown to be involved in the modulation of feeding, stress, and metabolic responses. Recently, increasing evidence has supported a modulatory role of nesfatin-1 in cardiovascular activity. We have previously reported that nesfatin-1 causes an increase in blood pressure in normotensive and hypotensive rats by increasing plasma catecholamine, vasopressin, and renin levels. Recent reports suggest that nesfatin-1 may activate the central cholinergic system. However, there is no evidence showing an interaction between central nesfatin-1 and the cholinergic system. Therefore, this study aimed to determine whether the central cholinergic system may have a functional role in the nesfatin-1-induced cardiovascular effect observed in normotensive rats.Intracerebroventricular injection of nesfatin-1 caused short-term increases in mean arterial pressure and heart rate responses including bradycardic/tachycardic phases in normotensive animals. Central injection of nesfatin-1 increased the acetylcholine and choline levels in the posterior hypothalamus, as shown in microdialysis studies. Central pretreatment with the cholinergic muscarinic receptor antagonist atropine and/or nicotinic receptor antagonist mecamylamine blocked nesfatin-1-induced cardiovascular effects. In conclusion, the results show that centrally administered nesfatin-1 produces a pressor effect on blood pressure and heart rate responses including bradycardic/tachycardic phases in normotensive rats. Moreover, according to our findings, the central cholinergic system can modulate nesfatin-1-evoked cardiovascular activity.

Novel Gene Variant Associated with Exercise Pressor Reflex Responsiveness

PURPOSE: Activation of thinly myelinated and unmyelinated afferents innervating contracting skeletal muscle elicits the exercise pressor reflex. We hypothesized that single nucleotide polymorphisms (SNPs) of genes encoding ionotropic and metabotropic receptors commonly found on skeletal muscle afferents might account for part of the typical variation in blood pressure responses to exercise. METHODS: 101 healthy, college age, men and women of European ancestry participated. Multivariate modeling of the mean arterial pressure response to post-exercise circulatory arrest following 3-min of static handgrip exercise (30% of maximum) was used to stratify subjects into quartiles. Subjects from the highest (N=33) and lowest (N=25) quartiles provided buccal mucosa cells. DNA was extracted, amplified, and analyzed for common (minor allele frequency >20%), non-synonymous SNPs of genes with functional associations to autonomic disorders. We evaluated selected variants of the TRP (N=18), ASIC (N=3) and P2X (N=4) receptor families (real-time PCR, custom OpenArray™) and used contingency table analysis to compare the frequency of homozygotes and trait allele carriers between the two groups. RESULTS: Trait allele carriers of rs8065080, a T-to-C missense mutation of TRPV1, were more frequent in the high response group (73% vs 48%, P<0.1). Frequencies of all other SNPs did not differ between groups. CONCLUSIONS: Data from this pilot investigation suggest that intra-subject variation in mean arterial pressure during post-exercise circulatory arrest may associate with SNPs of genes putatively linked to the metabolic component of the exercise pressor reflex. Additional work is warranted to confirm these observations and explore the mechanistic role of TRP channels in exercise pressor reflex responsiveness. Supported in part by the Huck Institutes of the Life Sciences and the College of Health and Human Development.

Interface pressure, perceptual, and mean arterial pressure responses to different blood flow restriction systems.

This study examined the cuff to limb interface pressure during blood flow restriction (BFR), and the perceptual and mean arterial pressure responses, in different BFR systems. Eighteen participants attended three experimental sessions in a randomised, crossover, counterbalanced design. Participants underwent inflations at 40% and 80% limb occlusive pressure (LOP) at rest and completed 4 sets of unilateral leg press exercise at 30% of one repetition maximum with BFR at 80% LOP. Different BFR systems were used each session: an automatic rapid-inflation (RI), automatic personalized tourniquet (PT) and manual handheld pump and sphygmomanometer (HS) system. Interface pressure was measured using a universal interface device with pressure sensors. Perceived exertion and pain were measured after each set, mean arterial pressure (MAP) was measured pre-, 1-minute post- and 5-minutes post-exercise. Interface pressure was lower than the set pressure in all BFR systems at rest (P<.05). Interface pressure was, on average, 10±8 and 48±36mm Hg higher than the set pressure in the RI and HS system (P<.01), with no differences observed in the PT system (P>.05), during exercise. Pain and exertion were greater in sets 3 and 4 in the RI and HS system compared to the PT system (P<.05). MAP was higher in the RI and HS system compared to the PT system at 1-minute and 5-minutes post-exercise (P<.05). BFR systems applying higher pressures amplify mean arterial pressure and perceptual responses. Automatic BFR systems appear to regulate pressure effectively within an acceptable range during BFR exercise.

Acute Aerobic Exercise Does Not Alter the Pressor Response to the Cold Pressor Test

Circulating vasodilator compounds are elevated after acute aerobic exercise, which contribute to post‐exercise hypotension and orthostatic intolerance. This suggests that the pressor response during sympathoexciation is blunted following acute aerobic exercise. The cold pressor test (CPT) is a sympathoexcitatory maneuver that increases heart rate and blood pressure. However, it is not known if cardiovascular dynamics during 2 minutes of the CPT are altered following acute aerobic treadmill exercise.PurposeTest the hypothesis that cardiovascular responses to the CPT following acute aerobic treadmill exercise are blunted.MethodsTwelve healthy participants (23±4 years, 6 females) completed a CPT before and 10 minutes after treadmill exercise (20 minutes at 65–70% of age predicted maximum heart rate). During the CPT, a hand was submerged up to the wrist in ice water (~0°C) for 120 seconds. Heart rate (ECG) and blood pressure (photoplethysmography) were continuously recorded. Stroke volume was determined using Modelflow. Cardiac output was calculated as the product of heart rate and stroke volume. Total peripheral resistance was determined by dividing mean arterial pressure by cardiac output. Data were analyzed in 30 second increments. Perceived pain (0 = no pain, 10 = most severe pain) was obtained after each CPT. Data during the CPT are presented as a change from baseline and analyzed using repeated measures ANOVA.ResultsBaseline heart rate was higher post exercise (64 ± 8 vs. 86 ± 13 bpm, P &lt; 0.01). Baseline mean arterial pressure (85 ± 10 vs. 80 ± 8 mmHg, P = 0.05) and systolic blood pressure (122 ± 14 vs. 114 ± 12 mmHg, P &lt; 0.01) were lower post exercise. Baseline diastolic blood pressure (63 ± 8 vs. 61 ± 6 mmHg, P = 0.25), stroke volume (99 ± 14 vs. 97 ± 16 mL, P = 0.35), cardiac output (6.2 ± 0.8 vs. 6.6 ± 0.8 L/min, P = 0.16), and total peripheral resistance (13.9 ± 2.8 vs. 12.3 ± 1.8 mmHg/L/min, P = 0.10) were not different between pre‐ and post‐exercise. During the CPT, the increase in heart rate was greater pre‐ vs. post‐exercise at 30 seconds (22 ± 16 vs. 17 ± 13 bpm, P = 0.02) and 60 seconds (18 ± 16 vs. 12 ± 9 bpm, P &lt; 0.01). Pre‐ and post‐exercise mean arterial pressure increased throughout the CPT and peaked at 90 seconds for pre‐ (26 ± 10 bpm, P &lt; 0.01) and post‐exercise (27 ± 9 mmHg, P &lt; 0.01). There were no differences in the mean arterial pressure responses to the CPT between pre‐and post‐exercise (P &gt; 0.99). Pre‐ and post‐exercise total peripheral resistance increased throughout the CPT and peaked at 120 seconds for pre‐ (5.7 ± 4.7 mmHg/L/min, P &lt; 0.01) and post‐exercise (5.0 ± 3.3 mmHg/L/min, P &lt; 0.01). There were no differences in the total peripheral resistance responses during the CPT between pre‐ and post‐exercise (P &gt; 0.13 for all). Perceived pain of the CPT was not different between pre‐ and post‐exercise (5 ± 2 vs. 6 ± 2 a.u., P = 0.13).ConclusionPost‐exercise heart rate responses to the CPT were blunted while mean arterial pressure and total peripheral resistance responses were not different between pre‐ and post‐exercise. These data indicate that the pressor responses to the CPT are not influenced by acute aerobic exercise whereas the heart rate response is attenuated.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sphingosine‐1‐phosphate induced vasoconstrictor responses decreased in cerebral arteries of endotoxemic rats

IntroductionSepsis is the leading cause of mortality in intensive care units. Vascular dysfunction is the most important cause of death in sepsis. There are some data in the literature for vascular hyporesponsiveness to miscellaneous vasopressors. However most of the data are about resistance mesenteric artery and aorta which is the biggest artery in the body. The responses of cerebral arteries to vasopressors were not investigated in vitro while the brain blood flows were investigated in sepsis.Sphingosine‐1‐phosphate (S1P) is a bioactive lipid mediator which has several physiological functions in cell growth, inflammation, endothelial barrier integrity and vascular tone. Serum S1P levels decrease in sepsis and this decrement is correlated with the severity of sepsis. S1P is a vasoconstrictor lipid mediator which has more vasoconstrictor responses in small sized vessels and brain arteries. Our aim is to study the vasoconstrictor responses of the brain and mesenteric arteries to S1P in sepsis.Material and Methods10 mg/kg lipopolysaccharide (serotype O55:B5) were given intraperitoneally to rats to make an animal model os sepsis. Rats were anesthetized with gaseous carbon dioxide and decapitated 20 hours after injection, Basilar, anterior cerebral, middle cerebral and 3rd branch of mesenteric arteries were mounted in a wire myograph. Arteries were stimulated with 124 nM K+‐PSS after 30 min stabilization. Concentration‐response curves for S1P were evaluated.ResultsHigh K+ responses did not change in brain and peripheral arteries. S1P‐induced vasoconstrictor responses decreased in anterior and prominently in middle cerebral arteries. S1P‐induced vasoconstrictor responses in basilar and mesenteric arteries did not change.ConclusionsThis is the first study that show the alterations of S1P‐induced vasoconstrictor responses of brain arteries in sepsis. The difference in the alteration of S1P responses of cerebral arteries may explain the alteration and redistribution of cerebral perfussion in sepsis.Support or Funding InformationThis study was funded by Hacettepe University Scientific Research Projects Coordination Unit (TSA‐2017‐12848).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blocking Interleukin‐6 Signal Pathway Attenuates Exaggerated Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

A rat model of femoral artery occlusion was employed to study the exercise pressor reflex in peripheral artery disease. Prior studies have shown that pro‐inflammatory interleukin‐6 (IL‐6) is engaged in the amplified blood pressure response to static muscle contraction in occluded rats. IL‐6 complexes with soluble IL‐6 receptor (IL‐6R) to activate cells expressing the signal transducer glycoprotein (gp130). Thus, the current study was to determine the role played by IL‐6 activated signal complex (IL‐6‐gp130) in regulating the exercise pressor reflex in rats with femoral occlusion. Following 72 hours of femoral artery occlusion, the levels of protein expression of IL‐6R and gp130 were increased in dorsal root ganglion (DRG). In addition, we examined the pressor response to static muscle contraction after 62.5 ng/kg and 125 ng/kg of SC144 (a gp130 inhibitor) were injected into the arterial blood supply of the hindlimb muscle of control rats and occluded rats. We found that SC144 significantly attenuated the pressor response to contraction in occluded rats, but the effect of SC144 was not observed in control rats. In control rats, peak response of mean arterial pressure (MAP) was 15±2 mmHg after saline and 12±3 mmHg after 125 ng/kg of SC144 (n=6; P &gt; 0.05 vs. saline). In occluded rats, peak MAP response was 25±5 mmHg after saline and 14±5 mmHg after 125 ng/kg of SC144 (n=6; P &lt; 0.05 vs. saline). There was no difference in developed muscle tension between saline group and group injected with SC144 (528±28 g in saline control vs. 545±29 g with SC144 injection, P &gt; 0.05). Overall, our data suggest that IL‐6 signal mechanisms in muscle sensory nerves contribute to the exaggerated sympathetic and pressor responsiveness observed during exercise in experimental rats with peripheral artery disease.Support or Funding InformationThis study was supported by NIH P01 HL134609This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Heme‐oxygenase 2 (HMOX2) variants associated with evolutionary adaptation and hemoglobin concentration in Tibetans are common in Andean Highlanders

Andean and Tibetan populations have developed distinct adaptations to high altitude. The heme oxygenase 2 gene (HMOX2) is under selection in Tibetans and is associated with hemoglobin concentration in Tibetan men. Putatively adaptive variants within this gene are also prevalent in lowland population but have not been examined in Andean highlanders and could influence variation in hypoxia responses in this population. We genotyped ten variants within the HMOX2 gene region (rs2058812, rs2270363, rs6500606, rs3747584, rs4786509, rs860891, rs8129, rs11639998, rs9934267, and rs17761816) in 128 Quechua Andean highlanders in Cerro de Pasco, Peru (4,350 m) (female = 61; male = 67). We found that the frequencies in Andean highlanders are not as elevated as Tibetans' but similar to those observed in Han Chinese. After controlling for sex and age, there was no significant association between these SNPs and hematocrit (Hct), mean arterial pressure (MAP), oxygen saturation (SpO2), nor hypoxic ventilatory response (HVR). These results suggest that the putatively adaptive high‐altitude HMOX2 variants identified in Tibetans are found at intermediate frequencies in Andeans, although they may not be regulators of hemoglobin concentration in this population.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Low-Dose Epinephrine Boluses for Acute Hypotension in the PICU.

To describe the use of low-dose bolus epinephrine in critically ill children during an acute hypotensive episode or prearrest condition. Institutional Review Board approved, single-center, retrospective medical chart review. Large medical-surgical PICU within a freestanding, tertiary care children's hospital. Patients admitted to the PICU between June 1, 2015, and June 1, 2016, who received low-dose (≤ 5 µg/kg) IV bolus epinephrine. None. Twenty-four resuscitation episodes (63 doses; 19 patients) were analyzed. Median age and weight of patients were 9 years (interquartile range, 1-15 yr) and 38.5 kg (interquartile range, 12-54.8 kg). Median Pediatric Risk of Mortality III score was 17 (interquartile range, 10-27). Mean epinephrine dose was 1.3 ± 1.1 µg/kg. Median number of doses per patient was two. If more than one dose was provided, median dosing interval was 6.5 minutes. Heart rate and mean arterial blood pressure were compared at the time of epinephrine administration and 1-4 minutes (median = 1 min) following administration. Heart rate changed from 130 ± 41 to 150 ± 33 beats/min (p < 0.05), and mean arterial blood pressure changed from 51 ± 17 to 75 ± 27 mm Hg (p < 0.001). Variability in mean arterial blood pressure response was observed; nonresponders required extracorporeal membrane oxygenation; 66% of doses resulted in up to 100% mean arterial blood pressure increase, and 21% of doses resulted in greater than 100% mean arterial blood pressure increase. Doses below 1 µg/kg were associated with a lower mean arterial blood pressure increase than doses between 1 and 5 µg/kg (mean percent change in mean arterial blood pressure = 6.6% vs 60%, respectively). Children less than or equal to 2 years old had the greatest percentage increase in heart rate and mean arterial blood pressure. Provision of low-dose bolus epinephrine during periods of acute hypotension can result in a significant increase in mean arterial blood pressure and heart rate. This dosing strategy may provide temporary stabilization while other therapies are added or adjusted, but further research is needed.

Denervation of Peripheral Chemoreceptors Decreases Heart Rate During Bilateral Carotid Occlusion in Unanesthetized Rats

Bilateral carotid occlusion (BCO) has been used as a maneuver to cause global reflex activation of the sympathetic nervous system in both unanesthetized and anesthetized animals. It is known that the cardiovascular effects of BCO involve not only the baroreceptors but also the chemoreceptors. However, to our knowledge, the cardiovascular responses produced during BCO in the absence of the peripheral chemoreceptors has not been studied in unanesthetized rats. Therefore, the present study aimed to examine the responses of arterial pressure and heart rate to BCO in unanesthetized rats with selective denervation of peripheral chemoreceptors. Under ketamine/xylazine anesthesia Wistar Hannover rats were implanted with pneumatic cuffs around the common carotid arteries for BCO. Catheters were also inserted into the femoral artery and vein for blood pressure recording and drug administration (to test the effectiveness of denervation), respectively. Rats were divided into two groups: INTACT (n = 7) and chemoreceptors removed (CHEMO‐X; n = 8). In the next day, BCO was performed for 20s in unanesthetized rats. As compared to baseline condition BCO promoted, in both groups, an increase in systolic (INTACT: 133 ± 5 vs. 211 ± 8 mmHg; CHEMO‐X: 142 ± 3 vs. 210 ± 4 mmHg), diastolic (INTACT: 92 ± 5 vs. 145 ± 7 mmHg; CHEMO‐X: 100 ± 2 vs. 140 ± 3 mmHg) and mean arterial pressure (INTACT: 111 ± 5 vs. 173 ± 7 mmHg; CHEMO‐X: 119 ± 2 vs. 168 ± 3 mmHg). Of note, the increase in arterial pressure was similar in both groups; however, while BCO did not promote a change of the heart rate in the INTACT group (321 ± 9 vs. 318 ± 7 bpm), the rats from the QUIMIO‐X group displayed significant bradycardia (352 ± 7 vs. 315 ± 14 bpm). These findings indicate that the presence of the peripheral chemoreceptors did not affect the hypertensive response elicited by BCO, but their absence determined a reflex bradycardia during this occlusive maneuver. This mechanism deserves further investigation.Support or Funding InformationFAPESP (Proc. 2017/05163‐6 and 2013/20549‐7).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Responses of cerebral blood flow and tissue oxygenation to low frequency oscillations during simulated hemorrhagic stress in humans

IntroductionHemorrhage is a leading cause of death from traumatic injury in both the military and civilian populations. Use of lower body negative pressure (LBNP) as a model of hemorrhage in humans has revealed that there is a spectrum of tolerance to this stress. Recent evidence from our laboratory suggests that low frequency (LF; ~0.1 Hz) oscillations in mean arterial pressure (MAP) and middle cerebral artery velocity (MCAv) play a role in this tolerance; high tolerant subjects exhibit greater LF power in MAP and MCAv when compared to low tolerant subjects. We hypothesize that exogenously inducing LF oscillations via oscillatory LBNP (OLBNP) will attenuate reductions in cerebral blood flow and oxygenation during simulated hemorrhagic stress.Methods11 young, healthy subjects (9M/2F) were exposed to two LBNP profiles with an average chamber pressure of −60 mmHg in a randomized and counterbalanced design: 1) static LBNP (0 Hz) and, 2) oscillatory LBNP (0.1 Hz). During both profiles, chamber pressure was gradually reduced to −60 mmHg over 1‐min after which pressure remained at −60 mmHg (0 Hz) for 9‐min or oscillated between −30 mmHg and −90 mmHg (0.1 Hz) for 9‐min. Profiles were separated by a 5‐min recovery. Physiological measurements included arterial pressure and stroke volume via finger photoplethysmography, MCAv via transcranial Doppler ultrasound, and regional cerebral oxygenation of the frontal lobe (ScO2) via near infrared spectroscopy. Hemodynamic data was analyzed using a paired t‐test. Tolerance was assessed with a Fischer's exact test.ResultsNo differences were observed between profiles for MAP (0 Hz, 79.8±2.5 mmHg vs. 0.1 Hz, 80.0±1.9 mmHg; P=0.93) and MCAv (0 Hz, 42.4±3.3 cm/s vs. 0.1 Hz, 43.5±3.7 cm/s P=0.43). The reduction in ScO2 was attenuated (P=0.05) during the 0.1 Hz profile (−4.1±1.2 %) compared to the 0 Hz profile (−6.1±1.1 %). A similar attenuation was observed in the stroke volume response (0 Hz, −42.6±2.5 % vs. 0.1 Hz, −30.6±2.5 %; P&lt;0.001). Importantly, 8/11 subjects completed the 0.1 Hz profile compared with just 5/11 subjects for the 0 Hz profile (P=0.048).DiscussionIn partial support of our hypothesis, cerebral oxygenation was protected during the 0.1 Hz OLBNP profile. While MCAv was similar between conditions, we propose that the oscillatory pattern of cerebral blood flow may elicit a shear‐stress induced vasodilation, so assessment of velocity may be masking an increase in flow. This possibility is further supported by the finding that stroke volume was also protected during the 0.1 Hz profile, which may reflect an increase in venous return during the upstroke period of the OLBNP profile. Importantly, more subjects were able to tolerate the 0.1 Hz profile compared to the static 0 Hz profile, despite similar arterial pressure responses. These findings emphasize the potential importance of hemodynamic oscillations in maintaining perfusion and oxygenation of cerebral tissue during a hemorrhagic stress.Support or Funding InformationUNTHSC ICMD Junior Faculty Seed GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses

ObjectiveCardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Resistance arteries can adapt their vessel diameter independently by pressure and by flow. Ryanodine receptors (RyRs) are major Ca2+ release channels in the sarcoplasmic reticulum (SR) membrane of myocytes contributing to contractility. Vascular smooth muscle cells (VSMCs) exhibit three different RyR isoforms (RyR1, 2, 3), but the impact of individual RyR isoforms on vascular adaptive responses is largely unknown.MethodsWe generated tamoxifen‐inducible smooth muscle cell (SM) specific RyR2 deficient mice and tested the hypothesis that VSMC RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of SR released Ca2+ sparks and the associated Ca2+ activated potassium (BKCa) channel currents, leading to increased myogenic arterial tone in peripheral arteries and systemic blood pressure. RyR2 deficiency enhanced the pulmonary artery pressure response to sustained hypoxia, but had no effect on flow‐dependent effects, including blood flow recovery in ischemic hind limbs.ConclusionOur results identify a specific contribution of RyR2 in mediating VSMC Ca2+ sparks relevant for regulating myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. VSMC expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.Support or Funding InformationThis study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to M.G and M.W. (SFB‐TR84 C3 and C6), and the Deutsche Akademische Austauschdienst (DAAD) to M.G. and I.S, and the NIH (R37 DK053832, R01 HL121706, PO1 HL095488, R01 HL131181), Fondation Leducq, and the Totman Medical Research Trust to M.T.N., and by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) to M.G. and M.K. We thank Dr. Kirill Essin for help in Ca2+ spark recordings using line scan imaging. CFG‐P is recipient of Ministerio de Educación Cultura y Deporte, Fundación San Pablo‐CEU and Banco Santander fellowships.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Muscle Strength Influences Pressor Responses to Static Handgrip in Men and Women.

Whether differences in absolute muscle strength affect blood pressure (BP) responses to relative intensity static exercise remains controversial but could contribute to known sex-based differences and influence the interpretation of cross-sectional data. One hundred thirty-two healthy participants (66 men and 66 women; age, 22 ± 3 yr) underwent continuous seated measurements of BP (Finometer) and heart rate (electrocardiography) during baseline rest and 2 min of static handgrip (30% maximal voluntary contraction (MVC)). BP and heart rate responses were quantified in 30-s epochs during exercise and compared between men and women with and without statistical adjustment (ANCOVA) for differences in baseline BP (or heart rate), forearm girth, and handgrip MVC. Within each sex, BP and heart rate responses were compared also between tertiles of handgrip MVC (n = 22 per group). Men had larger systolic, diastolic, and mean arterial pressure responses during static handgrip than did women (interaction term, all P < 0.0005), although heart rates responses were similar (interaction term, P = 0.25). These sex-based BP differences persisted after statistical adjustment for differences in baseline BP or forearm girth; however, controlling for handgrip MVC abolished differences in BP responses during static handgrip exercise between men and women (interaction term, all P > 0.35). In men, BP responses were smaller within the lowest tertile of handgrip MVC (interaction term, all P < 0.006), whereas in women, BP responses were larger within the highest tertile of handgrip MVC (interaction term, all P < 0.04). Our findings suggest an important between- and within-sex role of absolute handgrip strength in mediating the BP response to static handgrip exercise and highlight the importance of controlling for interindividual differences in future work.

Renal Sympathetic Nerves and Inflammation in Hypertension: Assessing Temporal Renal Inflammation Responses to Renal Denervation by Urinary Cytokine Excretion in the DOCA‐Salt Rat

Preclinical and clinical studies demonstrate renal sympathetic denervation (RDN) may be an effective treatment for hypertension and end stage renal disease; however, the mechanisms of this effect remain unknown. We recently reported (RDN) mitigates hypertension in addition to the concomitant renal inflammation in the deoxycorticosterone acetate (DOCA)‐salt rat model. In this model, renal inflammation is hypothesized to drive the hypertension, but the timing and relationship to arterial pressure remain elusive. In this study, we aimed to elucidate the temporal renal inflammatory and arterial pressure response to DOCA‐salt through repeated‐measurement of urinary pro‐inflammatory cytokine excretion, and test the responsiveness to renal sympathetic denervation. We hypothesize that (a) RDN would mitigate renal and urinary cytokine content, and (b) a decrease urinary cytokine content due to RDN would precede changes in arterial pressure. To test this hypothesis, 12 uninephrectomized adult male Sprague Dawley rats (300–325 g) were implanted with radiotelemeters to measure 24‐hour mean arterial pressure (MAP) weekly, and received either surgical renal denervation (RDN; n=6) or sham procedure (Sham; n=6). One week following, both groups were administered DOCA (100 mg, s.c.) and 0.9% saline for 21 days. 6‐hour urine samples were collected weekly over ice using metabolic cage housing. At day 21, rats were anesthetized, and renal tissue was collected for cytokine and histological analysis. Pro‐inflammatory cytokines (IL‐1β, IL‐2, IL‐6, GRO/KC, MCP‐1) were measured by Luminex assay in both urine and renal tissue. Renal and urinary cytokine content were normalized to total protein and creatinine, respectively. Temporal response data analyzed by two‐way repeated measured ANOVA with Bonferroni post‐hoc test (α=0.05). All other data were analyzed by Student's t‐test. Data presented as mean±SEM. MAP response over 21‐day DOCA‐salt treatment was attenuated (*p&lt;.05) by RDN vs. Sham, where MAP significantly diverged at Days 14–21 (see Data Table). Similarly, all measured pro‐inflammatory cytokines in renal parenchymal protein isolates were markedly reduced (*p&lt;.05) in RDN vs. Sham ‐ a reduction of 42–70% of Sham values (see Data Table). Interestingly, urinary cytokine excretion on day 21 mirrored this effect, where each cytokine was lower (*p&lt;.05) in RDN vs. Sham – similarly reduced by 44–84% Sham values (see Data Table). Of note, no difference was observed between RDN and Sham urinary cytokine content on Days 0–7, and only urinary IL‐1β and IL‐2 were reduced (*p&lt;.05) at Day 14 (see Data Table). Histological analysis of renal injury and immune cell (macrophage, T‐cell) infiltration is currently underway to establish the end organ damage and immune cell specificity in the reported anti‐inflammatory effects of RDN. Taken together, these data support our first hypothesis of urinary cytokines reflect renal inflammatory cytokine content, and both are abated by RDN. However, our second hypothesis was not supported by the current data, as MAP was reduced in the RDN‐treated group prior to a significant reduction of most urinary cytokines. With these findings, we hypothesize that DOCA‐salt hypertension may precede the renal inflammation in this model. Further studies are necessary to elucidate the source of renal inflammation in this model, and its relationship to arterial pressure control.Support or Funding InformationThis project was supported in part by NIH HL116476 (JWO) and AHA 17POST33661003 (CTB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.