Arterial Pressure Responses Research Articles

Exaggerated Activities of P2X3 and ASIC3 Signaling Pathway in Muscle Afferent Following Himblimb Muscle Ischemia‐Reperfusion

BackgroundPeripheral artery disease (PAD) is one of the major cardiovascular concerns and dramatically reduces the blood flow supply in the affected limbs. A combination of revascularization surgery in the femoral artery and supervised exercise intervention is among the most general approaches for the treatment of PAD. The approach of revascularization inevitably induces ischemia‐reperfusion (IR) injury in the tissues with the reperfusion of blood flow. Notably, following muscle IR in rats, we have observed an exaggerated exercise pressor reflex (EPR) indicating a risk of cardiovascular diseases, as the increased blood pressure (BP) response during exercise. In specific, a time‐course study (18, 66 and 114 hours post‐IR) showed that an increment in BP response was most profound in 18 hours post‐IR (IR 18h) among all the time points. However the underlying molecular mechanism leading to the IR‐induced exaggerated EPR has yet poorly understood.AimsWe targeted if the hindlimb muscle IR alters the activities of two key signaling pathway in muscle afferent nerves in regulating the EPR, namely P2X3 and ASIC3.MethodsWestern blot technique was used to determine the protein expression of P2X3 and ASIC3 in L4‐6 dorsal root ganglion (DRG) of sham rats and IR 18h rats. Meanwhile, the mean arterial pressure (MAP) responses to α‐β‐me‐ATP and lactic acid intra‐arterially injected into the hindlimb were examined to assess the P2X3 and ASIC3‐mediated EPR, respectively. Whole‐cell patch clamp was applied to evaluate the P2X and ASIC3 currents in the isolated muscle DRG neurons in both sham and IR 18h rats. All data were presented as mean ± standard deviation.ResultsCompared with sham rats, there were significant increases in both P2X3 and ASIC3 protein expression in L4‐6 DRGs in IR 18h rats (P2X3: 1.56±0.10 in IR 18h rats/n=4 vs. 1.00±0.10 in sham rats/n=6; P<0.05; and ASIC3: 1.42±0.47 in IR 18h rats/n=8 vs. 1.00±0.07 in sham rats/n=10; P<0.05). In addition, compared with sham rats, the MAP responses following the injection of α‐β‐me‐ATP (0.125 mM) and lactic acid (2 and 4 µmol/kg) were significantly amplified in IR 18h rats (α‐β‐me‐ATP: 29±8 mmHg in IR 18h rats/n=5 vs. 20±5 mmHg in sham rats/n=2; P<0.05; Lactic acid: 2 µmol/kg, 28±8 mmHg in IR 18h rats/n=15 vs. 21±7 mmH in sham rats/n=8, P<0.05; 4 µmol/kg, 37±10 mmHg in IR 18h rats/n=15 vs. 25±6 mmH in sham rats/n=9, P<0.01). In the isolated DRG neurons, amplitude of both P2X and ASIC3 currents was significantly higher in IR 18h rats than that in sham rats. i.e., P2X transient currents: 1281.64±776.74 pA in IR 18h rats/n=25, vs. 717.91±556.2 pA in sham rats/n=9, (P<0.05); and sustain currents: 466.94±168.68 pA in IR 18h rats/n=11, vs. 271.49±200.90 pA in sham rats/n=8 (P<0.05).ConclusionThe activities of the P2X3 and ASIC3 signaling pathways in the muscle afferents are exaggerated following muscle IR. Results of this study shed light upon the future potential intervention strategy to minimize the IR‐induced exaggerated EPR response in the post‐revascularization PAD patients.

Intramuscular insulin administration potentiates sympathetic and pressor responses to capsaicin in rats

Insulin centrally activates the sympathetic nervous system. However, little is known about the effects of insulin on peripheral primary sensory neurons. Transient receptor potential vanilloid 1 (TRPV1), of which capsaicin (CAP) is an agonist, is widely expressed in small dorsal root ganglia (DRG) neurons subserving skeletal muscle thin‐fiber afferents expressing sensory nociceptors and/or metabolically sensitive skeletal muscle receptors. Evidence suggests that insulin increases the sensitivity of these sensory receptors as well as translocation of TRPV1 from cytosol to plasma membrane in DRG neurons. We therefore hypothesized that insulin potentiates the responsiveness of thin fiber muscle afferents to TRPV1 activation.PurposeThe aim of this investigation was 1) to examine whether TRPV1 and insulin receptors (IR) are co‐localized in small‐diameter (< 30 µm) DRG neurons subserving thin‐fiber afferents (C‐fibers or A‐delta fibers), and 2) to determine the effects of insulin on renal sympathetic nerve activity (RSNA) and mean arterial blood pressure (MAP) responses to stimulation of TRPV1 by injection of CAP into the arterial supply of the hindlimb in decerebrated rats.MethodsL4‐L6 DRGs were harvested from Sprague‐Dawley rats (n=3, 19 weeks, body weight: 518 ± 6 g). The percentage of neurons that expressed IR and/or isolectin B4 binding (IB4, a C‐fiber neuronal marker) in TRPV1 positive small DRGs neurons were assessed. RSNA and MAP responses to intra‐arterial administration of CAP (0.3 µg/100 µL) were measured in decerebrate Sprague‐Dawley rats (10 ± 1 weeks, body weight: 330 ± 43 g) before and after intramuscular injection of either insulin (5 U/mL, 30 µL) or saline (vehicle control, 30 µL). To avoid insulin/saline spill over into the systemic circulation, a vascular occluder placed around the abdominal aorta was inflated immediately prior to intramuscular administration of insulin or saline.ResultsImmunohistochemical staining demonstrated that 22 % of TRPV1 positive DRG neurons expressed IR and IB4 binding. Intramuscular insulin administration did not change blood glucose as well as plasma insulin levels assessed from the jugular vein. The RSNA response to CAP after insulin administration was significantly greater than post injection of vehicle (vehicle: 25 ± 24, n=9, vs. insulin: 54 ± 32 %, n=8, P=0.04). While the MAP response to CAP was not significantly changed by vehicle injection (before: 26 ± 13 vs. after: 24 ± 12 mmHg, n=18), insulin administration significantly increased MAP responsiveness (before: 24 ± 1 vs. after: 29 ± 15 mmHg, n=22, P=0.01).ConclusionThe data demonstrate that 1) TRPV1 and IR co‐localize on small DRG neurons and 2) intramuscular insulin administration significantly augments sympathetic and pressor responses to chemical stimulation of skeletal muscle afferents. These findings suggest that insulin potentiates TRPV1 responsiveness at the muscle tissue level, possibly contributing to insulin‐induced sympathoexcitation.

Orexin facilitates the ventilatory and behavioral responses of rats to hypoxia.

Orexin neurons are sensitive to CO2 and contribute to cardiorespiratory homeostasis as well as sensorimotor control. Whether orexin facilitates respiratory and behavioral responses to acute hypoxia is unclear. We hypothesized that orexin neurons are activated by acute hypoxia and that orexin facilitates the hypoxic ventilatory response (HVR), as well as the arterial blood pressure (ABP) and behavioral (movement) responses to acute hypoxia. We further hypothesized that orexin has greater effects in the active phase of the rat circadian cycle, when orexin neurons have high activity. Using whole body plethysmography with EEG, EMG, and the dual-orexin receptor (OxR) antagonist suvorexant (20 mg/kg ip), we determined the effect of OxR blockade on the respiratory, ABP, and behavioral responses of adult rats to acute, graded hypoxia ([Formula: see text]= 0.15, 0.13, 0.11, and 0.09) and hyperoxic hypercapnia ([Formula: see text]= 0.05; [Formula: see text]= 0.95). OxR blockade had no effect on eupnea. OxR blockade significantly reduced the HVR in both inactive and active phases, with a stronger effect in the active phase. OxR blockade reduced the behavioral response to acute hypoxia in the active phase. The central component of the ventilatory and the ABP responses to hypercapnia were reduced by OxR blockade solely in the inactive phase. In the inactive phase, hypoxia activated ∼10% of orexin neurons in the perifornical hypothalamus. These data suggest that orexin neurons participate in the peripheral chemoreflex to facilitate the ventilatory and behavioral responses to acute hypoxia in rats, particularly in the active phase. Orexin also facilitates central chemoreflex responses to CO2 in the inactive phase.

Cooling strategies for firefighters: Effects on physiological, physical, and visuo-motor outcomes following fire-fighting tasks in the heat

ObjectivesDue to the nature of firefighting, most effective cooling interventions to reduce heat strain and optimise performance are not practically viable. This study quantified the effects of two practical cooling strategies, co-designed with subject-matter experts, on physiological strain and physical, perceptual, and visuo-motor performance during simulated firefighting in the heat. DesignRandomised cross-over. MethodsOn three occasions 14 firefighters completed an 80-min simulation in a hot-humid environment (32.0[0.9]°C, 59[3]%RH) including two 20-min firefighting tasks in full protective clothing, each followed by 20-min seated recovery. Recovery involved removal of protective clothing and one of three interventions – control (CON; ambient-temperature water consumption), basic (BASIC; cool-water consumption, ambient-forearm immersion/towels, fan), and advanced (ADV; ice-slushy consumption, cool-forearm immersion/ice packs, misting-fan). Thermal (core temperature) and cardiovascular (heart rate, arterial pressure) responses were measured throughout, whilst physical (handgrip/balance), visuo-motor (reaction time/memory recall) and perceptual (fatigue/thermal sensation/comfort) measures were assessed pre- and post-trial. ResultsCompared to CON, core temperature was lower in BASIC and ADV following the second task (ADV: 37.7[0.4]; BASIC: 38.0[0.4]; CON: 38.3[0.4]°C) and recovery protocol (ADV: 37.5[0.3]; BASIC: 37.7 [0.3] CON: 38.3[0.4]°C). This was paralleled by lowered heart rate, rate pressure product, and thermal sensation following the recovery protocols, in the ADV and BASIC condition compared to CON (p < .05). No physical or visuo-motor outcomes differed significantly between conditions. ConclusionWhilst these observations need to be extended to field conditions, our findings demonstrate that two novel cooling interventions developed in collaboration with subject-matter experts offered benefits for reducing thermal strain and optimising firefighter safety.

Acute Effects of Electronic and Tobacco Cigarette Smoking on Sympathetic Nerve Activity and Blood Pressure in Humans.

: IntroductionAcute tobacco cigarette (TC) smoking increases blood pressure and sympathetic nerve activity, whereas there are scarce data on the impact of electronic cigarette (EC) smoking. We assessed the acute effects of TC, EC and sham smoking on blood pressure, heart rate and sympathetic nervous system. Methods: We studied 12 normotensive male habitual smokers (mean age 33 years) free of cardiovascular disease. The study design was randomized and sham controlled with three experimental sessions (sham smoking, TC smoking and EC smoking). After baseline measurements at rest, the subjects were then asked to smoke (puffing habits left uncontrolled) two TC cigarettes containing 1.1 mg nicotine, EC smoking or simulated smoking with a drinking straw with a filter (sham smoking), in line with previous methodology. Results: EC smoking at 5 and 30 min compared to baseline was accompanied by the augmentation of mean arterial pressure (MAP) and heart rate (p < 0.001 for all). The muscle sympathetic nerve activity (MSNA) decrease was significant during both TC and EC sessions (p < 0.001 for both comparisons) and was similar between them (−25.1% ± 9.8% vs. −34.4% ± 8.3%, respectively, p = 0.018). Both MSNA decreases were significantly higher (p < 0.001 for both comparisons) than that elicited by sham smoking (−4.4% ± 4.8%). Skin sympathetic nerve activity increase was significant in both TC and EC groups (p < 0.001 for both comparisons) and similar between them (73.4% ± 17.9% and 71.9% ± 7%, respectively, p = 0.829). Conclusions: The unfavorable responses of sympathetic and arterial pressure to EC smoking are similar to those elicited by TC in healthy habitual smokers.

Venoconstrictor responses to activation of bradykinin-sensitive pericardial afferents involve the region of the hypothalamic paraventricular nucleus.

Veins are important in the control of venous return, cardiac output, and cardiovascular homeostasis. However, the effector systems modulating venous function remain to be fully elucidated. We demonstrated that activation of bradykinin‐sensitive pericardial afferents elicited systemic venoconstriction. The hypothalamic paraventricular nucleus (PVN) is an important site modulating autonomic outflow to the venous compartment. We tested the hypothesis that the PVN region is involved in the venoconstrictor response to pericardial injection of bradykinin. Rats were anesthetized with urethane/alpha chloralose and instrumented for recording arterial pressure, vena caval pressure, and mean circulatory filling pressure (MCFP), an index of venous tone. The rats were fitted with a pericardial catheter and PVN injector guide tubes. Mean arterial pressure (MAP), heart rate (HR), and MCFP responses to pericardial injection of bradykinin (1, 10 µg/kg) were recorded before and after PVN injection of omega conotoxin GVIA (200 ng/200 nl). Pericardial injection of saline produced no systematic effects on MAP, HR, or MCFP. In contrast, pericardial injection of bradykinin was associated with short latency increases in MAP (16 ± 4 to 18 ± 2 mm Hg) and MCFP 0.35 ± 0.19 to 1.01 ± 0.27 mm Hg. Heart rate responses to pericardial BK were highly variable, but HR was significantly increased (15 ± 9 bpm) at the higher BK dose. Conotoxin injection in the PVN region did not affect baseline values for these variables. However, injection of conotoxin into the area of the PVN largely attenuated the pressor (−1 ± 3 to 6 ± 3 mm Hg), MCFP (−0.19 ± 0.07 to 0.20 ± 0.18 mm Hg), and HR (4 ± 14 bpm) responses to pericardial bradykinin injection. We conclude that the PVN region is involved in the venoconstrictor responses to pericardial bradykinin injection.

Effectiveness of Angiotensin II for Catecholamine Refractory Septic or Distributive Shock on Mortality: A Propensity Score Weighted Analysis of Real-World Experience in the Medical ICU.

This study examined ATII as a third-line vasopressor based on institutional approval. Retrospective observational cohort study. Medical ICU at an academic tertiary care medical center. Adult patients requiring 3 or more vasopressor agents for septic shock or other forms of distributed shock from September 1, 2018, to January 31, 2020. Effect of ATII after norepinephrine and vasopressin on mortality and mean arterial blood pressure response after 3 hours of administration. One-hundred forty-seven patients, 56 receiving ATII and 91 receiving another vasopressor (non-ATII), were enrolled. Patients in the ATII group had higher mortality compared to the non-ATII group, and more required 5 or greater vasopressor agents (p < 0.01). After propensity score weighting, there remains a trend in higher mortality in the ATII compared to non-ATII group, but not statistically significant (86.0% vs 71.0%, p = 0.16). More patients in the ATII group continued to require 5 or greater vasopressor agents compared to the non-ATII group after propensity score weighting (45.9% vs 12.5%, p < 0.01). SOFA score was the only variable associated with mortality (OR = 1.25, 95% CI, 1.05-1.49; p = 0.01). Patients were considered a "responder" if mean arterial pressure greater than 65 mm Hg at 3 hours after the third vasopressor was initiated. Among the ATII group, 37.5% patients were responders compared to 45.1% responders in the non-ATII group (relative risk = 1.07, 95% CI, 0.6-1.93; p = 0.81). Although previous data support the use of ATII due to its favorable hemodynamic response in patients with distributive shock, there was no observed benefit in mortality or hemodynamic response with ATII as a third-line vasopressor in our study of real-world patients.

Handgrip exercise induces sex-specific mean arterial pressure and oxygenation responses but similar performance fatigability.

Women exhibit an attenuated exercise pressor reflex (EPR) when compared to men. The influence of sex-specific mechanisms related to the EPR and performance fatigability remain to be fully elucidated. The purpose was to determine the impact of oxygenation and metabolic efficiency on sex-specific performance fatigability and increases in mean arterial pressure (MAP) resulting from a fatiguing isometric handgrip (IHG). Twenty-four adults volunteered to perform an IHG at 25% at maximal voluntary isometric contractions (MVICs). Pre- and posttest MVICs were conducted to quantify performance fatigability. MAP was collected at 3 timepoints. A near-infrared spectroscopy device was attached to the forearm to derive the following signals: oxy[haem], deoxy[haem], total[haem], and diff[haem]. These values were normalized and examined across time in 5% segments of time-to-task-failure. Metabolic efficiency was defined as the ratio force:deoxy[haem]. During the IHG, there was a decline in oxy[haem] for the men (b = -0.075), whereas the women demonstrated an increase (b = 0.117). For the men, the diff[haem] tracked the mean oxy[haem] response, but there was no change for the women. The men exhibited greater declines in metabolic efficiency, yet there were no sex differences in PF (46.6 ± 9.7% vs. 45.5 ± 14.2%). For relative MAP, the men (24.5 ± 15.1%) exhibited a greater (p = .03) increase than the women (11.0 ± 17.6%). These results indicated the EPR was more prominent for the men, perhaps due to differences in mechanical stimuli and a lack of ability to maintain metabolic efficiency. However, these physiological differences did not induce a sex difference in performance fatigability.

Sustained hypoxia in mice increases parasympathetic but not sympathetic tone.

The autonomic profile of mice submitted to sustained hypoxia (SH) was not yet fully evaluated. Herein, we characterized the cardiovascular and autonomic profile of conscious freely moving mice submitted to SH using two sequential experimental protocols to evaluate the parasympathetic and sympathetic tone to the heart and the sympathetic tone to the vascular resistance. In the first protocol the sequence of antagonists was methyl-atropine followed by propranolol and then by prazosin, while in the second protocol the sequence was propranolol followed by methyl-atropine and then by prazosin. In SH the baseline heart rate was significantly lower than in control mice and the antagonism of the parasympathetic and sympathetic tone to the heart in both experimental protocols indicated an increased parasympathetic tone in SH mice and no changes in the sympathetic tone. Antagonism of the sympathetic tone to the vascular resistance with prazosin produced similar changes in arterial pressure in control and SH mice. Altogether these findings support the concept that mice submitted to SH present a significant increase in the parasympathetic but not in the sympathetic tone, which may explain why the baseline arterial pressure was not increased in SH mice.

Hemodynamic patterns associated with activation of bradykinin-sensitive pericardial afferents.

The heart is endowed with reflexogenic areas capable of powerful blood pressure responses. Relatively little work has studied the hemodynamic mechanisms underlying these responses and whether these are sexually dimorphic. We hypothesized that activation of bradykinin-sensitive pericardial afferents would produce a sexually dimorphic cardiac output response. Male and female Sprague Dawley rats were anesthetized and instrumented with catheters for recording arterial pressure, with an aortic arch flow probe to record cardiac output and with a catheter in the pericardial sac. Mean arterial pressure (MAP), cardiac index (CI) and total peripheral resistance index (TPRI) responses to pericardial bradykinin injection (0.1, 1 μg/kg) were recorded. Pericardial bradykinin injection caused similar increases in MAP in male and female rats. However, the underlying hemodynamic patterns varied considerably. We identified a cluster of CI responders and TPRI responders in both male and female rats. Within CI responders, females exhibited greater CI increases than males. Conversely, in TPRI responders, males exhibited a greater TPRI increase than females. We conclude that aggregate activation of bradykinin-sensitive pericardial afferents is associated with a relatively uniform pressor response but different hemodynamic patterns with males exhibiting a more robust vascular response and females a more robust cardiac output response.

Changes in peripheral arterial blood pressure after resuscitative endovascular balloon occlusion of the aorta (REBOA) in non-traumatic cardiac arrest patients

BackgroundResuscitative endovascular balloon occlusion of the aorta (REBOA) may be an adjunct treatment to cardiopulmonary resuscitation (CPR). Aortic occlusion may increase aortic pressure and increase the coronary perfusion pressure and the cerebral blood flow. Peripheral arterial blood pressure is often measured during or after CPR, however, changes in peripheral blood pressure after aortic occlusion is insufficiently described. This study aimed to assess changes in peripheral arterial blood pressure after REBOA in patients with out of hospital cardiac arrest.MethodsA prospective observational study performed at the helicopter emergency medical service in Trondheim (Norway). Eligible patients received REBOA as adjunct treatment to advanced cardiac life support. Peripheral invasive arterial blood pressure and end-tidal CO2 (EtCO2) was measured before and after aortic occlusion. Differences in arterial blood pressures and EtCO2 before and after occlusion was analysed with Wilcoxon Signed Rank test.ResultsFive patients were included to the study. The median REBOA procedural time was 11 min and median time from dispatch to aortic occlusion was 50 min. Two patients achieved return of spontaneous circulation. EtCO2 increased significantly 60 s after occlusion, by a mean of 1.16 kPa (p = 0.043). Before occlusion the arterial pressure in the compression phase were 43.2 (range 12–112) mmHg, the mean pressure 18.6 (range 4–27) mmHg and pressure in the relaxation phase 7.8 (range − 7 – 22) mmHg. After aortic occlusion the corresponding pressures were 114.8 (range 23–241) mmHg, 44.6 (range 15–87) mmHg and 14.8 (range 0–29) mmHg. The arterial pressures were significant different in the compression phase and as mean pressure (p = 0.043 and p = 0.043, respectively) and not significant in the relaxation phase (p = 0.223).ConclusionThis study is, to our knowledge, the first to assess the peripheral invasive arterial blood pressure response to aortic occlusion during CPR in the pre-hospital setting. REBOA application during CPR is associated with a significantly increase in peripheral artery pressures. This likely indicates improved central aortic blood pressure and warrants studies with simultaneous peripheral and central blood pressure measurement during aortic occlusion.Trial registrationThe study is registered in ClinicalTrials.gov (NCT03534011).

Quantitative assessment of the central versus peripheral effect of intravenous clonidine using baroreflex equilibrium diagrams

Clonidine is a first-generation central antihypertensive that reduces sympathetic nerve activity (SNA). Although clonidine also exerts peripheral vasoconstriction, the extent to which this vasoconstriction offsets the centrally mediated arterial pressure (AP)-lowering effect remains unknown. In anesthetized rats (n = 8), we examined SNA and AP responses to stepwise changes in carotid sinus pressure under control conditions and after intravenous low-dose (2 μg/kg) and high-dose clonidine (5 μg/kg). In the baroreflex equilibrium diagram analysis, the operating-point AP under the control condition was 115.2 (108.5–127.7) mmHg [median (25th–75th percentile range)]. While the operating-point AP after low-dose clonidine was not significantly different with or without the peripheral effect, the operating-point AP after high-dose clonidine was higher with the peripheral effect than without [81.3 (76.2–98.2) mmHg vs. 70.7 (57.7–96.9), P < 0.05]. The vasoconstrictive effect of clonidine partly offset the centrally mediated AP-lowering effect after high-dose administration.

Associations of corin genetic polymorphisms with salt sensitivity, blood pressure changes, and hypertension incidence in Chinese adults.

Corin, a transmembrane serine protease that can cleave pro‐atrial natriuretic peptide (Pro‐ANP) into smaller bioactive molecule atrial natriuretic peptide, has been shown to be involved in the pathophysiology of hypertension, cardiac hypertrophy. We sought to examine the associations of corin genetic variations with salt sensitivity, blood pressure (BP) changes and hypertension incidence. We studied participants of the original Baoji Salt‐Sensitive cohort, recruited from 124 families from seven Chinese villages in 2004 who sequentially received a usual baseline salt diet, a 7‐day low salt diet (3 g/day) and a 7‐day high salt diet (18 g/day), respectively. They were followed up for 8 years (in 2009, 2012) to evaluate the development of hypertension. Corin SNP rs3749584 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) response to low‐salt diet, while rs4695253, rs17654278 were associated with pulse pressure (PP) response to low‐salt diet. SNPs rs4695253, rs12509275, rs2351783, rs2271036, rs2271037 were significantly associated with systolic BP (SBP), DBP, and MAP responses to high‐salt diet. In addition, SNPs rs12641823, rs6834933, rs2271036, and rs22710367 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP over 8 years of follow‐up. SNP rs73814824 was significantly associated with the incidence of hypertension over 8 years. Gene‐based analysis showed that corin gene was significantly associated with longitudinal BP changes and hypertension incidence after 8‐year follow‐up. This study suggests that corin may play a role in salt sensitivity, BP progression, and development of hypertension.

Differential effects of sex on adaptive responses of skeletal muscle vasodilation to exercise training in type 2 diabetes

AimsWe tested the hypotheses that exercise training improves the peak and dynamic responses of leg vascular conductance (LVC) in males and females with type 2 diabetes (T2DM). MethodsForty-one males and females with T2DM were assigned to two training groups and two control groups. Twelve weeks of aerobic/resistance training was performed three times per week, 60–90 min per session. Responses of calf muscle blood flow and systemic arterial pressure during incremental and constant-load (30% maximal voluntary contraction) intermittent plantar-flexion protocols in the supine position were recorded. ResultsTraining significantly increased peak LVC in males (4.86 ± 1.88 to 6.06 ± 2.06 ml·min−1·mm Hg−1) and females (3.91 ± 1.13 to 5.40 ± 1.38 ml·min−1·mm Hg−1) with no changes in control groups. For dynamic responses, training significantly increased the amplitude of the fast growth phase of LVC (1.81 ± 1.12 to 2.68 ± 1.01 ml·min−1·mm Hg−1) and decreased the time constant of the slow growth phase (43.6 ± 46.4 s to 16.1 14.0 s) in females, but no improvements were observed in control females or in any of the two male groups. ConclusionsThese data suggest that training increases the peak vasodilatory response in males and females, whereas the speed of the dynamic response of vasodilation is improved in females but not males.

Abstract 9053: ASIC3 Knockout Alleviates Exaggerated Blood Pressure Response Induced by P2X3 Activation in Hindlimb Muscle Afferent Nerves of Rats With Experimental Peripheral Artery Disease

Background: In peripheral artery disease (PAD), the metaboreceptor and mechanoreceptor in muscle afferent nerves contribute to accentuated sympathetic outflow via a neural reflex. Particularly, lactic acid and ATP produced in exercising muscles respectively stimulate acid sensing ion channel subtype 3 (ASIC3) and purinergic subunit P2X3 receptors in muscle afferent nerves, inducing the reflex sympathetic and arterial blood pressure responses during exercise. Methods: We examined that the P2X3 protein expression in the dorsal root ganglion (DRG) and P2X currents in DRG neurons using western blotting and patch-clamp methods, and the pressor response to P2X3 stimulation using the whole animal preparations. Four groups were included: 1. Wild type (WT) rats; 2. ASIC3 knockout (KO) rats; 3. WT-PAD rats with three days of femoral artery occlusion; 4. KO-PAD rats with three days of femoral artery occlusion. Results: First, P2X3 expression was significantly increased in KO rats compared with that in WT rats (optical density: 6.51±2.20/n=5; P &lt;0.05 vs. WT). However, the levels of P2X3 expression were not significantly increased in KO-PAD rats compared with the KO rats (optical density: 7.99±1.99/n=6; P &gt;0.05 vs. KO) . Second, in WT rats, as 10, 30 and 50 μM of αβ-me ATP (P2X3 agonist) were applied, peak amplitude of both transient and sustained P2X currents was increased by femoral artery occlusion (all P &lt;0.05 WT-PAD vs. WT). Insignificant differences in both transient and sustained P2X currents were found between KO rats and KO-PAD rats (all P &gt;0.05 vs. KO) when αβ-me ATP was applied except of the transient P2X current amplitude at 50 μM of αβ-me ATP. Third, there were insignificant differences in the mean arterial pressure response to 0.0625, 0.125 and 0.25 mM of αβ-me ATP injected into the hindlimb circulation between KO rats and KO-PAD rats (all P &gt;0.05 vs. KO). Conclusions: Compared with WT rats, augmented P2X3-mediated pressor response is blunted by ASIC3 KO in PAD rats and this is accompanied with downregulated P2X3 expression and suppressed activities in P2X3 signaling pathways in muscle afferent neurons.

Abstract 10234: Exaggerated Blood Pressure Response to Static Exercise Following Muscle Ischemia-Reperfusion: A Time-Course Investigation

Background: Peripheral artery disease (PAD) is one of the major cardiovascular concerns and dramatically reduces the blood flow supply in the affected limbs. A combination of revascularization surgery in the femoral artery and supervised exercise intervention is among the most general approaches for the treatment of PAD. However, the effects of ischemia-reperfusion (IR), which is one of the most predominant complications resulting from the revascularization surgery, on exercise-induced arterial blood pressure (BP) response are poorly understood. Methods: We examined the BP response to static muscle contraction in rats at different time points after the IR procedure. Four groups were included: 1. Sham rats; 2. Rats with 18 hours following IR (IR 18h); 3. Rats with 66 hours following IR (IR 66h); 4. Rats with 114 hours following IR (IR 114h). One-way ANOVA with LSD post-hoc test was applied to analyze the difference among groups. Data were presented as Mean ± Standard Deviation. Results: Compared with Sham group, the BP response to static muscle contraction was significantly increased in rats with all the investigated time points. The response of mean arterial pressure was 19±3 mmHg in Sham rats (n=6); 29±9 mmHg in IR 18h rats (n=8); 26±7 mmHg in IR 66h rats (n=10); 26±4 mmHg in IR 114h rats (n=9) ( P &lt;0.05; the groups at three time courses vs. Sham). There was no significant difference observed in the peak developed tension during muscle contraction among all the groups (Sham rats: 543±101g; IR 18h rats: 520±28g; IR 66h rats: 554±66g; IR 114h rats: 562±45g; P &gt;0.05). Conclusions: IR significantly exaggerates the static exercise-induced BP response. Whereas the BP response tends to decrease with the prolonged IR time, the exaggerated BP response remains through time points from post IR 18 hours to 114 hours. The data suggest that a chronic time course should be considered to alleviate IR-induced ischemic injury in PAD patients for clinical interventions appropriated and exercise.

Role of Renal Sympathetic Nerves in GLP-1 (Glucagon-Like Peptide-1) Receptor Agonist Exendin-4-Mediated Diuresis and Natriuresis in Diet-Induced Obese Rats.

BackgroundThe gut‐derived hormone GLP‐1 (glucagon‐like peptide‐1) exerts beneficial effects against established risk factors for chronic kidney disease. GLP‐1 influences renal function by stimulating diuresis and natriuresis and thus lowering arterial blood pressure. The role of the sympathetic nervous system has been implicated as an important link between obesity with elevated arterial pressure and chronic kidney disease. The primary aim of this study was to determine the contribution of renal sympathetic nerves on intrapelvic GLP‐1‐mediated diuresis and natriuresis in high‐fat diet (HFD)‐induced obese rats.Methods and ResultsObesity was induced in rats by HFD for 12 weeks, followed by either surgical bilateral renal denervation or chronic subcutaneous endopeptidase neprilysin inhibition by sacubitril for a week. Diuretic and natriuretic responses to intrapelvic administration of the GLP‐1R (GLP‐1 receptor) agonist exendin‐4 were monitored in anesthetized control and HFD rats. Renal GLP‐1R expression and neprilysin expression and activity were measured. The effects of norepinephrine on the expression of GLP‐1R and neprilysin in kidney epithelial LLC‐PK1 cells were also examined. We found that diuretic and natriuretic responses to exendin‐4 were significantly reduced in the HFD obese rats compared with the control rats (cumulative urine flow at 40 minutes, 387±32 versus 650±65 µL/gkw; cumulative sodium excretion at 40 minutes, 42±5 versus 75±10 µEq/gkw, P<0.05). These responses in the HFD rats were restored after ablation of renal nerves (cumulative urine flow at 40 minutes, 625±62 versus 387±32 µL/gkw; cumulative sodium excretion at 40 minutes, 70±9 versus 42±5 µEq/gkw, P<0.05). Renal denervation induced significant reductions in arterial pressure and heart rate responses to intrapelvic GLP‐1 in the HFD rats. Renal denervation also significantly increased the GLP‐1R expression and reduced neprilysin expression and activity in renal tissues from the HFD rats. Chronic subcutaneous neprilysin inhibition by sacubitril increased GLP‐1–induced diuretic and natriuretic effects in the HFD rats. Finally, exposure of the renal epithelial cells to norepinephrine in vitro led to downregulation of GLP‐1R expression but upregulation of neprilysin expression and activity.ConclusionsThese results suggest that renal sympathetic nerve activation contributes to the blunted diuretic and natriuretic effects of GLP‐1 in HFD obese rats. This study provides significant novel insight into the potential renal nerve–neprilysin–GLP‐1 pathway involved in renal dysfunction during obesity that leads to hypertension.

Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients

Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.

Sequential measurement of the neurosensory retina in hypertensive disorders of pregnancy: a model of microvascular injury in hypertensive emergency

Optical coherence tomography of the eye suggests the retina thins in normal pregnancy. Our objectives were to confirm and extend these observations to women with hypertensive disorders of pregnancy (HDP). Maternal demographics, clinical/laboratory findings and measurements of macular thickness were repeatedly collected at gestational ages <20 weeks, 20-weeks to delivery, at delivery and postpartum. The primary outcome was the change in macular thickness from non-pregnant dimensions in women with incident HDP compared to non-hypertensive pregnant controls. Secondary outcomes were the relationship(s) between mean arterial pressure (MAP) and macular response. Data show macular thicknesses diminished at <20 weeks gestation in each of 27 pregnancies ending in HDP (mean 3.94 µm; 95% CI 4.66, 3.21) and 11 controls (mean 3.92 µm; 5.05, 2.79; P < 0.001 versus non-pregnant dimensions in both; P = 0.983 HDP versus controls). This thinning response continued to delivery in all controls and in 7 women with HDP superimposed on chronic hypertension. Macular thinning was lost after 20 weeks gestation in the other 20 women with HDP. MAP at loss of macular thinning in women without prior hypertension (n = 12) was identical to MAP at enrollment. However, mean MAP subsequently rose 19 mmHg (15, 22) leading to de novo HDP in all 12 women. Loss of thinning leading to a rise in MAP was also observed in 8 of 15 women with HDP superimposed on chronic hypertension. We conclude the macula thins in most women in early pregnancy. Those who lose this early macular thinning response often develop blood pressure elevations leading to HDP.

Effect of breath-hold on the responses of arterial blood pressure and cerebral blood velocity to isometric exercise.

The present study examined the effect of breath-hold without a Valsalva maneuver during isometric exercise on arterial blood pressure (ABP) and cerebral blood flow (CBF). Twenty healthy adults (15 men and five women) randomly performed only breath-hold without a Valsalva maneuver (BH), and an isometric handgrip exercise for 30s at 40% of individual maximal voluntary contraction with continuous breathing (IHG) and with breath-hold without the Valsalva maneuver (IHG-BH). Mean ABP (MAP) and blood velocity in the middle (MCA Vmean) and posterior cerebral arteries (PCA Vmean) were continuously measured throughout each protocol. MAP was elevated during the IHG-BH compared with IHG (P < 0.001) and BH (P = 0.001). Similarly, both MCA Vmean and PCA Vmean were higher during IHG-BH compared with IHG and BH (all P < 0.001). Moreover, the relative change in MAP from the baseline was correlated with that in both cerebral blood velocities during the BH (MCA Vmean: r = 0.739, P < 0.001 and PCA Vmean: r = 0.570, P = 0.009) and IHG-BH (MCA Vmean: r = 0.755, P < 0.001 and PCA Vmean: r = 0.617, P = 0.003) condition, but not the IHG condition (P = 0.154 and P = 0.306). These results indicate that during isometric exercise, a breath-hold enhances an exercise-induced increase in MAP and, consequently, MCA Vmean and PCA Vmean.