Reduction In Mean Arterial Pressure Research Articles

Effects of dexmedetomidine combined with commonly administered opioids on clinical variables in dogs.

OBJECTIVE To evaluate cardiopulmonary, sedative, and antinociceptive effects of dexmedetomidine combined with commonly administered opioids in dogs. ANIMALS 8 healthy Beagles. PROCEDURES Dogs were sedated by IM administration of each of 7 treatments. Treatments comprised dexmedetomidine (0.01 mg/kg; Dex) and the same dose of dexmedetomidine plus butorphanol (0.15 mg/kg; Dex-But), meperidine (5 mg/kg; Dex-Mep), methadone (0.5 mg/kg; Dex-Meth), morphine (0.5 mg/kg; Dex-Mor), nalbuphine (0.5 mg/kg; Dex-Nal), or tramadol (5 mg/kg; Dex-Tram). Cardiorespiratory and arterial blood gas variables and sedative and antinociceptive scores were measured before drug injection (time 0; baseline) and at 15-minute intervals for 120 minutes. RESULTS Heart rate was reduced at all time points after injection of Dex-But, Dex-Mep, Dex-Meth, and Dex-Mor treatments. There was a significant reduction of mean arterial blood pressure for Dex-But, Dex-Mep, and Dex-Mor treatments at all time points, compared with baseline. There was a significant decrease in respiratory rate, compared with the baseline value, for Dex, Dex-But, Dex-Meth, and Dex-Tram treatments from 15 to 120 minutes. A significant decrease in arterial blood pH was detected from baseline to 120 minutes for all treatments, with differences among Dex, Dex-Mep, and Dex-Mor. Reduction in Pao2 was greater for the Dex-Mep treatment than for the other treatments. The highest sedation scores were detected for Dex-Mep and Dex-Meth treatments. Antinociceptive effects were superior for Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal treatments. CONCLUSIONS AND CLINICAL RELEVANCE Drug combinations caused similar cardiorespiratory changes, with greater sedative effects for Dex-Mep and Dex-Meth and superior antinociceptive effects for Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal.

Penehyclidine hydrochloride inhibits TLR4 signaling and inflammation, and attenuates blunt chest trauma and hemorrhagic shock-induced acute lung injury in rats.

Blunt chest trauma with hemorrhagic shock (THS) frequently induces pulmonary inflammation that leads to acute lung injury (ALI). Penehyclidine hydrochloride (PHC) possesses anti-inflammatory properties that may attenuate the systemic inflammatory response. The present study aimed to evaluate the molecular mechanism of PHC in modifying THS-induced ALI in rats. Rats underwent either THS or a sham procedure. At 6 h subsequent to blunt chest trauma, arterial blood was drawn for blood gas and pro-inflammatory factors analyses, and lung tissue samples were collected to examine pulmonary histopathological alterations, the wet/dry weight ratio, myeloperoxidase activity, and the protein expression levels of Toll-like receptor 4 (TLR4), phosphorylated (p-)p38 mitogen-activated protein kinase (MAPK), nuclear factor (NF)-κB and activator protein-1 (AP-1). THS caused significant reductions in heart rate and mean arterial blood pressure, and was associated with significant increases in tumor necrosis factor-α, interleukin (IL)-6, IL-1β, p-p38MAPK, NF-κB and AP-1 activation, in addition to TLR4 expression, in the lung. PHC effectively attenuated THS-induced ALI, and inhibited TLR4 expression, reduced the activation of p-p38MAPK, NF-κB and AP-1, and downregulated the expression of pro-inflammatory mediators. In conclusion, the results of the present study demonstrated that PHC may exert an anti-inflammatory effect and attenuate THS-induced ALI by inhibiting the TLR4 signaling pathway. These preclinical findings may offer a novel therapeutic strategy to restrict TLR4 overactivation in ALI.

Effect of acute hypoxemia on cerebral blood flow velocity control during lower body negative pressure.

The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. We tested the hypothesis that acute hypoxemia during simulated blood loss in humans would cause impairments in cerebral blood flow control. Ten healthy subjects (32 ± 6 years, BMI 27 ± 2 kg·m−2) were exposed to stepwise lower body negative pressure (LBNP, 5 min at 0, −15, −30, and −45 mmHg) during both normoxia and hypoxia (FiO2 = 0.12–0.15 O2 titrated to an SaO2 of ~85%). Physiological responses during both protocols were expressed as absolute changes from baseline, one subject was excluded from analysis due to presyncope during the first stage of LBNP during hypoxia. LBNP induced greater reductions in mean arterial pressure during hypoxia versus normoxia (MAP, at −45 mmHg: −20 ± 3 vs. −5 ± 3 mmHg, P < 0.01). Despite differences in MAP, middle cerebral artery velocity responses (MCAv) were similar between protocols (P = 0.41) due to increased cerebrovascular conductance index (CVCi) during hypoxia (main effect, P = 0.04). Low frequency MAP (at −45 mmHg: 17 ± 5 vs. 0 ± 5 mmHg2, P = 0.01) and MCAv (at −45 mmHg: 4 ± 2 vs. −1 ± 1 cm·s−2, P = 0.04) spectral power density, as well as low frequency MAP‐mean MCAv transfer function gain (at −30 mmHg: 0.09 ± 0.06 vs. −0.07 ± 0.06 cm·s−1·mmHg−1, P = 0.04) increased more during hypoxia versus normoxia. Contrary to our hypothesis, these findings support the notion that cerebral blood flow control is not impaired during exposure to acute hypoxia and progressive central hypovolemia despite lower MAP as a result of compensated increases in cerebral conductance and flow variability.

Abstract TP211: Gray and White Matter Hemodynamics and Metabolism Measured Using Magnetic Resonance Imaging

Background: Reliable methods used to measure cerebral hemodynamics, metabolism and autoregulation are time-consuming and invasive. Objectives: We sought to measure cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2 ), in the whole brain, gray and white matter and detect physiological changes in humans under normal and ≈10% reductions in mean arterial pressure (MAP). Methods: CBF was measured using pseudo continuous arterial spin labeling (pCASL). OEF was measured using a MRI asymmetric spin echo-planar imaging (EPI). The arterial content of oxygen (CaO 2 ) was computed. CMRO 2 was calculated using the equation CMRO 2 =CaO 2 xCBFxOEF. Cerebral autoregulation was determined by measuring changes in CBF, OEF and CMRO 2 in response to ≈10% reductions in MAP in stroke-free controls induced by IV Nicardipine infusion. Autoregulation was measured in the whole brain, gray matter and white matter. Autoregulatory Index (AI) was computed using the equation AI = %CBF change/% MAP change supplemented by CBF associated OEF changes. Results: A total of 30 subjects were consented (Mean age 31, 93% male, 40% white, 43% black and 17% others). At baseline, CBF was measured in the whole brain (52.5±9.5 ml/100g/min), gray matter (72.0±13.0 ml/100g/min) and white matter (30.2±8.4 ml/100g/min). OEF was measured in the whole brain (0.32±0.02), gray matter (0.33±0.02) and white matter (0.30±0.01). CMRO 2 was measured in the whole brain (3.2±0.8 ml/100g/min), gray matter (4.6±1.1 ml/100g/min) and white matter (1.8±0.5 ml/100g/min). A target of 10% MAP lowering was successfully achieved in 18 subjects, resulting in a change of mean CBF in the whole brain (52 vs. 50, p=0.1), gray matter (72 vs. 69, p=0.2) and white matter (30 vs. 28, p=0.08). This translated to a AI of 0.3 ± 0.9 in the whole brain, 0.2±1.0 in the gray matter and 0.5±1.7 in the white matter. These CBF changes corroborated with no significant changes in OEF and CMRO 2 . Conclusions: MR measurement of CBF, OEF and CMRO 2 , in the whole brain, gray and white matter was comparable to measures obtained by invasive methods. Differences in these measures, as well as AI in the gray and white matter, may help understand cerebrovascular diseases that affect white matter such as lacunar strokes.

318: Endothelial function is unaltered by prophylactic nitric oxide donor in women at high-risk for preeclampsia

To study the effect of low dose prophylactic isosorbide mononitrate (ISMN) 20mg/d on the endothelial function in high-risk women receiving standard aspirin prophylaxis Design: As part of a randomized double blind placebo-controlled parallel arm superiority trial. Setting: Antenatal clinic of a tertiary teaching hospital, south India Participants and methods: One hundred women fulfilling NICE guideline criteria for aspirin prophylaxis were recruited at 12 - 16 weeks and randomised to receive either 20mg/d of ISMN or placebo, in addition to 75mg/d of oral aspirin from recruitment till delivery. Outcome measure: Changes in indices of endothelial function Sample Size (for the primary outcome): One hundred women (50 in each arm) to detect a decrease of hypertensive disorders from 20% in the placebo group to 5% in the ISMN group with a power of 80% and α at 0.05 The groups were comparable in terms of age, BMI, parity, and risk factor for preeclampsia. The vascular indices of endothelial function were recorded at recruitment and again at 24 weeks. These included flow-mediated vasodilatation index (FMVD-i), brachial-ankle pulse wave velocity, ankle-brachial index, brachial arterial stiffness index, and ankle arterial stiffness index. (Table 1). There was no significant improvement in these indices following ISMN intake. The FMVD-i actually showed a decrease following ISMN treatment. Concomitantly, there was a reduction in mean arterial pressure. The composite rate of hypertensive disorders (gestational hypertension, preeclampsia, or superimposed preeclampsia) was not significantly different between the groups (14/50, 28% in ISMN vs. 12/50, 24% in placebo group; p = 0.7). Addition of nitric oxide donor, ISMN, does not improve the endothelial function in high risk women who are on low-dose aspirin. However, it results in a slight lowering of mean arterial pressure without a concomitant reduction in the clinical event rate of hypertensive disorders.

The Effects of the Quincke Spinal Needle Bevel Insertion on Postdural Puncture Headache and Hemodynamics in Obstetric Patients.

Aim:Spinal anesthesia is a widely used procedure in modern anesthesia. Although it is a reliable and frequently used anesthetic procedure, it involves complications, including postdural puncture headache caused by arachnoid punctured, which significantly affects postoperative well-being. In this study, we aimed to observe headache frequency with 26-G Quincke spinal needle in either transverse or sagittal planes.Materials and Methods:One hundred patients with American Society of Anesthesiologists status classes I and II who were scheduled for elective cesarean delivery with no contraindications for performing spinal anesthesia were randomly divided into two groups: Group I (transverse n = 50) and Group II (sagittal n = 50). Spinal anesthesia was performed with a 26-G Quincke needle, using 1.5–2.0 ml 0.75% hyperbaric bupivacaine. The anesthesiologists' experience, number of attempts for spinal anesthesia, volume of fluid administered preoperatively and intraoperatively, intervertebral space where spinal anesthesia was administered, and patient movements during the attempts were recorded. Mean arterial pressure and peak heart rates were recorded for 60 min intraoperatively and postoperatively. Headache and back pain complications were observed for 1 week postoperatively. Chi-square tests and statistical comparisons of the rates (statistical significance, P < 0.05) were used for assessments.Results and Conclusions:No significant differences were observed with respect to age, height, weight, headache, or incidence of back pain. No significant differences were observed for the number of spinal attempts, intervertebral space where spinal anesthesia was administered, experience of the anesthesiologists, patient movements during the attempts, volumes of fluid administered preoperatively and intraoperatively, or low back pain incidence. Significant reductions in mean arterial pressure were observed between groups after 10, 15, 30, 40, and 50 min. No significant differences were observed in headache or back pain frequency with 26-G Quincke spinal needle in either transverse or sagittal planes. Hypotension was frequently observed in the transverse group.

Hypotensive Response to Continuous Aerobic and High-Intensity Interval Exercise Matched by Volume in Sedentary Subjects

Abstract Background: Systemic arterial hypertension (SAH) is one of the main risk factors for heart disease. Among the benefits linked to different modalities of physical exercise, post-exercise hypotension (PEH) is a key point for exercise prescription in this condition. Objective: To investigate and compare PEH in response to continuous aerobic exercise (CONT) and high-intensity interval exercise (HIIE), matched by volume, in sedentary individuals. Methods: A randomized cross-over study, composed of sedentary, healthy male subjects submitted to two acute physical exercise protocols matched by volume, HIIE and CONT, on a treadmill. Hemodynamic measures for the evaluation of PEH were performed pre, immediately after exercise and every five minutes thereafter, during one hour of recovery. Two-way ANOVA with repeated measurements was used for comparisons between groups and Bonferroni post hoc test as appropriate. P < 0.05 was considered significant. Results: Both exercise protocols promoted significant PEH, with reductions in systolic blood pressure (SBP) and mean arterial pressure (MAP). HIIE promoted a reduction of SBP and MAP at the 15th minute, whereas the same effect was observed at the 30th following CONT. Conclusion: Both HIIE and CONT, matched by volume, promote PEH of similar magnitude. However, PEH occurs earlier following HIIE, suggesting a better time / effectiveness ratio, and an additional beneficial effect of this modality.

Caudal Analgesia for Hypospadias in Pediatrics: Comparative Evaluation of Adjuvants Dexamethasone and Dexmedetomidine Combination versus Dexamethasone or Dexmedetomidine to Bupivacaine: A Prospective, Double-Blinded, Randomized Comparative Study.

Background:Caudal block is the most commonly used regional anesthetic technique in pediatric surgeries; different additives have been used for better and safer outcome.Aim:The aim of this study is to compare the combination of dexamethasone and dexmedetomidine as adjuvants to bupivacaine versus using each agent solely with bupivacaine in pediatric caudal block as regards their efficiency in pain relief (the duration of postoperative analgesia, first time to request analgesia, and modified objective pain score [MOPS]).Study Design:This was a prospective, double-blinded, randomized study.Patients and Methods:Patients and Methods: Sixty-three children scheduled for hypospadias surgery wererandomized into three groupsaccording to the adjuvant drug added to caudal bupivacaine : Group I (n = 21): dexamethasone 0.1 mg/kg + 0.5 mg/kg bupivacaine 0.25%, Group II (n = 21): dexmedetomidine0.01 μg/kg + 0.5 mg/kg bupivacaine 0.25% and Group III (n = 21): dexamethasone 0.1 mg/kg + dexmedetomidine 0.01 μg/kg + 0.5 mg/kgbupivacaine 0.25%. Intraoperative and postoperative hemodynamics were recorded. In postoperative anesthesia care unit and then the ward, MOPS and sedation score were recorded at 30 min and 1, 2, 3, 6 and 12 h. Further, the time of first analgesic request and side effects were recorded.Statistical Analysis:Categorical data were presented as frequencies (%) and analyzed using Chi-square test. Continuous data were presented as mean (standard deviation) and median (quartiles). Continuous data were analyzed using one-way analysis of variance for single measures and two-way mixed model for repeated measures. Kaplan–Meier analysis was performed for the duration of analgesia.Results:In Group III, MOPS was lower than Groups I and II at the study times. Further, Group III had prolonged time for first request of analgesic. Sedation scores were prolonged in Group III and Group II than in Group I. There was a reduction in heart rates in Group III more than Group I and Group II but with no significant difference. However, there was a significant reduction in mean arterial blood pressure 30 min intraoperatively and postoperatively in Group III as compared to Groups I and II.Conclusion:The addition of combined dexmedetomidine at a dose of 1 μg/kg and dexamethasone 0.1 mg/kg to caudal bupivacaine seemed to be an attractive alternative to each drug if used alone with more prolonged analgesia and almost no adverse effects.

Burst patterning of hypothalamic paraventricular nucleus-driven sympathetic nerve activity in ANG II-salt hypertension.

ANG II-salt hypertension selectively increases splanchnic sympathetic nerve activity (sSNA), but the extent to which this reflects increased respiratory versus cardiac rhythmic bursting is unknown. Here, integrated sSNA was elevated in ANG II-infused rats fed a high-salt (2% NaCl) diet (ANG II-HSD) compared with vehicle-infused rats fed a normal-salt (0.4% NaCl) diet (Veh-NSD; P < 0.01). Increased sSNA was not accompanied by increased inspiratory or expiratory bursting, consistent with no group difference in central inspiratory drive. Consistent with preserved inhibitory baroreflex entrainment of elevated sSNA in ANG II-HSD rats, the time integral ( P < 0.05) and amplitude ( P < 0.01) of cardiac rhythmic sSNA were increased. Consistent with activity of hypothalamic paraventricular nucleus (PVN) neurons supporting basal SNA in ANG II-salt hypertension, inhibition of PVN with the GABA-A receptor agonist muscimol reduced mean arterial pressure (MAP) and integrated sSNA only in the ANG II-HSD group ( P < 0.001). PVN inhibition had no effect on respiratory rhythmic sSNA bursting in either group but reduced cardiac rhythmic sSNA in ANG II-HSD rats only ( P < 0.01). The latter likely reflected reduced inhibitory baroreflex entrainment subsequent to the fall of MAP. Of note is that MAP as well as integrated and rhythmic burst patterns of sSNA were similar in vehicle-infused rats whether they were fed a normal or high-salt diet. Findings indicate that PVN neurons support elevated sSNA in ANG II-HSD rats by driving a tonic component of activity without altering respiratory or cardiac rhythmic bursting. Because sSNA was unchanged in Veh-HSD rats, activation of PVN-driven tonic sSNA appears to require central actions of ANG II. NEW & NOTEWORTHY ANG II-salt hypertension is strongly neurogenic and depends on hypothalamic paraventricular nucleus (PVN)-driven splanchnic sympathetic nerve activity (sSNA). Here, respiratory and cardiac bursts of sSNA were preserved in ANG II-salt rats and unaltered by PVN inhibition, suggesting that PVN neurons drive a tonic component of sSNA rather than modulating dominant patterns of burst discharge.

BP Reduction, Kidney Function Decline, and Cardiovascular Events in Patients without CKD.

In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD. We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ≥40 mm Hg. We defined the primary outcome as kidney function decline (≥30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline. In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ≥40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ≥40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ≥40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16. In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01). A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Heterodimerization of apelin and opioid receptors and cardiac inotropic and lusitropic effects of apelin in 2K1C hypertension: Role of pERK1/2 and PKC

AimsKappa Opioid receptors (KORs) change the impact of apelin on the phosphorylated ERK1/2 (pERK1/2). However, the role of interaction between KOR and apelin receptors (APJ) on the cardiac contractility effects of apelin and in regulation of pERK1/2 and PKC in the heart of renovascular hypertensive (2K1C) rats is unknown. Main methodsHemodynamic factors, the heterodimerization of KOR and APJ, the expression of KOR mRNA and protein and pERK1/2 in the left ventricle of 2K1C rats were measured following APJ, KOR, PKC and Gi path inhibition by F13A, nor-BNI, chelerythrine and PTX respectively. Key findingsApelin in 40 and 60μg/kg doses increased cardiac contractility, and reduced mean arterial pressure. The cardiac impacts in both doses were reduced by F13A, nor-BNI and chelerytrine and blocked by PTX. Hypertension increased the expression of KORs and heterodimerization of APJ and KOR, and reduced pERK1/2 in the left ventricle. Apelin, in both doses reduced (normalized) heterodimerization and recovered the reduction in pERK1/2. The recovery of ERK1/2 phosphorylation was accompanied by reduction of KOR and APJ heterodimerization. Significance2K1C hypertension increased the expression of KORs and heterodimerization of APJ and KORs. The heterodimerization was associated by reduction of ERK phosphorylation and altered the cardiac inotropic and lusitropic effects of apelin. These changes may participate in pathophysiology of cardiac dysfunction in renovascular hypertension that is associated with subnormal level of serum apelin. Apelin- induced recovery of ERK1/2 phosphorylation and KOR-APJ dimerization may nominate apelin as a therapeutic goal in treatment of this kind of hypertension.

An open-label randomised controlled trial on the efficacy of adding intranasal fentanyl to intravenous tramadol in patients with moderate to severe pain following acute musculoskeletal injuries.

The use of intranasal fentanyl as an alternative type of analgesia has been shown to be effective in paediatric populations and prehospital settings. There are a limited number of studies on the use of intranasal fentanyl in adult patients in emergency settings. An open-label study was conducted to evaluate the effectiveness of the addition of 1.5 mcg/kg intranasal fentanyl to 2 mg/kg intravenous tramadol (fentanyl + tramadol arm, n = 10) as compared to the administration of 2 mg/kg intravenous tramadol alone (tramadol-only arm, n = 10) in adult patients with moderate to severe pain due to acute musculoskeletal injuries. When analysed using the independent t-test, the difference between the mean visual analogue scale scores pre-intervention and ten minutes post-intervention was 29.8 ± 8.4 mm in the fentanyl + tramadol arm and 19.6 ± 9.7 mm in the tramadol-only arm (t[18] = 2.515, p = 0.022, 95% confidence interval 1.68-18.72 mm). A statistically significant, albeit transient, reduction in the ten-minute post-intervention mean arterial pressure was noted in the fentanyl + tramadol arm as compared to the tramadol-only arm (13.35 mmHg vs. 7.65 mmHg; using Mann-Whitney U test with U-value 21.5, p = 0.029, r = 0.48). There was a higher incidence of transient dizziness ten minutes after intervention among the patients in the fentanyl + tramadol arm. Although effective, intranasal fentanyl may not be appropriate for routine use in adult patients, as it could result in a significant reduction in blood pressure.

Effects of the bioactive peptides Ile-Pro-Pro and Val-Pro-Pro upon autonomic neurotransmission and blood pressure in spontaneously hypertensive rats.

The bioactive peptides Ile-Pro-Pro (IPP) and Val-Pro-Pro (VPP) are believed to improve blood pressure and arterial function. To gain a better understanding of the mechanisms underlying the action of these peptides, we investigated their effects upon autonomic neurotransmission and blood pressure in spontaneously hypertensive rats (SHR). Both IPP and VPP caused a significant reduction in cutaneous arterial sympathetic nerve activity (CASNA) and reduced mean arterial pressure (MAP); however, both of these effects were eliminated following sub-diaphragmatic vagotomy. On the other hand, captopril, an angiotensin-converting enzyme inhibitor, reduced MAP without changing CASNA, and maintained this hypotensive effect following vagotomy. Moreover, the effects of IPP and VPP upon CASNA were observed following gastric administration but not by duodenal administration. These results suggest that IPP and VPP reduce CASNA via the stomach and afferent vagus nerve, thus causing reductions in MAP in SHR.

Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir.

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h (P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h (P < 0.0001) and nitric oxide (NO) at 24 and 48 h (P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP (P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality (P = 0.01), increased MAP (P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively (P ≤ 0.03), and plasma NO at both times (P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h (P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality.NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.

Abstract P234: 2-Methoxyestradiol Attenuates Angiotensin II Induced Hypertension: A Novel Paradigm

Estrogen metabolite 2-methoxyestradiol (2ME2) has therapeutic potential in a number of cardiovascular disorders, including hypertension. However, specific or potential targets remains to be determined. In this study, animals were surgically implanted with PA-C40 telemetry in the intra-aortic vessel and 2ME2 (20 mg/kg/day, i.p. injection) effects in AngII infused Wistar-Koyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were determined. In WKY rats 2ME2 treatment resulted in significant reduction in AngII induced blood pressure (BP) compared to vehicle control (systolic; 143.69 ± 2.68 vs. 169.75 ± 1.93 mm Hg, diastolic; 99.91 ± 2.49 vs. 120.16 ± 1.25 mm Hg, and mean arterial pressure; 118.94 ± 2.52 vs. 142.73 ± 1.47 mm Hg). We observed a decrease in heart rate in 2ME2 exposed animals compared to control group (272.67 ± 9.88 vs. 329.12 ± 6.14 BPM). In addition, 2ME2 mediated reduction in workload of the heart when we calculated the rate pressure product or pressure rate index by 13.46 ± 2.32 indicating that 2ME2 can reduce AngII induced hemodynamic stress of the heart. [ 3 H]AngII binding studies showed that in kidney cortex AT1R expression was inhibited by 2ME2 treatment compared to control (2112 ± 71 vs. 3341 ± 248 DPM/mg protein). In a separate 5-week study, 2ME2-treated SHRs displayed significant reduction in diastolic BP (114.31 ± 0.66 vs. 123.28 ± 0.70 mm Hg) and mean arterial pressure (146.35 ± 0.67 vs. 151.54 ± 0.89 mm Hg) without significant change in systolic BP compare to the vehicle treated animals. Moreover, we found significant decrease in heart rate in 2ME2-treated animals (290.03 ± 2.69 vs. 312.92 ± 1.50 BPM). Analyses of kidney cortical tissue revealed downregulation of AT1R expression after 2ME2 treatments (20227 ± 2211 vs. 9515 ± 2115 DPM/mg protein). Consistent with the reduction in BP, the indicators of cardiac hypertrophy including heart weight (1.28 ± 0.08 vs. 0.99 ± 0.02 gram), cardiac collagen deposit and α-smooth muscle actin (α-SMC) positive myofibroblasts were decreased. The data demonstrate for the first time that 2ME2 control BP through downregulation of AT1R in kidney and heart rate, which may provide an insight to the mechanism(s) of cardioprotective effects of 2ME2 through the blockade of AngII induced hypertension.

Rapid ventricular pacing for clip reconstruction of complex unruptured intracranial aneurysms: results of an interdisciplinary prospective trial.

OBJECTIVE To date, treatment of complex unruptured intracranial aneurysms (UIAs) remains challenging. Therefore, advanced techniques are required to achieve an optimal result in treating these patients safely. In this study, the safety and efficacy of rapid ventricular pacing (RVP) to facilitate microsurgical clip reconstruction was investigated prospectively in a joined neurosurgery, anesthesiology, and cardiology study. METHODS Patients with complex UIAs were prospectively enrolled. Both the safety and efficacy of RVP were evaluated by recording cardiovascular events and outcomes of patients as well as the amount of aneurysm occlusion after the surgical clip reconstruction procedure. A questionnaire was used to evaluate aneurysm preparation and clip application under RVP. RESULTS Twenty patients (mean age 51.6 years, range 28-66 years) were included in this study. Electrode positioning was easy in 19 (95%) of 20 patients, and removal of electrodes was easily accomplished in all patients (100%). No complications associated with the placement of the pacing electrodes occurred, such as cardiac perforation or cardiac tamponade. RVP was applied in 16 patients. The mean aneurysm size was 11.1 ± 5.5 mm (range 6-30 mm). RVP proved to be a very helpful tool in aneurysm preparation and clip application in 15 (94%) of 16 patients. RVP was used for a mean duration of 60 ± 25 seconds, a mean heart rate of 173 ± 23 bpm (range 150-210 bpm), and a reduction of mean arterial pressure to 35-55 mm Hg. RVP leads to softening of the aneurysm sac facilitating its mobilization, clip application, and closure of the clip blades. In 2 patients, cardiac events were documented that resolved without permanent sequelae in both. In every patient with successful RVP (n = 14) a total or near-total aneurysm occlusion was documented. In the 1 patient in whom the second RVP failed due to pacemaker electrode dislocation, additional temporary clipping was required to secure the aneurysm, but was not as sufficient as RVP. This led to an incomplete clipping of the aneurysm and finally a remnant on postoperative digital subtraction angiography. A pacemaker lead dislocation occurred in 3 (19%) of 16 patients, but intraoperative repositioning requires less than 20 seconds. Outcome was favorable in all patients according to the modified Rankin Scale. CONCLUSIONS To the best of the authors' knowledge this is the first prospective interdisciplinary study of RVP use in patients with UIAs. RVP is an elegant technique that facilitates clip reconstruction in complex UIAs. The safety of the procedure is good. However, because this procedure requires extensive preoperative cardiological workup of the patient and an experienced neurosurgery and neuroanesthesiology team with much cerebrovascular expertise, actually it remains reserved for selected elective cases and highly specialized centers. Clinical trial registration no.: NCT02766972 (clinicaltrials.gov).

Blood pressure reduction in patients with irreversible pulpitis teeth treated by non-surgical root canal treatment

Background/purposeThe hypotension in patients during non-surgical root canal treatment (NSRCT) has not yet investigated. This study aimed to assess the mean systolic blood pressure (MSBP), mean diastolic blood pressure (MDBP), and mean arterial blood pressure (MABP) reduction percentages in patients with irreversible pulpitis teeth treated by NSRCT. Materials and methodsWe prospectively recruited 111 patients with a total of 138 irreversible pulpitis teeth. All patients underwent two NSRCT sessions. The first NSRCT session involved mainly the removal of vital pulp tissue with the direct stimulation of the dental branches of the trigeminal nerve, and the second NSRCT session included the root canal debridement and enlargement with minimal disturbance to the dental nerves. The blood pressure of each patient was recorded before and during both NSRCT sessions. ResultsThere were significantly higher reduction percentages of MSBP, MDBP, and MABP in the first NSRCT session than in the second NSRCT session for all treated patients (all the P-values < 0.001). If the patients were divided into 2 or more groups according to the clinical variables including the patients' gender, age, tooth type, and anesthesia type, we also found significantly higher reduction percentages of MSBP, MDBP, and MABP in the first NSRCT session than in the second NSRCT session for all treated patients except for patients below 40 years of age and for patients with lower anterior teeth treated (all the P-values < 0.05). ConclusionThe decrease in blood pressure in patients receiving vital pulpal extirpation is a relatively common phenomenon.

Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats.

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.

Simvastatin Alleviates Pathology in a Rat Model of Preeclampsia Involving ERK/MAPK Pathway.

Preeclampsia (PE) is a pregnancy-specific condition characterized by new-onset hypertension. There is evidence suggesting that imbalances of angiogenic factors, oxidative stress, and inflammation may be central to the pathogenesis of PE. We sought to investigate whether simvastatin would reduce mean arterial pressure, restore the angiogenic balance, and ameliorate inflammation and oxidative stress in a nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. We found that blood pressure was significantly increased in the l-NAME group compared to normal pregnant dams ( P < .01), and simvastatin reduced this difference. In addition, dams from the l-NAME group showed lower vascular endothelial growth factor (VEGF) and interleukin (IL) 10 levels and higher plasma-soluble FMS-like tyrosine kinase 1 (sFlt-1), tumor necrosis factor α (TNF-α), and oxidative stress marker malondialdehyde (MDA) levels as compared to control dams ( P < .01, for all). Interestingly, simvastatin treatment significantly increased VEGF and IL-10 levels while decreased sFlt-1, TNF-α, and MDA levels compared to the untreated l-NAME group. Moreover, simvastatin treatment significantly upregulated protein expression of placental p-extracellular signal-regulated kinase (ERK1), p-p38 mitogen-activated protein kinase (MAPK), p-c-Jun N-terminal kinase, and p-protein kinase B compared to untreated l-NAME control. These results suggest that simvastatin treatment restores angiogenic balance and ameliorates inflammation and oxidative stress in a rat model of PE involving ERK/MAPK pathway.