mmHg In Response Research Articles

A Prototype Wearable Device for Noninvasive Monitoring of Transcutaneous Oxygen.

Transcutaneous oxygen monitoring is a noninvasive method for measuring the partial pressure of oxygen diffusing through the skin, which strongly correlates with changes in dissolved oxygen in the arteries. Luminescent oxygen sensing is one of the techniques for assessing transcutaneous oxygen. Intensity- and lifetime-based measurements are two well-known methods used in this technique. The latter is more immune to optical path changes and reflections, making the measurements less vulnerable to motion artifacts and skin color changes. Although the lifetime-based method is promising, the acquisition of high-resolution lifetime data is crucial for accurate transcutaneous oxygen measurements from the human body when skin is not heated. We have built a compact prototype along with its custom firmware for the lifetime estimation of transcutaneous oxygen with a provision of a wearable device. Furthermore, we performed a small experiment study on three healthy human volunteers to prove the concept of measuring oxygen diffusing from the skin without heating. Lastly, the prototype successfully detected changes in lifetime values driven by the changes in transcutaneous oxygen partial pressure due to pressure-induced arterial occlusion and hypoxic gas delivery. The prototype resolved a minimum change of 1.34ns in a lifetime that corresponds to ∼0.031mmHg in response to slow changes in the oxygen pressure in the volunteer's body caused by hypoxic gas delivery. The prototype is believed to be the first in the literature to successfully conduct measurements in human subjects using the lifetime-based technique.

Abstract 098: Double Deletion Of At 1a Receptors And Na + /h + Exchanger 3 In The Proximal Tubules Attenuates Angiotensin Ii-induced And 2k1c Goldblatt Hypertension In Proximal Tubule-specific Pt- Agtr1a -/- / Nhe3 -/- Mice

We have previously shown that genetic deletion of AT 1 (AT 1a ) receptors or Na + /H + exchanger 3 (NHE3) selectively in the proximal tubules attenuated the development of angiotensin II (Ang II)-induced hypertension in mice. The present study determined whether double deletion of AT 1a receptors and NHE3 selectively in the proximal tubules further attenuates the development of Ang II-induced or 2-kidney, 1-clip (2K1C) Goldblatt Hypertension. Proximal tubule-specific AT 1a receptor and NHE3 double knockout mice, PT- Agtr1a -/- / Nhe3 -/- , were generated using the iL- Sglt2-Cre / LoxP approach. Adult male wild-type (WT), PT- Agtr1a -/- , PT- Nhe3 -/- , and PT- Agtr1a -/- / Nhe3 -/- double knockout mice were treated with vehicle (or sham as time-controls), a slow pressor dose of Ang II infusion for 2 weeks (500 μg/kg body wt./day, i.p.), or induction of 2K1C Goldblatt hypertension by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks, respectively. In WT mice, control systolic blood pressure was 118 ± 3 mmHg (n=9), which increased to ~143 ± 5 mmHg in response to Ang II infusion ( P <0.01, n=10) or to induction of 2K1C Goldblatt hypertension (n=12, P <0.01). By comparison, control systolic blood pressure was 15 ± 2 mmHg lower in age-matched PT- Agtr1a -/- mice ( P <0.01), or 13 ± 3 mmHg lower in PT- Nhe3 -/- mice than WT mice ( P <0.01). Double deletion of AT 1a receptors and NHE3 selectively in the proximal tubules further but only moderately decreased basal blood pressure to 98 ± 2 mmHg in PT- Agtr1a -/- / Nhe3 -/- double knockout mice ( P <0.05, n=10). In response to Ang II infusion, systolic blood pressure increased only to ~126 ± 3 mmHg in PT- Agtr1a -/- or PT- Nhe3 -/- mice ( P <0.01). Interestingly, 2K1C Goldblatt hypertension was markedly attenuated in PT- Agtr1a -/- (108 ± 3 mmHg, P <0.01, n=10), PT- Nhe3 -/- (110 ± 2 mmHg, P <0.01, n=10), or PT- Agtr1a -/- / Nhe3 -/- double knockout mice (103 ± 2 mmHg, P <0.01, n=8), respectively. Taken together, these data strongly support the hypothesis that the intratubular Ang II/AT 1a receptor/NHE3 signaling plays a key role in maintaining basal blood pressure homeostasis and the full development of Ang II-induced or 2K1C Goldblatt hypertension.

Induction of severe hypoxemia and low lung recruitability for the evaluation of therapeutic ventilation strategies: a translational model of combined surfactant-depletion and ventilator-induced lung injury

BackgroundModels of hypoxemic lung injury caused by lavage-induced pulmonary surfactant depletion are prone to prompt recovery of blood oxygenation following recruitment maneuvers and have limited translational validity. We hypothesized that addition of injurious ventilation following surfactant-depletion creates a model of the acute respiratory distress syndrome (ARDS) with persistently low recruitability and higher levels of titrated “best” positive end-expiratory pressure (PEEP) during protective ventilation.MethodsTwo types of porcine lung injury were induced by lung lavage and 3 h of either protective or injurious ventilation, followed by 3 h of protective ventilation (N = 6 per group). Recruitment maneuvers (RM) and decremental PEEP trials comparing oxygenation versus dynamic compliance were performed after lavage and at 3 h intervals of ventilation. Pulmonary gas exchange function, respiratory mechanics, and ventilator-derived parameters were assessed after each RM to map the course of injury severity and recruitability.ResultsLung lavage impaired respiratory system compliance (Crs) and produced arterial oxygen tensions (PaO2) of 84±13 and 80±15 (FIO2 = 1.0) with prompt increase after RM to 270–395 mmHg in both groups. After subsequent 3 h of either protective or injurious ventilation, PaO2/FIO2 was 104±26 vs. 154±123 and increased to 369±132 vs. 167±87 mmHg in response to RM, respectively. After additional 3 h of protective ventilation, PaO2/FIO2 was 120±15 vs. 128±37 and increased to 470±68 vs. 185±129 mmHg in response to RM, respectively. Subsequently, decremental PEEP titration revealed that Crs peaked at 36 ± 10 vs. 25 ± 5 ml/cm H2O with PEEP of 12 vs. 16 cmH2O, and PaO2/FIO2 peaked at 563 ± 83 vs. 334 ± 148 mm Hg with PEEP of 16 vs. 22 cmH2O in the protective vs. injurious ventilation groups, respectively. The large disparity of recruitability between groups was not reflected in the Crs nor the magnitude of mechanical power present after injurious ventilation, once protective ventilation was resumed.ConclusionAddition of transitory injurious ventilation after lung lavage causes prolonged acute lung injury with diffuse alveolar damage and low recruitability yielding high titrated PEEP levels. Mimicking lung mechanical and functional characteristics of ARDS, this porcine model rectifies the constraints of single-hit lavage models and may enhance the translation of experimental research on mechanical ventilation strategies.

Toward rebalancing blood pressure instability after spinal cord injury with spinal cord electrical stimulation: A mini review and critique of the evolving literature.

High-level spinal cord injury commonly leads to blood pressure instability. This manifests clinically as orthostatic hypotension (OH), where blood pressure can drop to the point of loss of consciousness, and autonomic dysreflexia (AD), where systolic blood pressure can climb to over 300 mmHg in response to an unperceived noxious stimulus. These blood pressure fluctuations can occur multiple times a day, contributing to increased vessel shear stress and heightened risk of cardiovascular disease. The pathophysiology of both of these conditions is rooted in impairments in regulation of spinal cord sympathetic preganglionic neurons, which control blood pressure by mediating vascular resistance and catecholamine release. Recently, spinal cord electrical stimulation has provided evidence that it may modulate these blood pressure imbalances. Early proposed mechanisms suggest activation of spinal cord dorsal horn neurons that ultimately act upon the sympathetic preganglionic neuronal pathways. For OH, spinal cord stimulation likely induces local activation of these neurons to generate baseline sympathetic tone and accompanying vasoconstriction. The mechanisms for spinal stimulation regulating AD are less clear, though some suggest it activates inhibitory circuits to dampen the overactive sympathetic response. While questions remain, spinal cord electrical stimulation is an intriguing new modality that may restore blood pressure regulation following spinal cord injury.

Individual changes of central blood pressure in response to upright posture: different hemodynamic phenotypes.

Most studies about upright regulation of blood pressure have focused on orthostatic hypotension despite the diverse hemodynamic changes induced by orthostatic challenge. We investigated the effect of passive head-up tilt on aortic blood pressure. Noninvasive peripheral and central hemodynamics in 613 volunteers without cardiovascular morbidities or medications were examined using pulse wave analysis, whole-body impedance cardiography and heart rate variability analysis. In all participants, mean aortic SBP decreased by -4 (-5 to -3) mmHg [mean (95% confidence intervals)] and DBP increased by 6 (5--6) mmHg in response to upright posture. When divided into tertiles according to the supine-to-upright change in aortic SBP, two tertiles presented with a decrease [-15 (-14 to -16) and -4 (-3 to -4) mmHg, respectively] whereas one tertile presented with an increase [+7 (7-- 8) mmHg] in aortic SBP. There were no major differences in demographic characteristics between the tertiles. In regression analysis, the strongest explanatory factors for upright changes in aortic SBP were the supine values of, and upright changes in systemic vascular resistance and cardiac output, and supine aortic SBP. In participants without cardiovascular disease, the changes in central SBP during orthostatic challenge are not uniform. One-third presented with higher upright than supine aortic SBP with underlying differences in the regulation of systemic vascular resistance and cardiac output. These findings emphasize that resting blood pressure measurements give only limited information about the blood pressure status.

Unexpected hypotension in catecholamine reversal: a case report

BackgroundCatecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to catecholamine agents.Case presentationA 29-year-old Japanese man with schizophrenia was transferred to our emergency department. He was in shock and in coma. After fluid resuscitation, we induced catecholamine agents; however, his blood pressure decreased to 59/40 mmHg in response to catecholamine infusion. On the other hand, after we started vasopressin, his blood pressure markedly improved, and he finally became stable. On day 2, he admitted to ingesting a large amount of risperidone, and we diagnosed risperidone overdose. We believe that this unexpected hypotension in response to catecholamine infusion was caused by an α-adrenergic blockade effect of risperidone. Animal experiments proved that the simultaneous administration of adrenaline with an α-adrenergic blockade provoked a fall in blood pressure; this phenomenon is called “adrenaline reversal.” In our case, catecholamine infusion under the α-adrenergic blockade effect of risperidone might have caused a fall in blood pressure in the same mechanism; we call this phenomenon “catecholamine reversal.” In such a situation, because the mechanism of vasopressin is different from that of catecholamine, we recommend vasopressin for maintaining the blood pressure.ConclusionsWe described the first clinical case of “catecholamine reversal” and highlighted that if unexpected hypotension occurs in response to catecholamine infusion, we should suspect the use of α-adrenergic antagonists. In such situations, we should consider the administration of vasopressin instead.

Modified criteria for carotid sinus hypersensitivity are associated with increased mortality in a population-based study.

Carotid sinus hypersensitivity (CSH) is arbitrarily defined as ≥3 s asystole or vasodepression of ≥50 mmHg in response to carotid sinus massage (CSM). Using this definition, 39% of older people meet the criteria for CSH. It has been suggested that current criteria are too sensitive. Krediet et al. [The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace 2011;13:14-22] and Kerr et al. [Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls. Arch Intern Med 2006;166:515-20] have proposed modified criteria. This population-based study aimed to compare the prevalence of CSH defined according to standard, Krediet and Kerr criteria, and to establish if CSH defined according these criteria is associated with all-cause mortality. A total of 272 community-dwelling people aged ≥65 were recruited at random. Carotid sinus massage was performed for 5 s in supine and head-up positions. Heart rate and blood pressure response were recorded using an electrocardiogram and photoplethysmography. Cox regression analysis was used to examine the association between each definition of CSH and all-cause mortality. The prevalence of CSH defined according to standard, Krediet, and Kerr criteria was 39, 52, and 10%, respectively. Seventy-one participants died over a mean follow-up of 8.6 years (SD 2.1). Carotid sinus hypersensitivity defined according to standard and Krediet criteria was not associated with survival. Carotid sinus hypersensitivity defined according to Kerr criteria was associated with all-cause mortality independent of age and sex [hazard ratio (HR) 2.023 (95% confidence interval (95% CI) 1.131-3.618) P = 0.018)]. This remained significant after adjusting for cardiovascular risk factors [HR 2.174 (1.075-3.900) P = 0.009]. Carotid sinus hypersensitivity defined according to Kerr criteria is associated with increased mortality. This raises an interesting question as to the suitability of the current criteria used to define CSH.

Abstract 16248: Comparison of a Non-Invasive Respiratory Volume Monitor to End-Tidal CO2 in Measuring Changes in Minute Ventilation

Introduction: Monitoring respiratory performance is a challenge. Use of secondary indicators like oxygen saturation (SpO 2 ) and capnography (EtCO 2 ) have introduced delay in diagnosis and can produce false alarms. EtCO 2 in non-intubated patients has been problematic. We compared performance of an EtCO 2 monitor to a respiratory volume monitor (RVM), which provides accurate (error <10%) measurements of minute ventilation (MV), tidal volume & respiratory rate, to assess changes in respiratory status in non-intubated subjects. Methods: Continuous RVM (ExSpiron, Respiratory Motion, Waltham, MA) and capnography data (Capnostream 20, SmartCapnoLine Plus & Filterline Set, Covidien, Mansfield, MA) were collected from 39 subjects. The relationship between EtCO 2 & MV for each patient was quantified & EtCO 2 sensitivity to MV changes and mean EtCO 2 values were compared across the two EtCO 2 sampling techniques (paired t-test). Results: A strong negative correlation between MV changes and EtCO 2 changes was found (similar between nasal sampling (NS) and in-line sampling (IS) ( -0.6 ±0.1 v -0.7±0.1 mmHg/(L/min), p>0.1, Fig 1A)). IS readings were higher than NS for each patient. In the same patients (normal breathing) the average IS EtCO 2 was 36.7 ±0.7 vs 33.7±0.6 mmHg for NS (p<0.01) despite larger MV (8.74 ±0.5 vs 7.0±0.5 L/min). Similar disparity was present during hypo & hyperventilation (Fig 1B&C). Regardless of sampling methodology, EtCO 2 displayed poor resolution in response to large swings in MV (13 & 14 mmHg in response to 17 & 21 fold increase in MV; IS & NS, respectively). Conclusions: Under controlled experimental conditions & with an in-line sensor capable of capturing 100% of exhaled air, EtCO 2 did not report large swings in MV with fidelity. Commonly used nasal sampling introduced a systematic bias that could further delay informing clinicians of dangerously low MV. RVM provides a direct measure of MV, eliminating the lag between a change in MV and secondary measurements.

Abstract 255: Lymphocyte-Specific Adaptor Protein, LNK (SH2B3), Regulates Angiotensin-II Induced Hypertension and Renal/Vascular Inflammation

LNK, an adaptor protein primarily expressed in hematopoietic cells and endothelial cells, is a negative regulator of cytokine signaling and cell proliferation. A single nucleotide polymorphism in LNK is associated with hypertension, but the mechanism is unknown. Our objective was to determine the effect of LNK on hypertension and inflammation using LNK -/- mice. In response to angiotensin II (Ang II) infusion, LNK -/- mice exhibit elevated systolic BP (SBP) compared to wild type C57Bl/6J mice (WT) as measured by telemetry. At baseline, kidneys from LNK -/- mice exhibit greater levels of total leukocyte and T lymphocyte infiltration, superoxide production, and albuminuria compared to WT mice, and these parameters are further exacerbated by AngII infusion. Aortas from LNK -/- mice exhibit enhanced inflammation, reduced nitric oxide production, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies showed that loss of LNK in hematopoietic cells (not somatic cells) reproduced the phenotype of whole body deletion of LNK with SBP reaching 180 mmHg in response to a subpressor dose of Ang II. Splenic T cells from LNK -/- mice produce elevated levels of interferon-gamma (IFNγ) compared to WT mice. Furthermore, IFNγ -/- mice exhibit blunted hypertension in response to AngII infusion, suggesting that enhanced IFNγ production is at least partly responsible for the aggravated hypertension in LNK -/- mice. Data are summarized in the table (expressed as mean±SEM, n=5-10,* P <0.05 vs WT/Sham, # P <0.05 vs WT/AngII and † P <0.05 vs LNK -/- /Sham). In conclusion, LNK may serve as a novel therapeutic target for hypertension and its associated renovascular disorders.

SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction.

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean±sd of 106±7 mmHg in response to SuHx and decreased but remained elevated at 72±8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction.

Hepatic venous pressure gradient: clinical use in chronic liver disease.

Portal hypertension is a severe consequence of chronic liver diseases and is responsible for the main clinical complications of liver cirrhosis. Hepatic venous pressure gradient (HVPG) measurement is the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >10 mmHg. In this condition, the complications of portal hypertension might begin to appear. HVPG measurement is increasingly used in the clinical fields, and the HVPG is a robust surrogate marker in many clinical applications such as diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who had a reduction in HVPG of ≥20% or to ≤12 mmHg in response to drug therapy are defined as responders. Responders have a markedly decreased risk of bleeding/rebleeding, ascites, and spontaneous bacterial peritonitis, which results in improved survival. This review provides clinical use of HVPG measurement in the field of liver disease.

Comparison of Desflurane and Sevoflurane Anaesthesia in Relation to the Risk of Vagally Mediated Reflex Bradycardia during Gastrectomy

This study compared the risk of clinically significant reflex bradycardia during anaesthesia with sevoflurane or desflurane in patients undergoing gastrectomy. In this randomized prospective study, 100 patients undergoing gastrectomy were assigned to receive sevoflurane (n=50) or desflurane (n=50) anaesthesia. No anticholinergic prophylaxis was administered. Symptomatic reflex bradycardia was defined as a sudden decrease in heart rate to <50 beats/min, or a decrease to 50-59 beats/min if associated with a systolic arterial pressure of 70 mmHg in response to surgical manoeuvres. If reflex bradycardia developed, atropine or ephedrine were administered according to a predefined treatment protocol. Data from 85 patients were available for analysis. The proportion of patients with symptomatic reflex bradycardia in the sevoflurane and desflurane groups was similar (69.0% versus 55.8%, respectively) and both groups required a similar amount of atropine and/or ephedrine. Clinically significant reflex bradycardia occurred with a relatively high frequency during gastrectomy. Although desflurane is associated with sympathetic activation, it did not provide a protective effect against vagally mediated reflex bradycardia during gastrectomy compared with sevoflurane.

Wound Literature Review 2010

Wound Literature Review 2010

Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice

Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or N(G)-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 +/- 3 vs. 115 +/- 2 vs. 116 +/- 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 +/- 0.5 (n = 6) vs. 4.8 +/- 0.6 (n = 10) vs. 5.8 +/- 0.7 (n = 6) ml*min(-1)*g(-1) kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.

The clinical use of HVPG measurements in chronic liver disease

Portal hypertension is a severe, almost unavoidable complication of chronic liver diseases and is responsible for the main clinical consequences of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is currently the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >or=10 mmHg; above this threshold, the complications of portal hypertension might begin to appear. Measurement of HVPG is increasingly used in clinical hepatology, and numerous studies have demonstrated that the parameter is a robust surrogate marker for hard clinical end points. The main clinical applications for HVPG include diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who experience a reduction in HVPG of >or=20% or to <12 mmHg in response to drug therapy are defined as 'responders'. Responders have a markedly decreased risk of bleeding (or rebleeding), ascites, and spontaneous bacterial peritonitis, which results in improved survival.

Duration of the haemodynamic action of a 24‐h infusion of levosimendan in patients with congestive heart failure

To determine the duration of haemodynamic and neurohormonal action of a 24-h infusion of levosimendan in heart failure. This was a double-blind, parallel group study in patients with New York Heart Association class II to IV heart failure. Twenty-two patients, with left ventricular ejection fraction <35% and pulmonary capillary wedge pressure (PCWP) above 12 mmHg, were randomised to receive either levosimendan (12 microg/kg followed by a continuous infusion of 0.1-0.2 microg/min) or placebo. Invasively measured cardiac output (CO) increased from 4.3 l/min to 5.4 l/min in the levosimendan group at 6 h. PCWP decreased from 20 mmHg to 15 mmHg in response to levosimendan. Echocardiographically measured maximal effect on PCWP occurred after 6 h, whereas CO reached its highest value at 24 h. The estimated duration of the decrease in PCWP was 7-9 days, and in CO was 12-13 days. Plasma NT-proANP and NT-proBNP levels reached their lowest values at days 3 and 2, and the treatment effect was estimated to last 16 and 12 days, respectively. The long-acting haemodynamic responses reflect levels of the active metabolites OR-1896 and OR-1855, maximal metabolite levels occurred at day 3. Levosimendan infusion achieved a rapid improvement in haemodynamic parameters in patients with congestive heart failure with maximal effects occurring 1-3 days after starting the infusion, effects were sustained for up to at least a week.

Role of nitric oxide in modulating systemic pressor responses to different vasoconstrictors in man

Animal studies suggest that nitric oxide (NO) attenuates responses to endogenous vasoconstrictors. We investigated whether this also holds true in man by monitoring pressor responses to different vasoconstrictors during nitric oxide synthase (NOS) inhibition. Systemic hemodynamic responses to intravenous infusions of three doses (each for 5 min) of angiotensin II (AngII) (2, 4 and 8 ng/kg per min), noradrenaline (NOR) (10, 30 and 70 ng/kg per min) and phenylephrine (PE) (0.5, 1.0 and 1.5 microg/kg per min) were monitored in 44 healthy subjects during saline. A second dose-response curve was obtained during NOS inhibition with a subpressor dose of N- nitro-L-arginine-methyl ester (L-NAME) (5 microg/kg per min) or during a systemic NO clamp using combined systemic infusions of L-NAME (12.5 microg/kg per min) and nitroprusside. Blood pressure was measured in the brachial artery and other hemodynamic parameters were derived from this signal. Mean arterial pressure (MAP) increased 2 +/- 2, 6 +/- 1 and 16 +/- 2 mmHg in response to AngII during saline, 7 +/- 6, 15 +/- 5 and 26 +/- 6 mmHg during the subpressor dose of L-NAME (P < 0.05) and 11 +/- 10, 18 +/- 7 and 25 +/- 6 mmHg during the systemic NO clamp (P < 0.001). These augmented responses of MAP were due to enhanced increments in systemic vascular resistance. Infusions of NOR and PE during saline resulted in dose-dependent increments in MAP and systemic vascular resistance. These increments were of comparable magnitude as those seen during AngII, but were not affected by NOS inhibition. Our findings show that the systemic pressor response evoked by AngII, but not by NOR or PE, is enhanced during NOS inhibition, suggesting that AngII is associated with increased NO release that counteracts its blood pressure rising effect.

Visceral pain and public speaking stress: Neuroendocrine and immune cell responses in healthy subjects

Whereas responses to psychological stressors are well-characterized, little is known regarding responses to painful visceral stimuli. We analyzed the emotional, cardiovascular, neuroendocrine, and cellular immune responses to painful rectal stimulation and psychological stress in healthy individuals. Eleven healthy subjects were studied in three conditions on separate days: painful rectal distension, public speaking stress, and rest. Blood was drawn for endocrinological and immunological analyses; heart rate and blood pressure were measured continuously; state anxiety was assessed with a questionnaire (STAI-S). Anxiety scores were highest in the rectal distension condition. This was evident following rectal distension (mean STAI-S scores: 44.2 ± 3.5 post-distension vs. 36.6 ± 3.8 post-speech, p < .05), but anxiety was also elevated at baseline (41.6 ± 3.9 vs. 32 ± 3.2 recovery, p < .01). This anticipatory effect was reflected by elevated baseline cortisol ( p < .05) and baseline ACTH ( p < .01) levels, as well as circulating lymphocytes and lymphocyte subsets, including decreased basal CD3 +CD4 + cells ( p < .05) and increased CD16 +CD56 + cells ( p = .06) compared to rest. Both public speech and rectal distension induced cardiovascular activation, but the effect was more pronounced following rectal distension (+63.8 ± 9.4 mmHg in response to distension vs. +36.4 ± 6.2 mmHg in response to speech for systolic BP, p < .05). Different response patterns were also observed in the distribution of circulating leukocytes and lymphocyte subsets, including CD16 +CD56 + cells ( p < .05). An acute visceral pain stimulus causes profound emotional, neuroendocrine, and immune cell responses, which are markedly affected by anticipatory anxiety. These findings may have implications for conditions associated with visceral hyperalgesia.

Small-volume resuscitation with the hemoglobin substitute HBOC-201: effect on brain tissue oxygenation.

To investigate the effects of small-volume resuscitation with a hemoglobin based oxygen carrier on brain tissue oxygen tension (PbrO2) in hemorrhaged swine. Clark-type electrodes were inserted into the brain tissue of 6 swine to measure PbrO2 directly. Swine were hemorrhaged to a MAP of 40 mm Hg for 20 minutes. Resuscitation was performed with a bolus infusion of HBOC-201 (6 cc/kg; Biopure Corp.) and high-flow oxygen (100%). Swine were observed for an additional 2 hours. PbrO2 prior to hemorrhage was 48.7 +/- 4.7 mm Hg with 100% inspired oxygen. PbrO2 rapidly declined to 7.6 +/- 5.3 mm Hg in response to hemorrhage. Small-volume resuscitation with HBOC-201 and high-flow oxygen resulted in a significant increase (p < 0.001) in PbrO2 to 44.6 +/- 8.1 mm Hg. MAP was also significantly increased to 84% of baseline. These elevations were sustained during the observation period. Resuscitation with HBOC-201 can restore and sustain cerebral oxygenation and MAP. These results suggest that a small-volume bolus of HBOC-201 may provide adequate oxygen and pressure support during the initial management of hemorrhage.

Postural hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension.

To determine the relative importance of the cardiac and vascular sympathetic components of the orthostatic response to 90 degrees head-up tilt after N-type calcium-channel blockade in normotensive (sham renal cellophane wrap) and hypertensive (renal wrap) conscious rabbits. The effects of N-type calcium-channel blockade with omega-conotoxin GVIA (omega-CTX, 10 microg/kg i.v. bolus) were assessed in the absence or presence of cardiac block by propranolol and methscopolamine. These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus). In vehicle (0.9% saline) treatment groups, the response to tilt consisted of a small pressor effect (4 +/- 2 and 7 +/- 1 mmHg) and tachycardia (29 +/- 6 and 17 +/- 6 beats/min) in sham (n = 6) and wrap (n = 5) rabbits, respectively. After prazosin administration (with cardiac block), there were significant falls in MAP of 3 +/- 1 and 7 +/- 2 mmHg in sham (n = 7) and wrap (n = 6) rabbits, respectively, in response to tilt omega-CTX caused postural hypotensive responses of 8 +/- 2 and 13 +/- 2 mmHg in sham (n = 6) and wrap (n = 7) rabbits, respectively, and 7 +/- 1 and 14 +/- 2 mmHg in sham (n = 7) and wrap (n = 7) rabbits with prior cardiac block. Similarly, mecamylamine caused falls in MAP of 8 +/- 1 and 10 +/- 2 mmHg in response to tilt in sham (n = 6) and wrap (n = 9) animals, respectively. Sympathetic vasoconstrictor effectors are primarily responsible for maintaining blood pressure during tilt in conscious rabbits. The postural hypotension caused by sympatholytic agents is about double in hypertensive rabbits, and N-type calcium-channel blockade is as effective as ganglion blockade at inducing this syndrome.