Changes In Vasomotor Tone Research Articles

Anesthesia Blunts Carbon Dioxide Effects on Glymphatic Cerebrospinal Fluid Dynamics in Mechanically Ventilated Rats.

Impaired glymphatic clearance of cerebral metabolic products and fluids contribute to traumatic and ischemic brain edema and neurodegeneration in preclinical models. Glymphatic perivascular cerebrospinal fluid flow varies between anesthetics possibly due to changes in vasomotor tone and thereby in the dynamics of the periarterial cerebrospinal fluid (CSF)-containing space. To better understand the influence of anesthetics and carbon dioxide levels on CSF dynamics, this study examined the effect of periarterial size modulation on CSF distribution by changing blood carbon dioxide levels and anesthetic regimens with opposing vasomotor influences: vasoconstrictive ketamine-dexmedetomidine (K/DEX) and vasodilatory isoflurane. End-tidal carbon dioxide (ETco2) was modulated with either supplemental inhaled carbon dioxide to reach hypercapnia (Etco2, 80 mmHg) or hyperventilation (Etco2, 20 mmHg) in tracheostomized and anesthetized female rats. Distribution of intracisternally infused radiolabeled CSF tracer 111In-diethylamine pentaacetate was assessed for 86 min in (1) normoventilated (Etco2, 40 mmHg) K/DEX; (2) normoventilated isoflurane; (3) hypercapnic K/DEX; and (4) hyperventilated isoflurane groups using dynamic whole-body single-photon emission tomography. CSF volume changes were assessed with magnetic resonance imaging. Under normoventilation, cortical CSF tracer perfusion, perivascular space size around middle cerebral arteries, and intracranial CSF volume were higher under K/DEX compared with isoflurane (cortical maximum percentage of injected dose ratio, 2.33 [95% CI, 1.35 to 4.04]; perivascular size ratio 2.20 [95% CI, 1.09 to 4.45]; and intracranial CSF volume ratio, 1.90 [95% CI, 1.33 to 2.71]). Under isoflurane, tracer was directed to systemic circulation. Under K/DEX, the intracranial tracer distribution and CSF volume were uninfluenced by hypercapnia compared with normoventilation. Intracranial CSF tracer distribution was unaffected by hyperventilation under isoflurane despite a 28% increase in CSF volume around middle cerebral arteries. K/DEX and isoflurane overrode carbon dioxide as a regulator of CSF flow. K/DEX could be used to preserve CSF space and dynamics in hypercapnia, whereas hyperventilation was insufficient to increase cerebral CSF perfusion under isoflurane.

Continuous Blood Pressure Monitoring Using Nonpulsatile Photoplethysmographic Components for Low-Frequency Vascular Unloading

<italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Objective</i> : Continuous blood pressure (BP) monitoring gives a better understanding of a person’s cardiovascular health status than single BP measurements. The existing measurement techniques are often highly complex and expensive, or suffer from inaccuracies. We propose a simple yet effective technique for continuous blood pressure monitoring. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Methods</i> : Our method is based on the finding that the non-pulsatile (DC) component of the photoplethysmograph (PPG) correlates with blood pressure. By keeping the infrared PPG DC component constant by altering the applied external pressure using a feedback mechanism the BP can be measured continuously. This way the pressure read from the pressure sensor follows the mean intra-arterial BP. We call this low-frequency vascular unloading. We propose a method for assessing the measurement error introduced by changes in vasomotor tone. Green PPG was used for the vasomotor compensation method. We packaged the technology to a wearable finger-worn device similar to a pulse oximeter probe. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Results</i> : We measured over 90 minutes of continuous BP data from total of 7 subjects. The subjects were asked to perform different BP altering maneuvers during the measurement. The ability to track BP changes was verified by continuous mean arterial pressure (MAP) readings measured with the reference device (CNSystems CNAP 500) and our device, resulting in correlation of <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">r</i> = 0.894 and (( <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">mean</i> ± <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">SD</i> ) mmHg) of (0.3±4.3) mmHg for mean arterial pressure. Without vasomotor tone compensation the results were with slightly less accurate: <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">r</i> = 0.83, (-1.4±5.1) mmHg. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Conclusion</i> : The proposed technology performed well compared to traditional vascular unloading technique while requiring significantly less complex control logic and no fast-switching pneumatics. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Significance</i> : The proposed technique is simple, yet effective, low-cost solution and it can be constructed from off-the-shelf components and miniaturized into a wearable form factor. The technique has potential in the field of health wearables and remote continuous BP monitoring for personalized health applications.

Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat.

Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. We measured the acetaminophen dose-response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with L-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone CONCLUSIONS: In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.

Tako-Tsubo syndrome, spontaneous coronary dissection and microvascular disease: Sex-differences.

Up to 50% of the patients undergoing coronary angiography present no epicardial disease. Most of these patients are women. Takotsubo cardiomyopathy, coronary microvascular dysfunction, and spontaneous coronary artery dissection are the most common syndromes that affect these patients. Their mechanisms are complex, with a interplay between neurohormonal factors and a number of other systems. The present review describes how changes in the estrogen state may lead to changes in vasomotor tone and endothelial dysfunction which result in coronary epicardial and microvascular spasm and coronary arterial wall instability in these three conditions. The sex-dependent differences in prevalence, pathogenesis, and prognosis are described.

Toward Closed-Loop Transcutaneous Vagus Nerve Stimulation using Peripheral Cardiovascular Physiological Biomarkers: A Proof-of-Concept Study.

Transcutaneous vagus nerve stimulation (t-VNS) is a promising technology for modulating brain function and possibly treating disorders of the central nervous system. While handheld devices are available for t-VNS, stimulation efficacy can only be quantified using expensive imaging or blood biomarker analyses. Additionally, the parameters and "dosage" recommendations for t-VNS are typically fixed, as there are limited biomarkers that can assess downstream effects of the stimulation outside of clinical settings. In this proof-of-concept study, we evaluated non-invasive peripheral cardiovascular measurements as physiological biomarkers of t-VNS efficacy. Specifically, we hypothesized two physiological biomarkers: (1) the pre-ejection period (PEP) of the heart - a parameter closely linked to sympathetic tone - and (2) the amplitude of peripheral photoplethysmogram (PPG) waveforms - representing changes in vasomotor tone and thus parasympathetic / sympathetic activation. A total of six healthy human subjects participated in the multi-day study, half each undergoing active or sham t-VNS stimulus. The three subjects receiving t-VNS had no decrease in PEP and an increase in PPG amplitude following t-VNS, while the subjects receiving sham stimulus had a decrease in PEP and no change in PPG amplitude. When combined with mental stress (a traumatic script being read back to the subjects), the group with t-VNS had no decrease in PEP and only a slight decrease in PPG amplitude following stimulus, while the group receiving sham stimulus had a decrease in PEP and also a slight decrease in PPG amplitude. These studies suggest that PEP and PPG amplitude measures may provide non-invasive physiological biomarkers of t-VNS efficacy, including in the presence of mental stress.

Transient Receptor Potential Vanilloid 1 Antagonists Prevent Anesthesia-induced Hypothermia and Decrease Postincisional Opioid Dose Requirements in Rodents.

Intraoperative hypothermia and postoperative pain control are two important clinical challenges in anesthesiology. Transient receptor potential vanilloid 1 has been implicated both in thermoregulation and pain. Transient receptor potential vanilloid 1 antagonists were not advanced as analgesics in humans in part due to a side effect of hyperthermia. This study tested the hypothesis that a single, preincision injection of a transient receptor potential vanilloid 1 antagonist could prevent anesthesia-induced hypothermia and decrease the opioid requirement for postsurgical hypersensitivity. General anesthesia was induced in rats and mice with either isoflurane or ketamine, and animals were treated with transient receptor potential vanilloid 1 antagonists (AMG 517 or ABT-102). The core body temperature and oxygen consumption were monitored during anesthesia and the postanesthesia period. The effect of preincision AMG 517 on morphine-induced reversal of postincision hyperalgesia was evaluated in rats. AMG 517 and ABT-102 dose-dependently prevented general anesthesia-induced hypothermia (mean ± SD; from 1.5° ± 0.1°C to 0.1° ± 0.1°C decrease; P < 0.001) without causing hyperthermia in the postanesthesia phase. Isoflurane-induced hypothermia was prevented by AMG 517 in wild-type but not in transient receptor potential vanilloid 1 knockout mice (n = 7 to 11 per group). The prevention of anesthesia-induced hypothermia by AMG 517 involved activation of brown fat thermogenesis with a possible contribution from changes in vasomotor tone. A single preincision dose of AMG 517 decreased the morphine dose requirement for the reduction of postincision thermal (12.6 ± 3.0 vs. 15.6 ± 1.0 s) and mechanical (6.8 ± 3.0 vs. 9.5 ± 3.0 g) withdrawal latencies. These studies demonstrate that transient receptor potential vanilloid 1 antagonists prevent anesthesia-induced hypothermia and decrease opioid dose requirements for the reduction of postincisional hypersensitivity in rodents.

Activation of autonomic thermoeffectors preceding the decision to behaviourally thermoregulate in resting humans.

What is the central question of this study? Do increases in metabolic heat production and sweat rate precede the initiation of thermoregulatory behaviour in resting humans exposed to cool and warm environments? What is the main finding and its importance? Thermoregulatory behaviour at rest in cool and warm environments is preceded by changes in vasomotor tone in glabrous and non-glabrous skin, but not by acute increases in metabolic heat production or sweat rate. These findings suggest that sweating and shivering are not obligatory for thermal behaviour to be initiated in humans. We tested the hypothesis that acute increases in metabolic heat production and sweating precede the initiation of thermoregulatory behaviour in resting humans exposed to cool and warm environments. Twelve healthy young subjects passively moved between 17 and 40°C rooms when they felt 'too cool' (C→W) or 'too warm' (W→C). Skin and internal (intestinal) temperatures, metabolic heat production, local sweat rate (forearm and chest) and cutaneous vascular conductance (CVC; forearm and fingertip) were measured continually. Compared with pretest baseline (31.8±0.3°C), skin temperature was higher at C→W (32.0±0.7°C; P=0.01) and W→C (34.5±0.5°C; P<0.01). Internal temperature did not differ (P=0.12) between baseline (37.2±0.3°C), C→W (37.2±0.3°C) and W→C (37.0±0.3°C). Metabolic heat production was not different from baseline (40±9Wm-2 ) at C→W (39±7Wm-2 ; P=0.50). Forearm (0.06±0.01mgcm-2 min-1 ) and chest (0.04±0.02mgcm-2 min-1 ) sweat rate at W→C did not differ from baseline (forearm, 0.05±0.02mgcm-2 min-1 and chest, 0.04±0.02mgcm-2 min-1 ; P≥0.23). Forearm CVC was not different from baseline (0.30±0.21perfusion units (PU)mmHg-1 ) at C→W (0.24±0.11 PUmmHg-1 ; P=0.17), but was higher at W→C (0.65±0.33PUmmHg-1 ; P<0.01). Fingertip CVC was different from baseline (2.6±2.0PUmmHg-1 ) at C→W (0.70±0.42PUmmHg-1 ; P<0.01) and W→C (4.49±1.66PUmmHg-1 ; P<0.01). Thermoregulatory behaviour at rest in cool and warm environments is preceded by changes in vasomotor tone in glabrous and non-glabrous skin, but not by acute increases in metabolic heat production or sweat rate.

Ability of esCCO to track changes in cardiac output

We investigated whether cardiac output measured with pulse wave transit time (esCCO, Nihon Kohden, Tokyo, Japan) is able to track changes in cardiac output induced by an increase in preload (volume expansion/passive leg-raising) or by changes in vasomotor tone (variation in norepinephrine dosage) in critically ill patients. Eighty patients for whom the decision to give fluid (500 mL of saline over 15 min) (n=20), to perform passive leg-raising (n=20), and to increase (n=20) or to decrease (n=20) norepinephrine were included by the physician. Cardiac output was measured with pulse wave transit time (CO-esCCO) and transthoracic echocardiography (CO-TTE) before and after therapeutic intervention. Comparison between CO-TTE and CO-esCCO showed a bias of -0.7 l min(-1) and limits of agreement of -4.4 to 2.9 l min(-1), before therapeutic intervention and a bias of -0.5 l min(-1) and limits of agreement of -4.2 to 3.2 l min(-1) after therapeutic intervention. Bias was correlated with systemic vascular resistance (r(2)=0.60, P<0.0001). Percentage error was 61% before and 59% after therapeutic intervention. Considering the overall data (n=80), the concordance rate was 84%, polar plot analysis revealed an angular bias (sd) of -11°(35°) and radial limits of agreement of (sd 50°). With regard to passive leg-raising and volume expansion groups (n=40), the concordance rate was 83%, the angular bias (sd) was -20°(36°) and radial limits of agreement ( 50°). Considering variations in norepinephrine dosage groups (n=40), the concordance rate was 86%, the angular bias (sd) was -1.8°(33°) and radial limits of agreement (40°). esCCO was not able to track changes in cardiac output, induced by an increase in preload or by variations in vasomotor tone. Therefore, esCCO cannot guide haemodynamic interventions in critically ill patients.

Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation.

Histological specimen and textbook schematics evoke static pictures of vascular networks. However, the concept of a static system is grossly misleading as vessels and their arrangement into networks exhibit a high degree of adaptation in vessel tone and vessel wall structure.1–3 These adaptive responses include the fast adjustment of vessel diameter by changes in smooth muscle tone, the slower changes of structural vessel diameter, the addition or removal of vessels by angiogenesis (sprouting/splitting), or vascular pruning ( Figure 1 ). It is relevant to distinguish physiological adaptation, maintaining an adequate state of perfusion as well as perfusion reserve, from mal-adaptation, which may occur in the context of pathological conditions, such as a persistent increase in blood pressure. There are also differences between regulatory mechanisms in larger vessels (e.g. remodelling at the site of epicardial stenosis) and those in the microcirculation. Even within the microcirculation vascular control mechanisms are highly dependent on vessel size and type and the extent of changes in vasomotor tone and structure seem to increase with decreasing vessel size.4,5 Adaptive processes in the microcirculation are increasingly emerging as being crucial for maintenance of physiological function and for the development of relevant pathological conditions. This part of the coronary circulation, exhibiting that functional and structural plasticity requires more attention in both basic and clinical science as the basis to develop improved diagnostic and therapeutic approaches. Consequently, the present review will focus on adaptive events occurring in the coronary microcirculation which is beyond the domain of catheter investigation and intravascular imaging. Figure 1 Dynamics of vascular adaptation at various time scale (angioadaptation).57 While tone provides a rapid mechanism to adjust perfusion …

Thermoregulatory vasomotor tone of the rat tail and paws in thermoneutral conditions and its impact on a behavioral model of acute pain.

The tail and paws in rodents are heat exchangers involved in the maintenance of core body temperature (T(core)). They are also the most widely used target organs to study acute or chronic "models" of pain. We describe the fluctuations of vasomotor tone in the tail and paws in conditions of thermal neutrality and the constraints of these physiological processes on the responses to thermal nociceptive stimuli, commonly used as an index of pain. Skin temperatures were recorded with a calibrated thermal camera to monitor changes of vasomotor tone in the tail and paws of awake and anesthetized rats. In thermoneutral conditions, the sympathetic tone fluctuated at a rate of two to seven cycles/h. Increased mean arterial blood pressure (MAP; ∼46 mmHg) was followed by increased heart rate (HR; ∼45 beats/min) within 30 s, vasoconstriction of extremities (3.5-7°C range) within 3-5 min, and increased T(core) (∼0.7°C) within 6 min. Decreased MAP was followed by opposite events. There was a high correlation between HR and T(core) recorded 5-6 min later. The reaction time of the animal's response to a radiant thermal stimulus-heat ramp (6°C/s, 20 mm(2) spot) generated by a CO2 laser-directed to the tail depends on these variations. Consequently, the fluctuations in tail and paw temperature thus represent a serious confound for thermal nociceptive tests, particularly when they are conducted at thermal neutrality.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

Neck proprioceptors contribute to the modulation of muscle sympathetic nerve activity to the lower limbs of humans

Several different strategies have now been used to demonstrate that the vestibular system can modulate muscle sympathetic nerve activity (MSNA) in humans and thereby contribute to the regulation of blood pressure during changes in posture. However, it remains to be determined how the brain differentiates between head-only movements that do not require changes in vasomotor tone in the lower limbs from body movements that do require vasomotor changes. We tested the hypothesis that neck movements modulate MSNA in the lower limbs of humans. MSNA was recorded in 10 supine young adult subjects, at rest, during sinusoidal stretching of neck muscles (100 cycles, 35° peak to peak at 0.37 ± 0.02 Hz) and during a ramp-and-hold (17.5° for 54 ± 9 s) static neck muscle stretch, while their heads were held fixed in space. Cross-correlation analysis revealed cyclical modulation of MSNA during sinusoidal neck muscle stretch (modulation index 45.4 ± 5.3 %), which was significantly less than the cardiac modulation of MSNA at rest (78.7 ± 4.2 %). Interestingly, cardiac modulation decreased significantly during sinusoidal neck displacement (63.0 ± 9.3 %). By contrast, there was no significant difference in MSNA activity during static ramp-and-hold displacements of the neck to the right or left compared with that with the head and neck aligned. These data suggest that dynamic, but not static, neck movements can modulate MSNA, presumably via projections of muscle spindle afferents to the vestibular nuclei, and may thus contribute to the regulation of blood pressure during orthostatic challenges.

Improved pulse wave velocity estimation using an arterial tube-load model.

Pulse wave velocity (PWV) is the most important index of arterial stiffness. It is conventionally estimated by noninvasively measuring central and peripheral blood pressure (BP) and/or velocity (BV) waveforms and then detecting the foot-to-foot time delay between the waveforms wherein wave reflection is presumed absent. We developed techniques for improved estimation of PWV from the same waveforms. The techniques effectively estimate PWV from the entire waveforms, rather than just their feet, by mathematically eliminating the reflected wave via an arterial tube-load model. In this way, the techniques may be more robust to artifact while revealing the true PWV in absence of wave reflection. We applied the techniques to estimate aortic PWV from simultaneously and sequentially measured central and peripheral BP waveforms and simultaneously measured central BV and peripheral BP waveforms from 17 anesthetized animals during diverse interventions that perturbed BP widely. Since BP is the major acute determinant of aortic PWV, especially under anesthesia wherein vasomotor tone changes are minimal, we evaluated the techniques in terms of the ability of their PWV estimates to track the acute BP changes in each subject. Overall, the PWV estimates of the techniques tracked the BP changes better than those of the conventional technique (e.g., diastolic BP root-mean-squared errors of 3.4 versus 5.2 mmHg for the simultaneous BP waveforms and 7.0 versus 12.2 mmHg for the BV and BP waveforms (p <; 0.02)). With further testing, the arterial tube-load model-based PWV estimation techniques may afford more accurate arterial stiffness monitoring in hypertensive and other patients.

Age dependency of vasopressin pulmonary vasodilatory effect in rats

BackgroundVasopressin is a systemic vasoconstrictor. Its pulmonary vasodilatory effect is controversial and limited data are available on its use in neonates with pulmonary hypertension. Hypothesizing that the vasopressin-induced pulmonary vasodilation is developmentally regulated, we evaluated its pulmonary and systemic arterial response in newborn and adult rats.MethodsVessels were mounted on a wire myograph and the vasopressin-induced changes in vasomotor tone measured. The vessel- and age-dependent differences in vasopressin V1a and V2 receptors expression were evaluated by Western blotting.ResultsVasopressin induced a dose-dependent increase in mesenteric arterial tone at both ages, but of greater magnitude in adult vessels (P<0.01). At lower concentrations, vasopressin induced pulmonary vasodilation in adult vessels and vasoconstriction in newborn arteries. The adult vasopressin-induced pulmonary vasodilation was inhibited by ibuprofen suggesting that the response is prostaglandin mediated. Pulmonary tissue V1a receptor protein expression was higher in adult, when compared with newborn arteries (P<0.01). The adult vessels V1a expression predominated in the pulmonary arteries and V2 was only detected in mesenteric arteries.ConclusionThe vasopressin-induced pulmonary vasodilation is absent in newborn rats likely due to the lower tissue V1a expression early in life. These animal data challenge the therapeutic use of vasopressin in neonatal pulmonary hypertension.

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Effect of hypercapnia on pleth variability index during stable propofol: Remifentanil anesthesia

Background:The pleth variability index (PVI), which is calculated from respiratory variations in the perfusion index (PI), has been shown to predict fluid responsiveness in mechanically ventilated patients; however, vasomotor tone changes induced by hypercapnia can affect PI and hence may slim down the accuracy of PVI. This study was designed to find out the impact of mild hypercapnia on PVI.Methods:A total of 30 patients were randomized after induction of general anesthesia with target controlled infusion propofol and remifentanil to either hypercapnia, (etCO2 =45 mmHg), (group 1, 15 patients) or normocapnia (etCO2 =35 mmHg) (group 2, 15 patients). After a stabilization period of 10 min, patients were crossed over to the other intentional level of etCO2. Heart rate (HR), mean arterial pressure (MAP), PI, PVI were collected at the end of each stabilization period.Results:Patient characteristics and baseline values of HR, MAP, PI and PVI were comparable between the groups. Carryover effect was statistically excluded. Hypercapnia significantly increased PI and decreased PVI with significant negative correlation.Conclusion:Hypercapnia retracts back PVI values compared with normocapnia. Precise judgment of fluid responsiveness as indicated by PVI necessitates its comparison against similar etCO2 levels.

Abstract 547: 7-Ketocholesterol-Mediated Alterations in Vascular Function: A Link Between Vascular and Metabolic Complications of Chronic Particulate Matter Exposure

BACKGROUND: Both human and animal studies have suggested a compelling link between inhaled particulate matter &lt;2.5nm (PM2.5) exposure and acceleration of atherosclerosis. In this study, we assessed the hypothesis that 7-Ketocholesterol (7KC), a major redox product of cholesterol may mediate adverse vascular and metabolic effects of PM2.5 exposure. METHODS: Apolipoprotein E -/- (apoE-/-) mice were exposed to concentrated ambient PM2.5 or filtered air (FA) for 6 hours per day, 5 days per week for a total of 6 months in a versatile aerosol concentrator exposure system. Vasomotor tone changes were assessed in and atherosclerosis lesion quantification performed. 7KC and total cholesterol levels were determined by LC-MS in various tissues including aorta and 7KC accumulation and reverse transport studies in cultured murine macrophages subjected to PM2.5 exposure. eNOS activation and NO generation in response to 7KC exposure was assessed in cultured endothelial cells. RESULTS: PM2.5 increased aortic plaque (1.4-fold, p&lt;0.05 vs. FA; n=7). Relaxation to the endothelium-dependent agonist acetylcholine was attenuated (Rmax, 74.86±6.2 vs. 94.55±7.29%, p&lt;0.05 for PM2.5 vs. FA; n=7). 7KC levels in the aorta of PM2.5-exposed mice was significantly higher than that of FA (1251±453 vs. 8588±2088 ng/g tissue, p&lt;0.05 PM2.5 vs. FA; n=5) while levels in liver were 1-fold higher (p=0.06; n=5). 7KC reduced eNOS activation in cultured endothelial cells through regulation of 1177, 495 and 113 phosphorylation sites of eNOS in a time and dose dependent manner and reduced NO generation when assessed by EPR. Enhanced uptake of 7KC was demonstrated in cultured macrophages after PM2.5 pre-exposure (56.2±0.3 vs. 47.8± 0.9 % p =0.01 for PM2.5 vs. control; n=3) while reverse transport of 7-KC did not differ in the presence of HDL (50 μg/ml). CD36 expression inside macrophages increased after PM2.5 exposure (1.5-fold, p&lt;0.01; n=5) suggesting internalization of 7-KC via CD36 dependent mechanisms. CONCLUSIONS: Chronic PM2.5 exposure enhances 7KC levels paralleled by alterations in endothelial function through eNOS dependent pathways. These findings suggest novel secondary mediators by which air-pollution may modulate adverse vascular effects.

Autonomic Neural Regulation of the Immune System

The autonomic and the immune systems play major roles in the pathogenesis of cardiovascular disease and hypertension. To date, those 2 systems have been studied extensively but independently by cardiovascular biologists and by immunologists. The notion that the autonomic system can modulate the immune system and thereby influence the pathogenesis of cardiovascular disease and hypertension and their clinical outcome is novel and critical. In this brief review we focus on that interaction and an integrated understanding of the neuro-immune axis. We also highlight recent progress and future research directions. The main theme is that dysregulation of the autonomic system enhances the inflammatory response of the innate and adaptive immune systems leading to the initiation or acceleration of pathological processes and worsening of cardiovascular risks. The therapeutic potential of restoring an optimal autonomic control of the immune system is very promising. Both components of the neuro-immune axis may be involved in its disruption. One is the autonomic nervous system, which may be dysregulated or imbalanced with increased sympathetic and decreased parasympathetic activation. The other is the immune system itself, which may be abnormally sensitive to the modulatory influence of the autonomic system. These 2 components are briefly described below. #### Autonomic Dysregulation in Chronic Hypertension The complexity of cardiovascular mechanisms that contribute to hypertension has been challenging. The roles of vascular and renal abnormalities are undeniable. Changes in vasomotor tone, sodium retention, and renal renin release are all well established. For decades the contribution of the sympathetic nervous system to chronic hypertension was not fully appreciated. Its importance is now well recognized.1–5 In a 1982 review, we described the neural sites and mechanisms involved in exaggerated sympathetic nerve activity (SNA) in several animal models, as well as in human hypertension.1 Moreover, there has been a surge of data highlighting the damaging cardiovascular effects …

What is your strategy for fluid management?

Optimizing fluid management for operation has become a topic of increasing interest. The static parameters of cardiac preload, such as central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) are poor predictors of fluid responsiveness (FR) [1], and it is not appropriate to use these parameters for making decisions regarding fluid management. Two reasons can be given for this, considering the FrankStarling relationship. Firstly, markers of preload are not always accurate measures of cardiac preload. Secondly, assessment of preload is not assessment of preload responsiveness [2]. Alternatives for detecting FR have been investigated and the concept of respiratory variations of hemodynamic signals has emerged based on heart-lung interactions during mechanical ventilation [3]. Many dynamic parameters such as systolic pressure variability, pulse pressure variability (PPV) and stroke volume variability (SVV) from pulse-contour analysis have been shown to be predictive of FR [4]. These variables are highly accurate for FR and have a greater accuracy than the traditional static indices [5]. Recently, the noninvasive pulse oximeter-derived pleth variability index (PVI) was introduced. This index predicts FR as accurately as do SVV and PVI-based goal-directed fluid management reduced intraoperative and postoperative lactate levels [6]. However, these dynamic parameters cannot be used in patients who have spontaneous ventilation or cardiac arrhythmia. A low tidal volume also makes these variables poorly predictable [7]. The chest must be closed and intra abdominal pressure has to be within the normal range [8,9]. SVV is influenced by positive end-expiratory pressure and ventricular function. Likewise, the changes of vasomotor tone impact the plethysmographic waveform [10]. Researchers have thus sought alternative predictors of FR for use in patients with spontaneous breathing. The passive leg-raising (PLR) test was developed and is considered to be the gold-standard method for this group and can also be used in mechanically ventilated patients. Elevation of the patients’ legs to 45˚ autotransfuses around 300 ml of whole blood into the central circulation. Many studies show an increase in PAOP, left ventricular end-diastolic dimension, E-wave of mitral flow, and left ventricular ejection time during PLR [11]. Kweon et al. [12] in the current issue of the Korean Journal of Anesthesiology, compared the hemodynamic changes of PLR and exaggerated lithotomy position. They showed an increase in mean blood pressure, PAOP, CVP, the left ventricular enddiastolic area index, and systemic vascular resistance in both positions, but there was an increase of cardiac output in PLR only. Although FR is not the main subject of this article, it may be helpful to understand the hemodynamic response of fluid challenge in patients under general anesthesia. PLR has been validated for predicting FR, but it requires the determination of cardiac output with a fast-response device, because the hemodynamic changes may be transient. Available techniques are transthoracic echocardiography, transpulmonary thermodilution, transthoracic Doppler ultrasonography, and stroke volume from analysis of the systemic arterial pressure wave [13]. Although they have many limitations, dynamic parameters have the potential to help anesthesiologists in making decision about fluid therapy in patients under general anesthesia with mechanical ventilation. The PLR test may be helpful for the evaluation of the volume status of patients preoperatively, especially in an emergency operation in which there is not enough time to evaluate and correct volume status. There are many studies that show dynamic parameters and PLR test

Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.