Re-imagining occupational wellbeing: Development of an evidence-based framework.

BACKGROUND/AIM: Occupational therapists concern themselves with understanding engagement in everyday activity as a mode of facilitating wellbeing. However, there appears to be little consensus within the literature as to how engagement in meaningful activities contributes to wellbeing. Currently, there are no published evidence-based frameworks for wellbeing to support occupational therapy practitioners to address wellbeing with clients. The purpose of the study was to establish an evidence-based contemporary framework, domains and descriptive statements defining occupational wellbeing. METHODS: A multiphase, exploratory sequential mixed methods design, using both qualitative and quantitative approaches was used. Two phases were identified for data collection. The first phase involved exploration of the domains of occupational wellbeing, through conducting a literature review and two focus groups. The Delphi technique was employed in the second phase to refine and corroborate the domains of occupational wellbeing with an expert panel. RESULTS: Six new domains of occupational wellbeing were generated in the first phase of the study, namely: Competence, autonomy, contentment and pleasure, identity, hope and belonging. In the second phase, five out of the six domains reached a consensus level of 70% or more. Hope was the only domain not to reach consensus. CONCLUSION: The framework for occupational wellbeing produced by this study was created using evidence-based, replicable methodology and garnered support from a highly regarded expert key informant group of occupational therapy and occupational science academics. Further exploration to determine whether there is widespread support and applicability for these domains with normative and vulnerable population groups is required.

Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study.

BACKGROUND: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. METHODS: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration-response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. RESULTS: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. CONCLUSIONS: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

A systematic literature review of the clinical signs and symptoms of veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation in adults and children.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a rare, serious complication following haematopoietic cell transplantation (HCT). This systematic literature review evaluated differences in clinical manifestations of VOD/SOS post-HCT in adults and children. Medline and Embase were searched up to 4 March 2021 for reports of VOD/SOS post-HCT; VOD/SOS diagnostic guidelines were included. Publications were evaluated based on inclusion of five cardinal clinical features of VOD/SOS (ascites, hepatomegaly, hyperbilirubinaemia, right upper quadrant [RUQ] pain and weight gain ≥5%). Overall, 204 publications were included. At diagnosis, hyperbilirubinaemia was more common in adults (93%) versus children (82%), weight gain ≥5% and hepatomegaly were more common in children (86%, 89%) versus adults (73%, 76%) and ascites and RUQ pain were similar between age groups. While 40% of cases had all five cardinal features, age was not a substantial determinant of the likelihood of missing any single specific feature. The proportion of cases, where hyperbilirubinaemia was the first recorded feature, was higher in children versus adults; weight gain and RUQ pain appeared first in a greater proportion of adults versus children. VOD/SOS diagnosis can be challenging; features may not present in a distinct sequence. This necessitates continuous vigilance by those involved in patient monitoring post-HCT.

PI 3-kinase p110beta: a new target for antithrombotic therapy.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

Tandem free-radical addition/substitution chemistry and its application to the preparation of novel AT1 receptor antagonists.

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT(1) receptor antagonists, with pK(B) estimates of 7.2-9.5.

Pharmacological characterisation of the CB1 receptor antagonist activity of cannabidiol in the rat vas deferens bioassay.

Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 µM) or SR141716 (0.003-10 µM), cumulative concentrations of WIN 55,212-2 (0.001-30 µM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC50 values were applied to global regression analysis to determine the pKB. The antagonist potency of cannabidiol at the CB1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pKB values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pKB values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol's low micromolar CB1 antagonist pKB values suggest that at clinical blood levels (1-3 µM) it may act as a CB1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline.

Cannabidiol selectively inhibits the contraction of rat small resistance arteries: Possible role for CGRP and voltage-gated calcium channels.

The pharmacology of cannabidiol, the non-psychoactive major component of Cannabis sativa, is of growing interest as it becomes more widely prescribed. This study aimed to examine the effects of cannabidiol on a wide range of contractile agents in rat small resistance arteries, in comparison with large arteries, and to explore its mechanism of action. The vascular actions of cannabidiol were also contrasted with effects on the contractions of bronchial, urogenital, cardiac and skeletal muscles. Isolated small or large arteries were incubated with cannabidiol (0.3-3 µM) or vehicle and concentration-contraction response curves were completed to various agents, including endothelin-1, arginine vasopressin, methoxamine, 5-HT, α-methyl 5-HT and U46619. In small arteries, the effects of cannabidiol were tested in the presence of antagonists of CB1 or CB2 receptors, calcitonin gene-related peptide (CGRP), nitric oxide synthase, cyclooxygenase, PPARγ or a combination. The role of L-type voltage-operated calcium channels was also assessed. Cannabidiol 1-3 µM significantly inhibited the contraction of small resistance arteries to all tested agents through a combination of mechanisms that include CGRP and L-type calcium channels. However, large arteries were insensitive to cannabidiol. Cannabidiol (10-100 µM) was largely without effect in bronchi, atria and hemidiaphragm, but 100 µM attenuated maximum contractions in vasa deferentia. Cannabidiol's effects in the clinical range (1-3 µM) appear to be specific to small resistance arteries. This high sensitivity of the resistance arterial circulation to cannabidiol may offer a therapeutic opportunity in peripheral vascular disease that excludes off-target sites such as the heart and non-vascular smooth muscle.

Comparative bibliometric analysis of publications by past Royal Australasian College of Surgeons research scholarship recipients.

BACKGROUND: The Royal Australasian College of Surgeons awards scholarships to surgeons, surgical trainees and recipients focused on developing their clinical knowledge and improving outcomes for patients. A bibliometric analysis of research scholarship recipients publications and h-index scores was conducted to understand the benefits of receiving these scholarships. METHODS: A bibliometric analysis of Royal Australasian College of Surgeons scholarship recipients in 2015 was performed using Open Researcher and Contributor ID (ORCID), Scopus, Google Scholar, ResearchGate, LinkedIn and PubMed to identify the number of publications, h-index scores, field-weighted citation impact and the relative citation ratio. RESULTS: Nineteen research scholarship recipients authored 842 publications, with 491 (58%) published after completion of their scholarship. Seven recipients published 50% or more of their articles in the 5 years since completion. Five recipients have each published more than 45 articles since 2015. H-index scores varied between Scopus and Google Scholar (overall range: 4-34). Scopus identified the most publications, followed by ResearchGate. Determining publication numbers for recipients was problematic due to self-reporting in some databases (i.e. Google Scholar, ResearchGate), variations in author names (i.e. maiden to married name), duplication of publications and the inclusion of supplementary material (i.e. extra tables) in self-reporting databases. Field-weighted citation impact and relative citation ratio values exceeded 1 on 12 occasions demonstrating recipients are more cited than the global average. CONCLUSION: Continuous tracking of publication rates and h-index scores of scholarship recipients demonstrates recipients' continuing interest in advancing and disseminating medical knowledge to improve patient outcomes. The 2015 scholarship recipients publication numbers continued to increase after their scholarship tenure.

Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle.

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.

Estimation of the vascular resistance amplifier in the renal vascular bed in conscious hypertensive rabbits: comparison with the total peripheral vasculature.

OBJECTIVES: The vascular amplifier in hypertension is a result of structural changes in resistance arteries. We estimated the vascular amplifier hypertensive:normotensive (H:N) ratio in the renal bed compared with the total peripheral bed in conscious rabbits during infusion of vasoconstrictor and vasodilator stimuli. METHODS: Rabbits were subjected to bilateral renal cellophane wrap or sham operation. A perivascular ultrasonic flow probe was implanted on the left renal artery to measure renal blood flow. A catheter was inserted into the thoracic aorta for agonist administration. Blood pressure, heart rate and renal blood flow were measured on three separate days in conscious rabbits with intact effectors, ganglionic block or neurohumoral block. Dose-response curves were constructed to intra-arterial infusion of noradrenaline, angiotensin II, adenosine and acetylcholine. RESULTS: Resting renal vascular resistance in hypertensive rabbits was markedly decreased by ganglionic block and further by neurohumoral block. With effectors intact, ganglionic block or neurohumoral block, the H:N ratio for renal vascular resistance was 2.32, 1.72 or 1.72, respectively. The ratio was generally maintained during the infusion of constrictor and dilator drugs although distortions occurred at higher concentrations of constrictor or dilator drugs. CONCLUSIONS: Estimation of the renal resistance amplifier in renal wrap hypertension with neurohumoral block accords with our earlier estimates of the total peripheral resistance amplifier (1.79). This vascular resistance amplifier is consistent with a decrease in internal radius through structural remodelling in the renal vascular bed as is reflected in the total arterial circulation in hypertension.

The ß2-adrenoceptor agonist bronchodilators terbutaline and orciprenaline are also weak α1-adrenoceptor antagonists.

Recently, the ß2-adrenoceptor agonist terbutaline was shown to have α1-adrenolytic activity in mouse isolated pulmonary arteries in vitro and to lower pulmonary artery pressure in anaesthetised mice. The aim of our study was to determine the α1-adrenoceptor antagonist activity of terbutaline and its structurally close resorcinol, orciprenaline, in rat isolated small mesenteric arteries set up for myography. Their α1-adrenoceptor antagonist potency was then compared with their potency as ß2-adrenoceptor agonists. Concentration-response curves to methoxamine were competitively antagonised by terbutaline (30-300 µM) or orciprenaline (30-300 µM) with a pKB of 4.70 ± 0.09 or 4.79 ± 0.17, respectively. Both terbutaline and orciprenaline fulfilled the criteria for simple, silent competitive antagonism. Terbutaline (30-300 µM) had no effect on endothelin-1 concentration-contraction curves. Our findings suggest that after oral dosing of terbutaline, the maximum plasma levels would NOT reach levels to show α1-adrenoceptor antagonist activity. In conclusion, our work has provided additional quantitative evidence that terbutaline and orciprenaline are weak competitive α1-adrenoceptor antagonists, but this additional property is probably not therapeutically important in the clinical treatment of asthma or pulmonary artery hypertension with these more potent ß2-adrenoceptor agonists.

Vascular effects of FGF-2 and VEGF-B in rabbits with bilateral hind limb ischemia.

AIMS: To assess fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-B (VEGF-B) effects on flow reserve and morphological adaptation in the rabbit ischemic hind limb. METHODS: Following bilateral femoral artery ligation, calf blood pressure (C(BP)), flow reserve, collateral artery numbers and capillary numbers were assessed. Treatment consisted of rabbit serum albumin (RSA), FGF-2, VEGF-B or FGF-2 + VEGF-B. RESULTS: Ligation decreased C(BP); on day 14, a 48% deficit remained in the RSA group compared with a deficit of only 22% in FGF-2 and VEGF-B groups. On day 3, flow reserve was attenuated 60%, but recovered by day 14 (with no treatment effects). Collateral artery numbers increased with RSA (+28%), FGF-2 (+53%), VEGF-B (+47%) and FGF-2 + VEGF-B (+59%). Rectus femoris muscle total capillary profiles and fibers per cross-section were alike across groups. Tibialis anterior muscle cross-sectional area was lower with ligation and total capillary number was less in RSA and FGF-2 groups, providing evidence for angiogenesis with VEGF-B. Capillary/muscle fiber ratio was similar in each group. CONCLUSIONS: FGF-2 and VEGF-B enhanced lower limb perfusion as indicated by improved C(BP) and combined treatment increased collateral artery number. Flow reserve recovery was not enhanced by cytokine treatment. VEGF-B, but not FGF-2, caused angiogenesis in the tibialis anterior muscle. Overall, VEGF-B may have advantages over FGF-2 in this setting; however, their combination may further improve arteriogenesis.

Role of endothelin-1 clearance in the haemodynamic responses to endothelin-1 in the pulmonary and hindquarter vasculature of anaesthetised rats.

In the pulmonary vasculature there is clearance of endothelin-1 from the circulation mediated by endothelin ETB receptors. This study explored the haemodynamic effects of endothelin-1 and its clearance in the pulmonary and hindquarter vasculature in anaesthetised rats. Carotid and pulmonary artery pressures and pulmonary and hindquarter blood flows were measured. In each rat, a single endothelin-1 or sarafotoxin S6C cumulative dose-response curve was generated with or without antagonist pretreatment (i.v.). Endothelin-1 caused an acute fall in MAP and rise in hindquarter vascular conductance (HVC) followed by a marked increase in MAP at 5 min with falls in HVC and pulmonary vascular conductance (PVC). Bosentan (10, 20 & 30 mg/kg) pretreatment caused dose-dependent inhibition of the MAP increase as well as PVC and HVC decreases to endothelin-1. Similarly, macitentan (30 mg/kg) or ambrisentan (10 mg/kg) caused significant block of responses to endothelin-1. Sarafotoxin S6C caused acute falls in MAP and increases in HVC and then small falls in PVC and HVC, all prevented by pretreatment with ETB antagonist BQ788 (1 mg/kg). Pretreatment with BQ788 enhanced endothelin-1 potency by 2.5-fold in PVC and 2.4-fold in HVC. With BQ788 and bosentan, the fall in HVC response was completely blocked, but there were residual MAP rises and PVC falls at the highest endothelin-1 dose. Our work confirms the role of ETB receptors in the pulmonary vasculature that decrease the circulating levels of endothelin-1. This has important consequences in selecting an appropriate ETA and ETB dual receptor antagonist to effectively block endothelin-1-mediated pulmonary vasoconstriction.

The effects of varying Mg2+ ion concentrations on contractions to the cotransmitters ATP and noradrenaline in the rat vas deferens.

The vas deferens responds to a single electrical pulse with a biphasic contraction caused by cotransmitters ATP and noradrenaline. Removing Mg2+ (normally 1.2 mM) from the physiological salt solution (PSS) enhances the contraction. This study aimed to determine the effect of Mg2+ concentration on nerve cotransmitter-mediated contractions. Rat vasa deferentia were sequentially bathed in increasing (0, 1.2, 3 mM) or decreasing (3, 1.2, 0 mM) Mg2+ concentrations. At each concentration a single field pulse was applied, and the biphasic contraction recorded. Contractions to exogenous noradrenaline 10 µM and ATP 100 µM were also determined. The biphasic nerve-mediated contraction was elicited by ATP and noradrenaline as NF449 (10 µM) and prazosin (100 nM) completely prevented the respective peaks. Taking the contractions in normal PSS (Mg2+ 1.2 mM) as 100%, lowering Mg2+ to 0 mM enhanced the ATP peak to 170 ±â€¯7% and raising Mg2+ to 3 mM decreased it to 39 ±â€¯3%; the noradrenaline peak was not affected by lowering Mg2+ to 0 mM (97 ±â€¯3%) but was decreased to 63 ±â€¯4% in high Mg2+ (3 mM). Contractions to exogenous ATP, but not noradrenaline, were increased in Mg2+ 0 mM and both were inhibited with Mg2+ 3 mM. Changing Mg2+ concentration affects the contractions elicited by the cotransmitters ATP and noradrenaline. The greatest effects were to potentiate the contraction to ATP in Mg2+ 0 mM and to inhibit the contraction to both ATP and noradrenaline in high Mg2+. Future publications should clearly justify any decision to vary the magnesium concentration from normal (1.2 mM) values.

Cardiac tissue engineering in an in vivo vascularized chamber.

BACKGROUND: Cardiac tissue engineering offers the prospect of a novel treatment for acquired or congenital heart defects. We have created vascularized pieces of beating cardiac muscle in the rat that are as thick as the adult rat right ventricle wall. METHOD AND RESULTS: Neonatal rat cardiomyocytes in Matrigel were implanted with an arteriovenous blood vessel loop into a 0.5-mL patented tissue-engineering chamber, located subcutaneously in the groin. Chambers were harvested 1, 4, and 10 weeks after insertion. At 4 and 10 weeks, all constructs that grew in the chambers contracted spontaneously. Immunostaining for alpha-sarcomeric actin, troponin, and desmin showed that differentiated cardiomyocytes present in tissue at all time points formed a network of interconnected cells within a collagenous extracellular matrix. Constructs at 4 and 10 weeks were extensively vascularized. The maximum thickness of cardiac tissue generated was 1983 microm. Cardiomyocytes increased in size from 1 to 10 weeks and were positive for the proliferation markers Ki67 and PCNA. Connexin-43 stain indicated that gap junctions were present between cardiomyocytes at 4 and 10 weeks. Echocardiograms performed between 4 and 10 weeks showed that the tissue construct contracted spontaneously in vivo. In vitro organ bath experiments showed a typical cardiac muscle length-tension relationship, the ability to be paced from electrical field pulses up to 3 Hz, positive chronotropy to norepinephrine, and positive inotropy in response to calcium. CONCLUSIONS: In summary, the use of a vascularized tissue-engineering chamber allowed generation of a spontaneously beating 3-dimensional mass of cardiac tissue from neonatal rat cardiomyocytes. Further development of this vascularized model will increase the potential of cardiac tissue engineering to provide suitable replacement tissues for acquired and congenital defects.

Adaptation of hindquarter vascular reactivity to femoral artery ligation and hypercholesterolemia in the rabbit.

AIMS: The effects of ischemia and hypercholesterolemia on the function and morphological adaptation of the rabbit hindlimb were assessed. METHODS: In rabbits on normal or cholesterol diet, experiments were performed on days 0-28 following bilateral femoral artery ligation. Calf blood pressure (C(BP)), exercise tolerance, flow reserve, agonist vasodilatation, angiography and capillary density were examined and modeled. RESULTS: C(BP) decreased markedly post-ligation and returned to 41 and 68% of baseline by days 7 and 28. Exercise tolerance was attenuated 40% and flow reserve 50-60% on day 7, with recovery by day 28. Ligation caused decreases in 5-hydroxytryptamine-induced dilatation, while adenosine and acetylcholine responses were unaffected. Hypercholesterolemia attenuated acetylcholine-elicited dilatation. There was marked loss of adenosine dilatation on days 7-14 in the ligation plus hypercholesterolemia group. Ligation caused a doubling in the number of medium-sized collateral arteries. Hypercholesterolemia, either alone or combined with ligation, greatly augmented small vessel density. Capillary density was unaltered by any treatment. CONCLUSIONS: The rabbit hindlimb shows a remarkable ability to recover its muscle function through vascular adaptation and remodeling 4 weeks following ligation, with or without hypercholesterolemia. Exercise tolerance, flow reserve and vascular reactivity were mainly restored 28 days post-ligation.

Persistent depression of contractility and vasodilation with propofol but not with sevoflurane or desflurane in rabbits.

BACKGROUND: Propofol, sevoflurane, and desflurane may cause hemodynamic compromise during anesthesia and critical care management. The aim of the study was to compare these anesthetics during increased dose and recovery to maintenance level. METHODS: Anesthetized, open-chest New Zealand White rabbits were used to acquire dose-response curves with sevoflurane, desflurane, and propofol, followed by reduction to baseline infusion. Simultaneous high-fidelity left ventricular pressure and volume data were acquired during caval occlusion with a dual-field conductance catheter inserted via an apical stab. The preload recruitable stroke work and the end-diastolic pressure-volume relationship were used as the primary measures of contractility and diastolic function. RESULTS: The time-matched controls were stable over time. Propofol and desflurane but not sevoflurane caused dose-dependent reductions in myocardial contractility, although sevoflurane reduced contractility more at 1 minimal alveolar concentration. All anesthetics reduced mean arterial pressure, and significant recovery occurred for sevoflurane and desflurane but not for propofol. The end-diastolic pressure-volume relationship was increased by sevoflurane. Ejection fraction decreased with sevoflurane only. All anesthetics caused dose-dependent vasodilation, with recovery for desflurane and sevoflurane but not propofol. Heart rate was decreased with propofol without significant recovery. Propofol plasma concentrations remained elevated after dose return to baseline infusion rate, suggestive of distribution compartment saturation. CONCLUSION: All three anesthetics caused dose-dependent decreases in cardiovascular function. Recovery of cardiovascular function occurred rapidly with sevoflurane and desflurane, but persistent depression of contractility, vasodilation, mean arterial pressure, and heart rate occurred with propofol during a 30-min recovery period.