Norepinephrine Pressure Research Articles

Hepatorenal syndrome: Updates.

Hepatorenal syndrome: Updates.

A Nutraceutical Product Based on a Mixture of Algae and Extra Virgin Olive Oils and Olive Leaf Extract Attenuates Sepsis-Induced Cardiovascular and Muscle Alterations in Rats.

Nutraceuticals are products of natural origin widely used for the treatment and/or prevention of some chronic diseases that are highly prevalent in Western countries, such as obesity or type II diabetes, among others. However, its possible use in the prevention of acute diseases that can put life at risk has been poorly studied. Sepsis is an acute condition that causes cardiovascular and skeletal muscle damage due to a systemic inflammatory state. The aim of this work was to evaluate the possible beneficial effect of a new nutraceutical based on a mixture of algae oil (AO) and extra virgin olive oil (EVOO) supplemented with an olive leaf extract (OLE) in the prevention of cardiovascular alterations and skeletal muscle disorders induced by sepsis in rats. For this purpose, male Wistar rats were treated with the nutraceutical or with water p.o. for 3 weeks and after the treatment they were injected with 1mg/kg LPS twice (12 and 4 h before sacrifice). Pretreatment with the nutraceutical prevented the LPS-induced decrease in cardiac contractility before and after the hearts were subjected to ischemia-reperfusion. At the vascular level, supplementation with the nutraceutical did not prevent hypotension in septic animals, but it attenuated endothelial dysfunction and the increased response of aortic rings to the vasoconstrictors norepinephrine and angiotensin-II induced by LPS. The beneficial effects on cardiovascular function were associated with an increased expression of the antioxidant enzymes SOD-1 and GSR in cardiac tissue and SOD-1 and Alox-5 in arterial tissue. In skeletal muscle, nutraceutical pretreatment prevented LPS-induced muscle proteolysis and autophagy and significantly increased protein synthesis as demonstrated by decreased expression of MURF-1, atrogin-1, LC3b and increased MCH-I and MCH -IIa in gastrocnemius muscle. These effects were associated with a decrease in the expression of TNFα, HDAC4 and myogenin. In conclusion, treatment with a new nutraceutical based on a mixture of AO and EVOO supplemented with OLE is useful to prevent cardiovascular and muscular changes induced by sepsis in rats. Thus, supplementation with this nutraceutical may constitute an interesting strategy to reduce the severity and mortality risk in septic patients.

Xylometazoline Induced Isolated Left Medial Cerebellar Peduncle Infarct: A Rare Case Report

Xylometazoline, a sympathomimetic available as over the counter drug, acts as a nasal decongestant and has been reported as an independent risk factor for hemorrhagic and ischemic stroke. The chronic use of xylometazoline leads to either increased release of more potent vasoconstrictor norepinephrine in the presynaptic region, or acts directly on central adrenoreceptors which leads to dysfunction resulting in chronic progressive vasculopathy that manifests as an ischemic stroke. Sympathomimetics also activate 12-lipoxygenase pathways which induce proliferation and migration of vascular smooth muscle cells. 12-lipoxgenase also plays a significant role in regulating the degree and stability of platelet activation, as its activation significantly strengthens platelet activation and uncontrolled platelet activation, which may lead to myocardial infraction and stroke. The present case reports a rare case of young adult suffering from isolated left medial cerebellar peduncle infarct related to the chronic use of xylometazoline. Acute cerebellar stroke is rare, especially in young adults and represent only 3% of total ischemic and hemorrhagic strokes. Clinical symptoms, patient age at the onset of stroke, and lesion size had no significant effect on the clinical outcome. Symptoms are frequently underestimated and misdiagnosed which further lead to serious complications and poor functional outcomes.

Marjoram extract prevents ischemia reperfusion-induced myocardial damage and exerts anti-contractile effects in aorta segments of male wistar rats

Ethnopharmacological relevanceMarjoram (Origanum majorana L.) is an herb traditionally used as a medicine in different countries, as Morocco and Iran, because of its beneficial cardiovascular effects. Some studies suggest that these effects are due, at least in part, to the presence of phenolic compounds such as rosmarinic acid (RA) and luteolin. Aim of the studyTo analyze the possible cardiprotective effects of a marjoram extract (ME) reducing myocardial damage after coronary ischemia-reperfusion (IR) and its possible antihypertensive effects reducing the response of aorta segments to the vasoconstrictors noradrenaline (NA) and endothelin-1 (ET-1). Materials and methodsMale Wistar rats (300g) were used. After sacrifice, the heart was immediately removed and mounted in a perfusion system (Langendorff). The aorta was carefully dissected and cut in 2 mm segments to perform vascular reactivity experiments. ResultsIn the heart, ME perfusion after IR reduced heart rate and prevented IR-induced decrease of cardiac contractility, possibly through vasodilation of coronary arteries and through the upregulation of antioxidant markers in the myocardium that led to reduced apoptosis of cardiomyocytes. In the aorta, ME decreased the vasoconstrictor response to NA and ET-1 and exerted a potent anti-inflammatory and antioxidant effect. Neither RA nor 6-hydroxi-luteolin-O-glucoside, major compounds of this ME, were effective in improving cardiac contractility after IR or attenuating vasoconstriction to NA and ET-1 in aorta segments. ConclusionIn conclusion, ME reduces the myocardial damage induced by IR and the contractile response to vasoconstrictors in the aorta. Thus, it may be useful for the treatment of cardiovascular diseases such as myocardial infarction and hypertension.

Influence of Obesity on Vascular Dysfunction Following Hemorrhagic Shock

Obesity is associated with higher rates for complications after traumatic hemorrhage, including higher incidence of multiple organ failure, thrombosis, and mortality. These adverse events are associated with prolonged tissue hypoperfusion, hypercoagulability, and edema that reflect profound vascular damage. However, the combined impact of obesity and traumatic hemorrhage on vascular function is not well understood. Therefore, we sought to determine the impact of diet‐induced obesity on vasoconstrictor and vasodilator properties of arteries before and after hemorrhagic shock.Male Sprague‐Dawley rats were fed a control (CON; 13.5% kcal fat, n=10), moderate fat (MF, 33% kcal fat n=9) or high fat (HF, 60% kcal fat, n=10) diet for 6–8 weeks. Hemorrhagic shock was induced by laceration of a mesentery artery and a Grade V splenic injury under anesthesia, and a period of hypotension (mean arterial pressure = 30–40 mm Hg) was maintained for 30 minutes. We assessed vasoconstrictor and vasodilator properties in isolated mesenteric arteries harvested before and after hemorrhagic shock. Before hemorrhage, peak norepinephrine (NE) vasoconstriction was higher in CON rats (78±4%) versus HF (62±5%, p=0.01), while MF rats exhibited a peak NE vasoconstriction not different from either groups (71±3%, p>0.05 vs CON and HF). Baseline endothelium‐dependent dilation, assessed as the maximal response to acetylcholine, was not different between groups (CON: 97±1%, MF: 88±4%, HF: 92±3%, p=0.08). Hemorrhage lowered the peak NE vasoconstriction (post: 61±8%, p=0.05) and endothelium‐dependent dilation in CON rats (post: 90±2%, p<0.001), but had no effect on NE vasoconstriction and endothelium‐dependent dilation in MF and HF rats (p>0.05 vs pre‐hemorrhage). Endothelium‐independent dilation, assessed as the response to sodium nitroprusside, was similar pre‐ and post‐hemorrhage in all groups (p>0.05).In conclusion, we find traumatic hemorrhage induces vascular dysfunction characterized by a reduced vasoconstrictor response and impaired endothelial function, but only in rats fed a normal chow diet. While obesity results in vascular dysfunction at baseline, it does not contribute to a further worsening of function after traumatic hemorrhage.Support or Funding InformationFunded by a UO‐OHSU Collaborative Seed Grant

Phosphodiesterase-3 inhibitor cilostazol reverses endothelial dysfunction with ageing in rat mesenteric resistance arteries

Ageing impairs endothelial function, which is considered a hallmark of the development of cardiovascular diseases in elderly. Cilostazol, a phosphodiesterase-3 inhibitor, has antiplatelet, antithrombotic and protective effects on endothelial cells. Here, we hypothesized that cilostazol could improve endothelial function in mesenteric resistance arteries (MRA) from old rats. Using eight-week cilostazol-treated (100mg/kg/day) or untreated 72-week-old Wistar rats, we evaluate the relaxation to acetylcholine, sodium nitroprusside (SNP), forskolin and isoproterenol and the noradrenaline-induced contraction in MRA. Superoxide anion and nitric oxide (NO) was measured by dihydroethidium- and diaminofluorescein-2-emitted fluorescence, respectively. Normotensive old rats had impaired acetylcholine-induced NO- and EDHF-mediated relaxation and increased noradrenaline vasoconstriction than young rats. This age-associated endothelial dysfunction was restored by cilostazol treatment. Relaxation to SNP, forskolin or isoproterenol remained unmodified by cilostazol. Diaminofluorescein-2-emitted fluorescence was increased while dihydroethidium-emitted was decreased by cilostazol, indicating increased NO and reduced superoxide generation, respectively. Cilostazol improves endothelial function in old MRA without affecting blood pressure. This protective effect of cilostazol could be attributed to reduced oxidative stress, increased NO bioavailability and EDHF-type relaxation. Although these results are preliminary, we believe that should stimulate further interest in cilostazol as an alternative for the treatment of age-related vascular disorders.

Impact of high-fat diet and hypoxia on the serum levels of main vasoconstrictors in male rabbits.

Introduction: During atherosclerosis process, vasoconstriction phenomenon occurs which in turn leads to tissue hypoxia. A few studies have been performed on the combination of atherosclerosis and hypoxia as stressors that may accelerate secretion of constrictors. The aim of present study was to evaluate the effects of atherosclerosis and hypoxia on serum levels of main vasoconstrictors (epinephrine, norepinephrine and renin). Methods: In this interventional study, 32 New Zealand white rabbits were randomly divided into four groups (n = 8): normal diet (control group), normal diet exposed to hypoxia (11%, 10 days), high-fat diet (cholesterol-2%, 8 weeks), and high-fat diet with hypoxia. Later, serum levels of renin, epinephrine and norepinephrine were measured on second, 56th and 66th days. Results: High-fat diet and hypoxia caused significant increase in epinephrine and norepinephrine concentrations on days 56 and 66 compared to the control group (P < 0.05). Also, renin showed significance increase in high-fat diet and high-fat diet+ hypoxia groups compared to the control group (P < 0.05). Conclusion: Both high-fat diet and hypoxia increase renin levels in male rabbits. Furthermore, the combination of high-fat diet and hypoxia immensely increases renin levels. Both hypoxia and combined of high-fat diet and hypoxia increase norepinephrine levels. However epinephrine is only increased in the combination of high-fat diet and hypoxia. So the presence of hypoxia in combination with high-fat diet, cause accelerated and aggravated atherosclerosis.

Effects of Ambulation and Nondependent Transfers on Vital Signs in Patients Receiving Norepinephrine.

To assess the safety of mobilizing patients receiving low-dose norepinephrine (0.05 μg/kg per min) by examining mean arterial pressure and heart rate before and after activity with parameters set by the physician. Norepinephrine is a peripheral vasoconstrictor administered for acute hypotension. During activity, blood flows to the periphery to supply muscles with oxygen, which may oppose the norepinephrine vasoconstriction. The safety of mobilizing patients receiving norepinephrine is unclear. Heart rate, mean arterial pressure, norepinephrine dose, and activity performed were extracted retrospectively from charts of 47 cardiothoracic surgery patients during the first patient transfer to chair or ambulation with norepinephrine infusing. Mean arterial pressure and heart rate were compared before and after physical therapy (paired t tests). Differences among norepinephrine doses and physical activity levels were evaluated (Kruskal-Wallis test). Forty-one of the 47 patients (87%) tolerated the activity within safe ranges of vital signs. The change in patients' mean arterial pressure from before to after activity was not significant (P = .16), but a significant increase in heart rate occurred after activity (P < .001). A Kruskal-Wallis test showed no significant difference in the norepinephrine dose and activity level (χ2 = 6.34, P = .17). No instances of cardiopulmonary or respiratory arrest occurred during any physical therapy sessions. Infusion of low-dose norepinephrine should not be considered an automatic reason to keep patients on bed rest.

Relationship between plasma levels of vasoactive mediators and optic nerve head circulation shown by laser speckle flowgraphy.

To evaluate relationships between optic nerve head (ONH) circulation by laser speckle flowgraphy (LSFG), and secretion levels of plasma norepinephrine (NE), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma cortisol. Forty subjects were included in the study. The mean blur rates (MBR) throughout the ONH (MBR-all), in the tissue (MBR-tissue), and in vessels (MBR-vessel) were analyzed. In 29 subjects the following parameters were evaluated: plasma NE and ONH circulation in the evening and morning (Δ plasma NE, Δ MBR-all, -tissue, -vessel, and Δ area ratio of blood stream). Plasma NE was significantly correlated with MBR-all (r = 0.39, P = 0.01) and MBR-vessel (r = 0.51, P = 0.0008). Plasma cortisol was significantly correlated with MBR-vessel (r =0.35, P = 0.03). The PRA (r = 0.31, P = 0.05) and PAC (r = 0.31, P = 0.05) tended to correlate with MBR-vessel. The multiple regression analysis revealed that plasma NE, PAC, and ocular perfusion pressure (OPP) were identified as factors contributing independently to the MBR-vessel (plasma NE: standard regression = 0.48, t-value = 3.12, P = 0.004; PAC: 0.43, 3.10, 0.04; OPP: 0.58, 2.34, 0.03, r = 0.71). Positive correlations between Δ plasma NE and Δ MBR-all (r = 0.46, P = 0.01), Δ MBR-tissue (0.38, 0.04), Δ MBR-vessel (0.41, 0.03), and Δ area ratio of blood stream (0.38, 0.04) were observed. Our results clarified that the measurements of ONH circulation by LSFG is reflecting the plasma secretion levels of vasoactive mediators.

Role of catecholamines in maternal-fetal stress transfer in sheep

We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones. Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent. Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism. We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited.

Effect of intracerebral transplantation of mesenchymal stem cells on reactivity of pial arterioles in old rats.

Using a TV device for studying microcirculation (×160), we analyzed the responses of arterioles in the pia mater of the sensorimotor cortex in young (2-3 months) and old (22-24 months) rats after local application of a vasoconstrictor (norepinephrine, 10(-6) M) or vasodilator (acetylcholine, 10(-6) M). The responses of the arterioles were evaluated by changes in their diameter and by the number of responding vessels in the field of view. The constrictor responses of the pial arteries to norepinephrine did not significantly differ in intact young and old rats. The number and degree of dilatory responses to acetylcholine in old rats were lower than in young animals by 14 and 30%, respectively. Intracerebral transplantation of mesenchymal stem cells to old rats had practically no effect on reactivity of pial arterioles to acetylcholine, while the number of constricted vessels in response to norepinephrine increased by ~20%.

Effect of topical vasoconstrictor exposure upon tumoricidal radiotherapy

Topical application of the alpha adrenergic vasoconstrictors norepinephrine, phenylephrine or epinephrine to skin or mucosa in alcohol:water-based delivery vehicles minutes before irradiation has recently been shown to protect skin and mucosa cells against radiotherapy-induced toxicities in both preclinical and clinical studies. The protective mechanism is thought to involve transient skin or mucosal vasoconstriction with secondary, transient hypoxia and associated radioprotection. Regarding possible protection of tumor cell nests within the radiotherapy field, the endothelial cell-abnormal stroma constructed blood vessels generally found in human tumors commonly lack adrenergic receptor-containing smooth muscle cells that are required to achieve vasoconstriction. Consistent with this, we show here that topical application of norepinephrine or phenylephrine to broken or intact skin over human Cal-27 or A-431 xeonograft, or mouse solid L1210 allograft tumors growing subcutaneously in nude mice, showed no effect upon radiation-induced tumor growth inhibition. Although vasoconstrictor-induced nude mouse skin blanch was seen minutes after topical application of 600 mM norepinephrine, no blanching was seen within the A-431 xenograft tumors. Radiation dermatitis was severe 11 days post-irradiation (2 × 13.8 Gy) in the irradiated field containing xenograft tumors in mice that received topical delivery vehicle, but was absent in mice that received topical norepinephrine. Topical vasoconstrictor-conferred prevention of radiation dermatitis without discernible radioprotection of three histologically diverse xenograft or allograft tumors supports further development of the topical vasoconstrictor therapeutic strategy in humans.

Effect of neuropeptide Y on norepinephrine-induced constriction in the rabbit facial artery after carotid artery occlusion

Atherosclerotic-occlusive changes could be observed in orofacial branches of the external carotid artery. Atherosclerosis-induced ischemia caused alteration in production and release of endothelial factors. The aim of this study was to investigate the influence of carotid artery occlusion (10, 30 and 60 min) on vascular effects of norepinephrine (NOR) and neuropeptide Y (NPY) in the isolated glandular branch of the rabbit facial artery, the main feeding artery for the submandibular gland. Changes in isometric tension were recorded in organ bath studies with arterial rings, before and after carotid artery occlusion. Concentration-dependent vasocontractile effect of NOR was significantly augmented after 30 and 60 min of carotid occlusion, but only in the rings with intact endothelium. Given alone, NPY showed no effect in isolated glandular branch of the rabbit facial artery, but enhanced NOR vasoconstriction in all the investigated rings. NOR vasocontractile effect enhancement in the presence of NPY was attenuated after 30 and 60 min of carotid occlusion. Also, enhancement of NOR vasoconstriction by NPY was significantly higher in endothelium-intact rings compared to endothelium-denuded rings obtained after 30 and 60 min of carotid occlusion. The present investigation provides results of increased vasocontractile effect of NOR and decreased enhancing effect of NPY on NOR vasoconstriction in the rabbit facial artery after carotid occlusion that is related to altered endothelium function.

Maternal separation (MS) increases acute and chronic norepinephrine (NE) sensitivity revealing sympatho‐activation

We reported that MS, a model of early life stress (ELS), induces a greater drop in blood pressure in response to a ganglion blockade and a reduction in the renal filtration capacity that was normalized by renal denervation. We hypothesized that MS sensitizes the peripheral sympathetic system. The aims of this study were to evaluate 1) NE content in vasculature, kidney, spleen, and adrenal tissues, and 2) vascular tone in response to adrenergic agonists from 12 week old MS and control WKY rats. MS consisted of separating half of the male pups from the dam 3 hr a day from days 2–14 of life. NE was unchanged in plasma, thoracic and abdominal aorta while NE content was significantly increased in renal cortex (331±26 vs. 219±38 ng/g tissue), spleen (473±66 vs. 253±28 ng/g tissue) and adrenal gland (1152±189 vs. 303±99 vs. ng/g tissue) from MS vs. control rats (p&lt;0.05). Rats were injected with NE (2 μg/kg, i.p.) and blood pressure monitored by telemetry. Mean arterial pressure was exacerbated in MS vs. control rats (178±1 vs. 147±10 mmHg, p&lt;0.05) within 15 minutes. In a separate group of anesthetized rats, reduction in renal blood flow in response to phenylephrine was attenuated in MS rats compared to control rats (−1.8±0.2 vs. −2.8±0.2 Δml/min, p&lt;0.05, 100 ug/kg), suggesting an adrenergic desensitization. Thus, ELS sensitizes the sympathetic system impairing the normal acute and chronic vascular tone regulation.

Breast Feeding Increases Vasoconstriction Induced by Electrical Field Stimulation in Rat Mesenteric Artery. Role of Neuronal Nitric Oxide and ATP

ObjectivesThe aim of this study was to investigate in rat mesenteric artery whether breast feeding (BF) affects the vasomotor response induced by electrical field stimulation (EFS), participation by different innervations in the EFS-induced response and the mechanism/s underlying these possible modifications.MethodsExperiments were performed in female Sprague-Dawley rats (3 months old), divided into three groups: Control (in oestrous phase), mothers after 21 days of BF, and mothers that had recovered their oestral cycle (After BF, in oestrous phase). Vasomotor response to EFS, noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied. Neuronal NO synthase (nNOS) and phosphorylated nNOS (P-nNOS) protein expression were analysed and NO, superoxide anion (O2 .–), NA and ATP releases were also determined.ResultsEFS-induced contraction was higher in the BF group, and was recovered after BF. 1 µmol/L phentolamine decreased the response to EFS similarly in control and BF rats. NA vasoconstriction and release were similar in both experimental groups. ATP release was higher in segments from BF rats. 0.1 mmol/L L-NAME increased the response to EFS in both control and BF rats, but more so in control animals. BF decreased NO release and did not modify O2 .– production. Vasodilator response to DEA-NO was similar in both groups, while nNOS and P-nNOS expressions were decreased in segments from BF animals.ConclusionBreast feeding increases EFS-induced contraction in mesenteric arteries, mainly through the decrease of neuronal NO release mediated by decreased nNOS and P-nNOS expression. Sympathetic function is increased through the increased ATP release in BF rats.

Abstract P132: Diabetes-Induced Cardiac Dysfunction Is Rescued by Endothelial Cationic Amino Acid Transporter 1 Overexpression in Mice

Nitric oxide (NO) bioavailability is markedly impaired in diabetes, contributing to endothelial and myocardial dysfunction. Our aim was to determine if endothelial-specific overexpression of Cationic Amino Acid Transporter 1 (CAT-1, to enhance L-arginine uptake and NO generation) prevents diabetes-induced endothelial and cardiac dysfunction in diabetic mice. Male CAT-1 transgenic and non-transgenic (Ntg) 6 week old mice were administered streptozotocin (STZ, 55mg/kg ip daily for 5 days). Sham mice received citrate buffer vehicle. Myocardial function was assessed in anaesthetised mice in vivo 12 weeks later, via echocardiography. Vascular reactivity was then assessed in vitro. Compared to their non-diabetic littermates (n=6), Ntg STZ mice (n=6) exhibited reduced early-to-late blood flow velocity ratios (E/A, 1.7±0.2 vs 2.4±0.1, p&lt;0.01) and prolonged deceleration time (DT, 40±1 vs 31±2msec, p&lt;0.002), indicative of diastolic dysfunction. Decreased E-wave velocity (109±4 vs 76±12msec, p&lt;0.01) and increased A-wave velocity (45±3 vs 55±4msec, p&lt;0.05) were also observed. Systolic dysfunction was observed in Ntg STZ mice compared to shams, on reduced fractional shortening (FS, 30±1 vs 39±1%, p&lt;0.002). In CAT-1 mice, diabetes did not impair E/A ratio (2.1±0.2), FS (40±3%) or DT (33±1msec, n=8). Thoracic aortic responses to the endothelium-dependent vasodilator acetylcholine (ACh) were unchanged by diabetes in Ntg and CAT-1 Tg mice compared to sham Ntg mice (pEC50 7.0±0.1 vs 7.2±0.1 and 7.1±0.1). There was a non-significant trend for sham CAT-1 Tg mice to show greater sensitivity to ACh than sham Ntg mice (pEC50 7.5±0.1 vs 7.1±0.1). Responses to the endothelium-independent vasodilator sodium nitroprusside and the vasoconstrictor noradrenaline were unaffected by diabetes and/or genotype. In conclusion, our results suggest that endothelial-specific CAT-1 overexpression protects against cardiac dysfunction via a mechanism independent of the systemic vasculature. The involvement of the coronary vasculature remains to be determined. Endothelial CAT-1 up-regulation as a potential therapeutic target for diabetic cardiomyopathy is an exciting prospect.

Aldosterone alters the participation of endothelial factors in noradrenaline vasoconstriction differently in resistance arteries from normotensive and hypertensive rats

This study analyzed the effect of aldosterone (0.05 mg/kg per day, 3 weeks) on vasoconstriction induced by noradrenaline in mesenteric resistance arteries from WKY rats and SHR. Contraction to noradrenaline was measured in mesenteric resistance arteries from untreated and aldosterone-treatedrats from both strains. Participation of nitric oxide (NO), superoxide anions, thromboxane A 2 (TxA 2) and prostacyclin in this response was determined. 6-keto-prostaglandin (PG)F1alpha and thromboxane B 2 (TxB 2) releases were determined by enzyme immunoassay. NO and superoxide anion release were also determined by fluorescence and chemiluminiscence, respectively. Aldosterone did not modify noradrenaline-induced contraction in either strain. In mesenteric resistance arteries from both aldosterone-treated groups, endothelium removal or preincubation with NO synthesis inhibitor L-NAME increased the noradrenaline-induced contraction, while incubation with the superoxide anion scavenger tempol decreased it. Preincubation with either the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively) decreased the noradrenaline contraction in aldosterone-treated animals, while this response was not modified by COX-1 inhibitor SC-560. TxA 2 synthesis inhibitor (furegrelate), or TxA2 receptor antagonist (SQ 29 548) also decreased the noradrenaline contraction in aldosterone-treated animals. In untreated SHR, but not WKY rats, this response was increased by L-NAME, and reduced by tempol, indomethacin, NS-398 or SQ 29 548. Aldosterone treatment did not modify NO or TxB 2 release, but it did increase superoxide anion and 6-keto-PGF(1alpha) release in mesenteric resistance arteries from both strains. In conclusion, chronic aldosterone treatment reduces smooth muscle contraction to alpha-adrenergic stimuli, producing a new balance in the release of endothelium-derived prostanoids and NO.

Rituximab Induced Serum Sickness Masquerading as Septic Shock

Purpose We describe a case of serum sickness following rituximab infusion in Waldenström macroglobulinemia. Introduction Rituximab is a chimeric monoclonal anti-CD20 antibody used to treat hematologic malignancies and autoimmune diseases. Infusion reactions are very common with rituximab (77%), occurring within 30-120 min of the beginning of the infusion (rituximab package insert; Genentech, Inc); however, rituximab may cause a delayed serum sickness–like reaction as well. Description Our patient is a 51-year-old Caucasian woman diagnosed with Waldenström macroglobulinemia in 2004. At that time, she was treated with 3 cycles of rituximab therapy followed by plasmapheresis for a hyperviscosity reaction. Over the next 3 years she had an uneventful course. However, beginning in 2007 she started having unexplained severe headaches, painful peripheral sensory neuropathy, and night sweats. After a thorough work-up to rule out other etiological causes, we decided to re-challenge her with rituximab in November 2009. She was to undergo 3 cycles of plasmapheresis followed by rituximab infusions (375 mg/m2/week for 4 weeks). Prior to initiation of rituximab, her IgM level was 2447 mg/dL, and her serum viscosity was 2.0. She underwent 3 uneventful cycles of plasmapheresis, after which she received her first rituximab infusion. During the infusion, she did experience some nausea, abdominal pain, tactile hallucinations, and perioral numbness; however, these resolved with extra doses of steroids and antihistaminics. One week after the administration of the first rituximab infusion, she was found to be hypotensive with her systolic BP in the 60s mmHg and was febrile to 1015. She needed admission to the intensive care unit and was presumptively treated as having a catheter-related sepsis needing Norepinephrine pressor support and broad spectrum antibiotic coverage. Her IgM level at the time of admission was 1049 mg/dL, and her serum viscosity was 1.5. She did not have any skin rashes, thrombocytopenia, or proteinuria. During her hospital stay, all of her chemistries were within normal limits, and her microbiologic cultures were repeatedly negative. She did have elevated inflammatory biomarkers such as ESR (66 mm/hr) and CRP (17.5 mg/dL). On her third day in the intensive care unit, she complained of excruciating joint pains with swelling, particularly of her wrists and knees. At this point, her antibiotics were discontinued, and she was treated with systemic steroids leading to a significant improvement in her symptoms and discharge from the hospital. Conclusion Rituximab may present with a severe serum sickness like reaction masquerading as septic shock when used to treat hematologic malignancies. Almost all of the case reports that we reviewed on rituximab-induced serum sickness documented reactions such as fever, arthralgias, and rashes (Jacobs; Clin Nucl Med; 2007; 32:12, and Helfgott; J Rheumatol; 2007; 34:430-3); however, to our knowledge this is the first documented case of rituximab-induced serum sickness presenting with hypotension necessitating pressor support.

WHAT IS NEW IN SHOCK, JULY 2009?

WHAT IS NEW IN SHOCK, JULY 2009?

Increased Human Vascular Reactivity Via Cyclooxygenase-2 Inhibition During Acute Inflammation: Role of Prostaglandins E2 and I2

Cyclooxygenase-2 inhibition causes an increase of norepinephrine vasoconstriction. The aim of this study is to evaluate the role of increased prostaglandins (PG) E2/I2 on the vascular reactivity to norepinephrine under inflammatory conditions. Using organ bath experiments, the contraction induced by norepinephrine was studied on isolated human internal mammary arteries cultured for 24h in the presence or absence of both interleukin-1β and lipopolysaccharide. The expression of PG receptors and PG synthases was detected by immunohistochemistry. Contractions induced by norepinephrine in arteries submitted to inflammatory conditions, were significantly increased (55±18%, n=6, P<0.05) after treatment with the PGI2 receptor antagonist, CAY 10441, whereas no difference in reactivity was observed in presence of PGE2 receptor antagonists. Under these conditions, the expression of PG receptors and synthases was not modified. These results demonstrate that under inflammatory conditions, PGI2, but not PGE2, is responsible for the increase in vascular tone after cyclooxygenase-2 inhibition.