Peripheral Alpha Research Articles

Alpha2 Antagonist Vatinoxan Does Not Abolish the Preconditioning Effect of Dexmedetomidine on Experimental Ischaemia-Reperfusion Injury in the Equine Small Intestine.

Pharmacological preconditioning with dexmedetomidine has been shown to ameliorate intestinal ischaemia reperfusion injury in different species, including horses. However, it remains unknown if this effect is related to alpha2 adrenoreceptor activity. Therefore, the aim of this study was to determine the effect of dexmedetomidine preconditioning with and without the administration of the peripheral alpha2 antagonist vatinoxan. This prospective randomized experimental trial included 12 horses equally divided between two treatment groups. Horses in group Dex received a bolus of dexmedetomidine followed by a continuous rate infusion (CRI), while group DexV additionally received vatinoxan as bolus and CRI. A median laparotomy was performed under general anaesthesia, and jejunal ischaemia was applied for 90 min, followed by 30 min of reperfusion. Mucosal damage was evaluated in full thickness biopsies by use of a semiquantitative mucosal injury score and by determining the apoptotic cell counts with immunohistochemical staining for cleaved caspase-3 and TUNEL. Comparisons between the groups and time points were performed using non-parametric tests (p < 0.05). During pre-ischaemia and ischaemia, no differences could be found in mucosal injury between the groups. After reperfusion, group DexV showed lower mucosal injury scores compared to group Dex. The apoptotic cell counts did not differ between the groups. In conclusion, antagonizing the peripheral alpha2 adrenoreceptors did not negatively affect dexmedetomidine preconditioning.

PS-BPC04-4: PREVALENCE AND CLINICAL CHARACTERISTICS OF HYPERTENSION SUBTYPES ACCORDING TO HOME BLOOD PRESSURE CONTROL IN TREATED HYPERTENSIVE PATIENTS: A CROSS-SECTIONAL STUDY

Objective: To identify the prevalence and clinical characteristics of the different hypertension subtypes according to home blood pressure (BP) control in treated hypertensive patients. Design and method: This study was conducted in Siriraj hospital, Mahidol University, Thailand during 2019 to 2020. We included treated hypertensive patients with at least 1 antihypertensive medications and had self-home BP measurement. Hypertension subtypes were normotension (NT) (all home BPs were less than 135/85 mmHg), isolated morning hypertension (MHT)(morning BPs were only at least 135/85 mmHg), isolated evening hypertension (EHT)(evening BPs were only at least 135/85 mmHg) and sustained uncontrolled hypertension (SHT)(all home BPs were at least 135/85 mmHg). We analyzed the clinical data to evaluate blood pressure control rate and identify the associated clinical factors in the other groups. Results: Our study included 1,435 participants. The prevalence of home BP control was 55.82%, 12.61%, 7.32%, and 24.25% in NT, MHT, EHT, and SHT, respectively. Overall mean age was 63 years. There were 39.58% men. SHT group had significantly the highest body mass index, proportions of alcohol drinking and evening administration of antihypertensive medications. The participants in EHT group used the highest number of antihypertensive medication classes and chronic kidney disease was most found in this group. The multivariable analysis showed the significant association of history of CVD with MHT (OR 2.93, 95%CI (1.46 to 5.85)). The albuminuria of at least 300 mg/g was the significant associated factor of EHT (OR 3.05, 95%CI (1.23 to 7.57)) and SHT (OR 2.20, 95%CI (1.14 to 4.27)). Aging (OR 0.98, 95%CI (0.96 to 0.99)), use of thiazide diuretics (OR 3.38, 95%CI (1.03 to 11.11)), sprironolactone (OR 5.68, 95%CI (1.38 to 23.33)) and peripheral alpha1 blockers (OR 3.90, 95%CI (1.16 to 13.11)) were also strongly associated with SHT. Conclusions: BP control rate was fair. There were different clinical characteristics and independent associated factors in each subtypes.

Is peripheral alpha synuclein a marker for gait velocity in Parkinson’s disease?

BackgroundThe extent of gait abnormality is non-uniform across motor phenotypes of Parkinson’s disease (PD). The biological basis of this heterogeneity remains intriguing. Moreover, the relationship of gait impairment with various neurodegenerative protein markers in PD is not well established. ObjectivesHere, we aimed to explore the interplay between gait parameters and specific serum protein markers in PD. MethodsA total of 62 PD patients were consecutively recruited. Blood samples and gait data were acquired from 37 and 34 patients respectively. Two-dimensional spatio-temporal gait parameters were estimated using an electronic walkway (GAITRite®, CIR Systems Inc., USA). Serum phosphorylated alpha synuclein (p-Ser129-a-syn) and total a-syn levels were measured using commercially available ELISA kit. Data was analyzed using SPSS Version 20 (IBM). ResultsWe found that phosphorylated a-syn levels were significantly higher in PD patients with postural instability and gait difficulty compared to tremor dominant variant. Significant reduction in gait velocity was also observed with increasing levels of this pathological form of a-syn. Regression modelling showed that phosphorylated a-syn is an independent predictor of gait velocity. DiscussionOur findings indicate that concentrations of peripheral p-Ser129-a-syn but not total a-syn could be a potential contributor of gait impairment in PD. Further investigation on the systemic role of phosphorylated a-syn on gait would bridge the gap between central and peripheral mechanisms underlying phenotypic variability in PD.

Use of Midodrine in Heart Failure: Two Case Reports and a Review of the Literature.

Hypotension in patients with heart failure is much more frequent in daily clinical practice than the 10–15% reported in clinical trials. In patients with heart failure with reduced ejection fraction (HFrEF), hypotension frequently limits the initiation and up-titration of guideline-directed medical therapy (GDMT). Midodrine is a peripheral alpha-1 agonist and a vasopressor anti-hypotensive agent approved for the treatment of orthostatic hypotension. We describe two cases where midodrine was prescribed in patients with HFrEF and hypotension.LEARNING POINTSHypotension in patients with systolic heart failure is a frequent presentation and can limit the initiation and optimization of guideline-directed medical therapy.Midodrine is a peripheral alpha-1 agonist and anti-hypotensive agent approved for the treatment of orthostatic hypotension.Midodrine may be used off-label in patients with heart failure with reduced ejection fraction (HFrEF) and symptomatic hypotension to allow optimization of medical therapy.

Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration

Abstract Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged &amp;gt;3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p&amp;lt;0.05) DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Repurposing of Iloperidone: Antihypertensive and ocular hypotensive activity in animals

PurposeIloperidone, second generation antipsychotic drug, reported in clinical trial to produce orthostatic hypotension as side effect. It was claimed to be antagonistic at alpha adrenergic receptor in central nervous system. We evaluated effect of Iloperidone on peripheral alpha 1 adrenoreceptor by in silico and in vitro methods while in vivo hypotensive, antihypertensive and ocular hypotensive activity was evaluated in animals. MethodsPharmacological activity prediction of Iloperidone was done using PASSOnline and SwissTargetPrediction softwares and molecular docking with Alpha 1A adrenoreceptor using AutoDock Vina. Hypotensive activity in normotensive and antihypertensive activity against DOCA-salt induced hypertension in rats were evaluated at doses 0.03 mg/Kg and 0.1 mg/Kg, i.p of Iloperidone. Blood pressure was measured by invasive blood pressure measurement technique using PowerLab 4/30 and intraocular pressure was measured using digital tonometer. ResultsIloperidone (0.1 mg/Kg) showed significant decrease in blood pressure (38.96 ± 1.1%) in normotensive rats, while in DOCA salt induced hypertensive rats, systolic blood pressure was found to be decreased by 29.04 ± 1.45% and 31.43 ± 1.21% in 0.03 mg/Kg and 0.1 mg/Kg treated rats respectively. Iloperidone prevented rise in systolic BP with adrenaline. Intraocular pressure was found to be decreased by 36.66 ± 3.15% in rabbits after 1 h of instillation of 0.1% Iloperidone. ConclusionIloperidone exerted hypotensive and/or anti-hypertensive activity in rats and ocular hypotensive activity in rabbits.

Fast determination of mazindol in hair sample using UPLC-MS/MS: An isotopic identification approach

Accidents on Brazilian highways kill more than 40 thousand people every year, not considering those who are injured and/or disabled by them. Since the implementation of federal law 13103/2015 to control the use of drugs by truck drivers, where the control is done by analysis of the substance in hair by a retroactive minimum period of 90 days, more than 100.000 people have been detected with a presence of one or more prohibited drugs in their hair samples. The Mazindol (cutoff of 0.5 ng/mg) is on of fourteen prohibited substances in the list and the second most stimulant in use. Mazindol is a sympathomimetic agonist causing central nervous system stimulation, acting together at peripheral alpha and beta-receptors. However, a serious side effect is the alteration of perception, which can be associated with accidents involving roads. In Brazil, the National Sanitary Agency (ANVISA) banned the production and marketing of this substance throughout the national territory in 2011, as the drug did not present proven effectiveness in its main indication: the treatment of obesity. After six years, in June of 2017 the federal law by the Brazilian congress (13.454/2017) authorizes once again the production and marketing of mazindol, amphetamine, sibutramine and femproporex. Nowadays, the majority of Brazilian laboratories use the mass spectrometry technique as a screening and confirmatory test on their routine analyses. The present study presents the use of isotopic separation by UPLC-MS/MS to confirm the presence of mazindol in a hair sample. Hair samples collected from real cases were obtained from authorized patients for the study. The method was validated and accredited to ISO/IEC 17025 standards for the specificity, sensitivity, linearity, accuracy, precision, recovery, and stability using 10 mg of hair. LOD and LOQ were 0.25 ng/mg. The chromatography run time was 2.2 min. The hair samples were washed and then extracted with organic solvent in the presence of deuterated analogues followed by an incubation under 60 °C for 8 h Reverse phase separation was performed with the Acquity BEH C18 chromatographic column (50 × 2.1 mm × 1.7 μm). Mazindol has chlorine atom in its chemical structure; it's possible to perform an isotopic separation and identification as the approach to confirm mazindol in hair. Considering the chlorine isotope has 35 Cl and 37 Cl in 1/3 proportion, the mass spectrometry was set to determine 285.1 and 287.1 m/z with transition 44 m/z. Instead of evaluating one parent ion and one product ion, we evaluated two parent ions (isotopic) and the same product ion. Due the mazindol presents interference in the most intense fragment in a fast-chromatographic analysis, the fragment 285.2 > 44 m/z has no interference in real samples. For mazindol quantitation, the transition 285.1 > 44 m/z can be used and for confirmation criteria an isotope transition of mazindol 287.1 > 44 m/z can be used, thus increasing the reliability of the generated data without interference. The method was applied in a two real sample and mazindol was determined and confirmed by the present method, 1.18 ng/mg and 2.18 ng/mg. The isotope separation and identification by tandem triple quads is a useful way to confirm chemical structure when there is no formation or there is a no abundant formation of ion for quality analysis and confirmation the presence of substance using a fat chromatographic separation.

Amitraz : Unusual human toxicity

Amitraz is a chemical which is widely used as an insecticide in pest control. Toxicity of amitraz is seen due to its agonistic action on central and peripheral alpha receptors. Amitraz poisoning mimics organophosphate poisoning. We present a case of nine year old boy who ingested six ml of amitraz accidentally and slept. He was found having nausea, dizziness followed by vomiting. He was rushed to the hospital within 2 hrs of ingestion were gastric lavage was done and child was referred to emergency department at Pgims rohtak. He was managed supportively and symptomatically in emergency department for bradycardia and miosis. There is no specific antidote for amitraz poisoning. The mangement is supportive and symptomatic.

AUTONOMIC DYSREGULATION IN PRIMARY HYPERTENSION

Objective: Introduction: Would cardiovascular autonomic reflexes help in understanding the diagnosis and the management of primary hypertension (PHT). The purpose of this study was to evaluate the cardiovascular autonomic reflexes in patients with primary hypertension (PHT), including masked hypertension (MHT), hypertension with type 2 diabetes (DHT), orthostatic hypertension (OHT) and orthostatic hypotension (OHypoT). Design and method: Patients and Methods. This prospective study included two groups: normotensive group, NT (N = 120) and primary hypertensive group, PHT (N = 120). The PHT group was divided in different subgroup: N1 = subgroup of MHT, N2 = subgroup of DHT, N3 = subgroup of OHT and N4 = subgroup of OHypoT. The PHT group as well as the subgroups were compared to NT group. The cardiovascular autonomic tests performed in these groups, included deep breathing (DB), hand-grip (Hg), mental stress (MS) and orthostatic (Orth) tests. Statistical analysis was done using the Student's t-test. Results: Results. Cardiovascular autonomic reflexes responses were as follows: Compared to NT, 1. Central alpha adrenergic response to mental stress test was of 20,0 ± 9,8% vs 15,2 ± 8,6% (p < 0,001) in PHT; 24,7 ± 7,2% vs 15,2 ± 4,5% (p < 0,001) in MHT; and 23,48 ± 9,82% vs 20,28 ± 9,60%(p = 0,243) in DHT. 2. Peripheral alpha adrenergic response to hand grip test of 16,7 ± 7,5% vs 13,3 ± 6,5% (p < 0,001) in PHT; 27,0 ± 5,4% vs 16,4 ± 4,5% (P < 0,001) in MHT; and 20,03 ± 8,05 vs 21,71 ± 11,23% (p = 0,588) in DHT. 3. Vagal response to deep breathing test was of 30,2 ± 8,1% vs 46,1 ± 2,1% (p < 0,001) in PHT; 30,5 ± 10,4% vs 32,7 ± 11,3% (p = 0,1) in MHT; and 23,09 ± 11,06% vs 34,15 ± 17,7% (p < 0,001) in DHT. Of interest orthostatic test showed that 70% of PHT had orthostatic hypertension and 15% orthostatic hypotension. Conclusions: Conclusion. PHT, hypertensive with type 2 diabetes, MHT have a significantly higher sympathetic response when compared to controls and vagal response significantly lower. The latter is accentuated by the association of diabetes to hypertension. The results attest that cardiovascular autonomic reflexes study is of high interest in assessing PHT

Antipsychotics, chlorpromazine and recurrent priapism: a review over a case

Priapism is a rare urological emergency characterized by painful erection exceeding 4-6 h and generally occurring independently of sexual desire and sexual relations. The etiology is broad and various. The ischemic type represents 95% of all cases of priapism. No cause is determined in 60% of cases of ischemic priapism, while hematological diseases, a history of drug use, malignity or a history of neurological disease can be identified in 40%. The drugs most commonly associated with priapism are antipsychotics, antidepressants, anticoagulants and antihypertensives. Although antipsychotic agents are implicated in 15-26% of cases of priapism, the mechanism involved in drug-associated priapism is unclear. The peripheral alpha 1 blocking activities of psychotropic agents or central serotonin-like activities are, however, implicated. The phenothiazine group antipsychotic agents chlorpromazine and thioridazine have the highest alpha adrenergic activity and are the antipsychotics most reported in association with priapism. Chlorpromazine is an antipsychotic with high alpha 1 antagonistic activity, and cases of priapism associated with use of chlorpromazine at varying doses and for varying durations have been reported. In this case report, the priapism in the patient with schizoaffective disorder is associated with intramuscular injection of chlorpromazine, in this regard the priapism cases and predictive factors in the literature is reviewed for the aim of increasing the sensitivity of clinician across the adverse effects of drugs and the importance of adequate psychiatric history and medical history taking and registering adverse effects of drugs is emphasized.

Prolonged Use of Dexmedetomidine Infusion in an Infant for Sedation as Adjuvant Therapy

Dexmedetomidine, a central and peripheral alpha-2 receptor agonist approved by the FDA for the use in patients 18 years old and older, it has been increasingly used in the pediatric population for sedation and analgesia due to its advantage of minimal respiratory depression and lack of abuse/dependence. This is a case report of a successful use of dexmedetomidine in an infant for 15 weeks achieving; symptom control, reduction in the dose of opioids and benzodiazepines by 50% and a safe transition to oral equivalents.

Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release.

Pathophysiological mechanisms of chronic visceral pain (CVP) are unknown. This study explores the association between the sympathetic system and bladder nociceptors activity by testing the effect of a prolonged adrenergic stimulation on transient receptor potential vanilloid 1 (TRPV1) activity and on urothelial adenosine triphosphate (ATP) release. Female Wistar rats received saline, phenylephrine (PHE), PHE+silodosin, PHE+naftopidil or PHE+prazosin. TRPV1 knockout and wild-type mice received saline or PHE. Visceral pain behaviour tests were performed before and after treatment. Cystometry was performed, during saline and capsaicin infusion. Fos immunoreactivity was assessed in L6 spinal cord segment. Human urothelial ATP release induced by mechanical and thermal stimulation was evaluated. Subcutaneous, but not intrathecal, PHE administration induced pain, which was reversed by silodosin, a selective alpha 1A adrenoceptor antagonist, but not by naftopidil, a relatively selective antagonist for alpha 1D adrenoceptor. Silodosin also reversed PHE-induced bladder hyperactivity and L6 spinal cord Fos expression. Thus, in subsequent experiments, only silodosin was used. Wild-type, but not TRPV1 knockout, mice exhibited phenylephrine-induced pain. Capsaicin induced a greater increase in voiding contractions in PHE-treated rats than in control animals, and silodosin reversed this effect. When treated with PHE, ATP release from human urothelial cells was enhanced either by mechanical stimulation or by lowering the thermal threshold of urothelial TRPV1, which becomes abnormally responsive at body temperature. This study suggests that the activation of peripheral alpha 1A adrenoceptors induces CVP, probably through its interaction with TRPV1 and ATP release.

Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane

ObjectiveTo investigate MK-467 as part of premedication in horses anaesthetized with isoflurane. Study designExperimental, crossover study with a 14 day wash-out period. AnimalsSeven healthy horses. MethodsThe horses received either detomidine (20 μg kg−1 IV) and butorphanol (20 μg kg−1 IV) alone (DET) or with MK-467 (200 μg kg−1 IV; DET + MK) as premedication. Anaesthesia was induced with ketamine (2.2 mg kg−1) and midazolam (0.06 mg kg−1) IV and maintained with isoflurane. Heart rate (HR), mean arterial pressure (MAP), end-tidal isoflurane concentration, end-tidal carbon dioxide tension, central venous pressure, fraction of inspired oxygen (FiO2) and cardiac output were recorded. Blood samples were taken for blood gas analysis and to determine plasma drug concentrations. The cardiac index (CI), systemic vascular resistance (SVR), ratio of arterial oxygen tension to inspired oxygen (PaO2/FiO2) and tissue oxygen delivery (DO2) were calculated. Repeated measures anova was applied for HR, CI, MAP, SVR, lactate and blood gas variables. The Student's t-test was used for pairwise comparisons of drug concentrations, induction times and the amount of dobutamine administered. Significance was set at p < 0.05. ResultsThe induction time was shorter, reduction in MAP was detected, more dobutamine was given and HR and CI were higher after DET+MK, while SVR was higher with DET. Arterial oxygen tension and PaO2/FiO2 (40 minutes after induction), DO2 and venous partial pressure of oxygen (40 and 60 minutes after induction) were higher with DET+MK. Plasma detomidine concentrations were reduced in the group receiving MK-467. After DET+MK, the area under the plasma concentration time curve of butorphanol was smaller. Conclusions and clinical relevanceMK-467 enhances cardiac function and tissue oxygen delivery in horses sedated with detomidine before isoflurane anaesthesia. This finding could improve patient safety in the perioperative period. The dosage of MK-467 needs to be investigated to minimise the effect of MK-467 on MAP.

Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs

The haemodynamic interactions of a step infusion with medetomidine (MED) and the peripherally acting alpha-2 antagonist MK-467 (MK) were compared with MED infused alone in isoflurane-anaesthetised dogs. Eight purposely-bred Beagles were used in a randomised crossover study. Anaesthesia was induced with propofol intravenously (IV) and maintained with isoflurane in oxygen. Dogs received 1.25 µg/kg MED as a 1 min loading dose IV, along with a step-down MED infusion at rates of 8.0 µg/kg/h (step 1: 0–20 min), 5.5 µg/kg/h (step 2: 20–40 min) and 4.0 µg/kg/h (step 3: 40–95 min). Five minutes after starting the MED infusion, the dogs received MK-467 in a step-up infusion at rates of 100 µg/kg/h (step 1: 5–35 min), 200 µg/kg/h (step 2: 35–65 min) and 500 µg/kg/h (step 3: 65–95 min). Heart rate (HR), systolic (SAP) and mean arterial (MAP) blood pressures and arteriovenous oxygen content differences (a-vO2 diff) were calculated. Plasma drug concentrations were analysed. Repeated-measures general linear mixed models with Bonferroni correction were used for statistical analyses.MED infusion alone increased SAP maximally by 24.9%, MAP by 34.7% and a-vO2 diff by 222.5%, and reduced HR by 32.3%, but these changes were significantly attenuated by MK-467. Most MED effects returned to baseline during step 2 of MK-467 infusion and step 3 of MED infusion (MED/MK-467 ratio 1:18 to 1:50). Plasma concentrations of MED tended to be lower with the addition of MK-467. The use of step infusions helped to narrow down the therapeutic range for the MED/MK-467 infusion dose ratio during isoflurane anaesthesia in dogs.

Sympathetic Overactivity in Hypertension and Cardiovascular Disease

From the first description of its anatomy by T. Willis to the novel therapeutic manipulations, it is unanimously recognized that the sympathetic nervous system (SNS) holds a crucial role in cardiovascular homeostasis. The introduction of sophisticated techniques, as microneurography and regional norepinephrine spillover provided the evidence for the role of sympathetic overactivity in various cardiovascular disease entities. Sympathetic activation is common in patients with essential hypertension and contributes to initiation, maintenance and progression of the disease and it contributes to the manifestation of its major complications. A considerable body of evidence relates SNS overactivity with high sodium intake in experimental animals and humans and the underlying mechanisms have nowadays been elucidated. SNS activity is more pronounced in patients with resistant hypertension and there are several conditions that lead to this phenomenon, as older age, kidney disease, obesity and metabolic syndrome, mental stress and sleep apnea. SNS overactivity holds also a key physiopathological role in heart failure, acute coronary syndromes and arrhythmias. Moreover, inhibition of sympathetic overactivity by various means, including central SNS suppressing drugs, peripheral alpha- and beta- adrenergic receptor blockers, or novel approaches as renal sympathetic denervation have been used successfully in the treatment of all these disorders.

The role of the sympathetic nervous system in the resuscitative effect of stimulating the central serotonin 1A receptors in haemorrhagic shock in rats

Haemorrhagic shock is a life threatening condition, and, as such, it is important to understand the mechanisms taking part in its reversal. In the 1990s, it was shown that activation of serotonin 1A receptors is responsible for the circulatory decompensation and development of the sympathoinhibitory phase. In previous reports, it was demonstrated that activation of serotonin 1A receptors induces resuscitative effects in haemorrhaged rats. However, the effectory mechanisms still require further investigation. The aim of the present study was to determine whether the sympathetic nervous system participates in the effects of serotonin through central serotonin 1A receptors in haemorrhagic shock in rats. In order to determine the role of the sympathetic nervous system alpha-1-, alpha-2-, and beta-adrenergic receptor agonists – prazosin, yohimbine and propranolol, respectively, were used. We found that stimulation of the central serotonin 1A receptors by the administration of a selective agonist – 8-hydroxy-2-(di-n-propylamino)tetralin, 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (8-OH-DPAT) into the lateral brain ventricle is connected with the activation of compensation mechanisms leading to the increase in the heart rate and blood pressure. The current results demonstrate that the stimulation of peripheral alpha-1-, alpha-2- and beta-adrenergic receptors plays an essential role in the resuscitative effect triggered by the stimulation of central serotonin 1A receptors.

Plasma Nitric Oxide (NO) and Tumor Necrosis Factor-α (TNF-α) Levels, Adenosine Deaminase (ADA), Gamma Glutamyl Transferase (GGT) Activities and to Determine the Rate of Lymphocytes in the Peripheral Blood Leukocytes Alpha Naphthyl Acetate Esterase (ANAE) in Cattle with Leptospirosis

Plasma Nitric Oxide (NO) and Tumor Necrosis Factor-α (TNF-α) Levels, Adenosine Deaminase (ADA), Gamma Glutamyl Transferase (GGT) Activities and to Determine the Rate of Lymphocytes in the Peripheral Blood Leukocytes Alpha Naphthyl Acetate Esterase (ANAE) in Cattle with Leptospirosis

Chronic Stress in the Development of Essential Hypertension, Role of Rilmenidine in the Treatment of Stress Induced Hypertension

Hypertension is an independent risk factor of cardiovascular diseases. Several factors contribute to its development, including chronic stress, which may induce hypertension by increasing sympathetic activity. The signs of increasing sympathetic activity can be primarily detected in the initial phase of hypertension, which is characterized by the increase in cardiac output. In addition to the hemodynamic consequences (increase in cardiac output, tachycardia, coronary vasoconstriction, proarrhythmia), the increase in sympathetic activity has many harmful effects. Numerous metabolic (insulin resistance, dyslipidemia), structural and trophic effects (endothelial dysfunction, vascular hypertrophy, myocardial hypertrophy), as well as thrombotic and humoral processes (procoagulation, enhancement of thrombocyte aggregation, sodium retention, activation of the renin-angiotensin-aldosterone axis) may develop and consequently damage body functions at many targets. Several different antihypertensive drug classes are available for reducing increased sympathetic activity, including peripheral alpha and beta blockers and compounds with central effects. First generation antihypertensive drugs with central mechanisms of action (e.g. clonidine, guanfacine, alpha-methyldopa) is currently rarely administered and only for a few indications as they have a significant adverse events profile. Among second generation compounds with central effects, rilmenidine stimulates imidazoline-1 receptors and thus beneficially influences mild or moderate hypertension that involves enhanced sympathetic nervous system activity.

Dermal Exposure to a Compounded Pain Cream Resulting in Severely Elevated Clonidine Concentration

Clonidine is an imidazoline derivative antihypertensive medication that is also used as adjunctive therapy for neuropathic pain disorders via topical administration. Clonidine overdose can manifest both central and peripheral alpha-adrenergic agonist effects. A 23-year-old man presented to an emergency department with altered mental status, bradycardia, and hypertension after suspected overdose. He had rubbed a specially compounded medicinal cream over his entire body containing clonidine 0.2% (w/w), gabapentin 6%, imipramine 3%, ketamine 10%, lidocaine 2%, and mefenamic acid 1%. The patient presented with severe hypertension, bradycardia, and altered mental status. He was found to have a subarachnoid hemorrhage and was treated for hypertensive emergency. Toxicological analysis of initial blood samples revealed a serum clonidine concentration of 5,200ng/ml. At 6-month follow-up, the patient had made a full recovery. There are limited reports of topical clonidine toxicity, and to our knowledge, this case involves the highest concentration yet reported following clonidine overdose by any route of exposure. The severely elevated serum clonidine concentration found in our patient demonstrates the possibility of toxicity resulting from inappropriate use of such a product. At high serum concentrations, the pharmacodynamic effects of clonidine appear to cause significant peripheral alpha-1 adrenergic stimulation. Toxicologists should be aware of the increasing use of topical clonidine preparations for the treatment of neuropathic pain and the potential for toxicity.

55 Adverse Events Following the Combination of Dexmedetomidine with Therapeutic Hypothermia in a Piglet Asphyxia Model

BackgroundDexmedetomidine (DXM) is a potent, selective a2 adrenoceptor agonist which exerts sedative, neuroprotective, analgesic and anti-inflammatory properties that may be beneficial for neonatal asphyxia. The safety of DXM combined with...