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 (α) adrenoceptor antagonist.

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.

Pharmacological characterisation of the CB 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 CB receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline.

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.

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.

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.

The β-adrenoceptor agonist bronchodilators terbutaline and orciprenaline are also weak α-adrenoceptor antagonists.

Recently, the β-adrenoceptor agonist terbutaline was shown to have α-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 α-adrenoceptor antagonist activity of terbutaline and its structurally close resorcinol, orciprenaline, in rat isolated small mesenteric arteries set up for myography. Their α-adrenoceptor antagonist potency was then compared with their potency as β-adrenoceptor agonists.

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.

The effects of varying Mg 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 Mg (normally 1.2 mM) from the physiological salt solution (PSS) enhances the contraction.

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 ET 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.

Distortion of K estimates of endothelin-1 ET and ET receptor antagonists in pulmonary arteries: Possible role of an endothelin-1 clearance mechanism.

Dual endothelin ET and ET receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ET receptor-mediated clearance of endothelin-1 at specific vascular sites may compromise this targeted therapy. Concentration-response curves (CRC) to endothelin-1 or the ET agonist sarafotoxin S6c were constructed, with endothelin receptor antagonists, in various rat and mouse isolated arteries using wire myography or in rat isolated trachea.

Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro.

Background: Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ET-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro.

Novel technique to determine the pK of clonidine at prejunctional α-adrenoceptors in cardiac and vascular sympathetic transmission.

Analytical pharmacology draws heavily on the concept of equilibrium of agonist and silent antagonist concentrations competing at a specific receptor site. This condition breaks down in nerve transmission when transmitter release is inhibited by prejunctional α-adrenoceptors activated by an agonist such as clonidine. We have developed a method that allows the agonist dissociation constant K of clonidine to be determined in a robust isolated right atrial assay of mouse, rat and guinea pig.

Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau.

Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer's disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects.

Novel α-adrenoceptor antagonism by the fluroquinolone antibiotic trovafloxacin.

Trovafloxacin, a fluroquinolone antibiotic, was recently found to be an inhibitor of pannexin-1 channels through which ATP is released as "find-me" signals in apoptotic Jurkat cells. Our interest in the role of pannexin-1 channels in α-adrenoceptor-mediated vasoconstriction led us to the novel finding reported here. Concentration-response curves to methoxamine and phenylephrine were competitively antagonised by trovafloxacin (1-30µM) with a pK of 5.

Vascular reactivity of rabbit isolated renal and femoral resistance arteries in renal wrap hypertension.

In rabbits with cellophane renal wrap hypertension, hindquarter and total vascular resistance changes to pressor and depressor agents are amplified compared to those of normotensive rabbits. The aim of the present study was to evaluate the in vitro pharmacodynamics of hypertensive and normotensive rabbit small artery segments isolated from the renal and hindquarter vascular beds. Using wire myography, the full range (Emax) and sensitivity (EC50) to a range of agonists of segments of renal interlobar (≈ 600 µm i.

ATP is not involved in α1-adrenoceptor-mediated vasoconstriction in resistance arteries.

Recent publications suggest that α1-adrenoceptor stimulation by exogenous agonists such as phenylephrine in resistance arteries cause contraction through the release of ATP from within the vascular smooth muscle cells. This ATP exits the cell through pannexin-1 channels to act back "autocrine-like" on P2 receptors on the smooth muscle that cause the contraction. In this work we directly test this hypothesis by using a selective P2X1 purinoceptor antagonist NF449 (1-10µM) against phenylephrine and ATP concentration-response curves in small mesenteric arteries of the rat and thoracodorsal arteries of the mouse.

Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat.

Morphine and methadone share the property of μ-opioid receptor agonism yet have markedly different cardiovascular actions suggesting additional properties are at play. We investigated the i.v.

Pannexin-1 channels do not regulate α1-adrenoceptor-mediated vasoconstriction in resistance arteries.

Recent reports have provided evidence for a new concept that in small resistance arteries α1D-adrenoceptor-mediated contraction is intimately linked to pannexin-1 (Px1) hemichannels that open to allow the release of ATP, from the smooth muscle effector cell, that acts back on P2Y purinoceptors to cause contraction. This concept mainly relied on using mefloquine 10-20μM as a putative selective Px1 channel-blocking agent to completely inhibit the contraction to phenylephrine, but not K(+) 40mM. Lower concentrations of mefloquine had no effect.

The role of voltage-operated and non-voltage-operated calcium channels in endothelin-induced vasoconstriction of rat cerebral arteries.

Endothelin-1 has been identified as a potential mediator in the pathogenesis of ischaemic stroke and cerebral vasospasm. The aim of this study was to analyse the role of voltage-operated calcium channels (VOCC) and non-VOCC in endothelin-1 induced vasoconstriction of rat cerebral arteries. Arterial segments were dissected from different regions of the cerebral circulation and responses assessed using wire myography.

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.

Dual action molecules: bioassays of combined novel antioxidants and angiotensin II receptor antagonists.

In this study we have investigated the in vitro angiotensin II receptor antagonist and antioxidant activity of a series of compounds in which the antioxidant pharmacophores (selenium, phenol, benzothiophene, ebselen or nitroxide) have been incorporated into the AT(1) receptor antagonist (sartan) milfasartan. Activity of these compounds was assessed in tissue-based assays. The novel molecules (30nM), nitrasartan or phenol-milfasartan, retained AT(1) receptor antagonist potency in rat isolated right atria.

Exogenous glutathione is essential in the testing of antioxidant capacity using radical-induced haemolysis.

Introduction: Radical-induced haemolysis has been employed by many investigators to determine the antioxidant capacity of novel compounds. However the free radical generator 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) results in the complete depletion of intracellular reduced glutathione (GSH) in cells that can no longer synthesise macromolecules. As GSH is essential in recycling certain antioxidants back to their active form, the current study examined the effects of exogenous GSH on the antioxidant capacity of quercetin, phenol, ebselen and nitroxide detected using AAPH-induced haemolysis.