title: Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat.
abstract: 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. dose-response relationships of the opioids on cardiovascular metameters in anaesthetised rats in the absence or presence of H1- and H2-receptor antagonism and the μ-opioid antagonist naloxone. In vitro tissue assays were employed to define more clearly cardiac and vascular mechanisms of action. Morphine (9, 30, 90mg/kg i.v.) decreased heart rate (HR) and mean arterial pressure (MAP) - responses that were blocked by naloxone pretreatment (10mg/kg i.v.). In contrast, methadone (3, 10, 30mg/kg i.v.) caused dramatic short-lived (1-3min) bradycardia, hypotension and lengthening of the QT interval before stabilising 5min after i.v. dosing. Only the steady-state responses of HR and MAP were blocked by naloxone. Mepyramine (10mg/kg i.v.) and cimetidine (100mg/kg i.v.) also blocked the naloxone-sensitive components. In isolated small mesenteric arteries precontracted by K(+) 62mM or endothelin-1, methadone (1-30μM) relaxed vessels while morphine (1-100μM) had no effect. Pretreatment with naloxone (10μM), indomethacin (30μM) or nitro-l-arginine (100μM) did not affect the relaxation to methadone. In rat isolated left atria, morphine and methadone inhibited inotropic responses at high concentrations (100μM). In rat papillary muscle and right atria, methadone was more than 30 times more potent at lengthening the refractory period and slowing the atrial rate than morphine. We conclude that methadone is a potent vasodilator agent, possibly through blocking L-type calcium channels.
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: to.kentung@gmail.com.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Tung
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jamesaa@unimelb.edu.au.
authors.forename: James A
authors.initials: JA
authors.lastname: Angus
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: cewright@unimelb.edu.au.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wright
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008691:Methadone / Q000009:adverse effects* / Q000494:pharmacology; D009020:Morphine / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D017450:Receptors, Opioid, mu; D009020:Morphine; D008691:Methadone
keywords: Arterial blood pressure; Cimetidine (PubChem CID: 50963); Endothelin-1 (PubChem CID: 44284481); Heart rate; Indomethacin (PubChem CID: 3715); Left atria; Mepyramine maleate (PubChem CID: 6039); Mesenteric artery; Methadone; Methadone hydrochloride (PubChem CID: 4095); Morphine; Morphine sulphate (PubChem CID: 5464280); Naloxone; Naloxone hydrochloride (PubChem CID: 5464092); Nifedipine (PubChem CID: 4485); Nω-nitro-l-arginine (PubChem CID: 440005); Papillary muscle; QT interval; Rat; Right atria