Journal Article

Zolmitriptan: A Novel Portal Hypotensive Agent Which Synergizes with Propranolol in Lowering Portal Pressure

Alegre, Félix, Banales, Jesús M., García, Mónica, Reboredo, Mercedes, Rodríguez-Ortigosa, Carlos M., Prieto, Jesús, Morán, Asunción, Barbero, Roberto, Quiroga, Jorge, Sangro, Bruno, Carreño, Norberto, Herrero, Ignacio, Pérez-Vizcaíno, Francisco, Chang, Haisul C. Y.

2013

Overview

Only a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol. ZOLMITRIPTAN, PROPRANOLOL OR BOTH WERE TESTED IN TWO RAT MODELS OF PORTAL HYPERTENSION: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan. In both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of β2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by β2-agonists. Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adrenergic beta-Antagonists - pharmacology / Adrenergic beta-Antagonists - therapeutic use / Anesthesia / Animal models / Animals / Antihypertensive Agents - pharmacology / Antihypertensive Agents - therapeutic use / Bile / Bile ducts / Biology / Blood flow / Blood pressure / Body Weight - drug effects / Carbon Tetrachloride / Cardiac output / Catecholamines - pharmacology / Cirrhosis / Common Bile Duct - drug effects / Common Bile Duct - pathology / Common Bile Duct - physiopathology / Cyclic adenosine monophosphate / Cyclic AMP / Cyclic AMP - metabolism / Descent / Drug dosages / Drug Synergism / Drug Therapy, Combination / Gastroenterology / Gene therapy / Heart diseases / Hemodynamics / Hepatology / Hypertension / Hypertension, Portal - drug therapy / Hypertension, Portal - physiopathology / Infusions, Intravenous / Kidneys / Laboratories / Ligation / Liver cirrhosis / Liver Cirrhosis, Experimental - drug therapy / Liver Cirrhosis, Experimental - physiopathology / Lypressin - analogs & derivatives / Lypressin - pharmacology / Lypressin - therapeutic use / Medical research / Medicine / Mesenteric Artery, Superior - drug effects / Mesenteric Artery, Superior - pathology / Mesenteric Artery, Superior - physiopathology / Oxazolidinones - administration & dosage / Oxazolidinones - pharmacology / Oxazolidinones - therapeutic use / Patients / Perfusion / Pharmacology / Portal Pressure - drug effects / Propranolol / Propranolol - pharmacology / Propranolol - therapeutic use / Rats / Regional Blood Flow - drug effects / Renal Artery - drug effects / Renal Artery - physiopathology / Rodents / Splanchnic Circulation - drug effects / Surgery / Sympathectomy / Sympathetic nervous system / Tryptamines - administration & dosage / Tryptamines - pharmacology / Tryptamines - therapeutic use / Vasoconstriction / Vasodilation - drug effects / Veins & arteries / Venous pressure / Zolmitriptan