Zolmitriptan: a novel portal hypotensive agent which synergizes with propranolol in lowering portal pressure.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Pamplona, Spain. mmreboredo@unav.es
Mercedes
M
Reboredo
Haisul C Y
HC
Chang
Roberto
R
Barbero
Carlos M
CM
Rodríguez-Ortigosa
Francisco
F
Pérez-Vizcaíno
Asunción
A
Morán
Mónica
M
García
Jesús M
JM
Banales
Norberto
N
Carreño
Félix
F
Alegre
Ignacio
I
Herrero
Jorge
J
Quiroga
Jesús
J
Prieto
Bruno
B
Sangro
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride; D002395:Catecholamines / Q000494:pharmacology; D003135:Common Bile Duct / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology*; D007262:Infusions, Intravenous; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D008236:Lypressin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D023303:Oxazolidinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010477:Perfusion; D017082:Portal Pressure / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects; D013562:Sympathectomy; D000077585:Terlipressin; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002395:Catecholamines; D023303:Oxazolidinones; D014363:Tryptamines; C089750:zolmitriptan; D008236:Lypressin; D000077585:Terlipressin; D011433:Propranolol; D002251:Carbon Tetrachloride; D000242:Cyclic AMP