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

Abstract

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 orbothwere tested intwo ratmodelsof portal hypertension: commonbileduct ligation(CBDL) andCCl4-inducedcirrhosis. Intheseanimalswemeasureddifferenthemodynamicparameters including portalvenouspressure,arterial renal flow,portalbloodflowandcardiacoutput.Wealsostudiedthechanges insuperior mesenteric artery perfusionpressure and inarterial wall cAMP levels inducedby zolmitriptan, propranolol or both. Moreover,wedeterminedtheeffectofsplanchnicsympathectomyontheresponseofPVPtozolmitriptan. Results:Inbothmodelsofportalhypertensionzolmitriptaninducedadose-dependenttransientdescentofportalpressure accompaniedbyreductionofportalflowwithonlyslightdecreaseinrenalflow. Incirrhoticrats,splanchnicsympathectomy intensifiedandprolongedzolmitriptan-inducedportalpressuredescent.Also,propranololcausedmoreintenseanddurable portalpressurefallwhencombinedwithzolmitriptan.Mesentericarteryperfusionpressurepeakedforabout1minupon zolmitriptanadministrationbutshowednochangewithpropranolol.Howeverpropranololenhancedandprolongedthe elevation inmesenteric artery perfusionpressure inducedby zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of b2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranololandzolmitriptansignificantlyreducedtheelevationofcAMPcausedbyb2-agonists. Conclusion:Zolmitriptanreducesportalhypertensionandnon-selectivebeta-blockerscanimprovethiseffect.Combination therapydeservesconsiderationforpatientswithportalhypertensionfailingtorespondtonon-selectivebeta-blockers.