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

Abstract

ObjectiveOnly 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.MethodsZolmitriptan, 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.ResultsIn 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.ConclusionZolmitriptan 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.

Effects of new generation triptans – frovatriptan and almotriptan – on hemodynamic parameters in intact male and female rats

“…This effect is a possible explanation for the results in our experiments with almotriptan and frovatriptan on intact animals. Reboredo et al (8) suggest that 5-HT 1B/1D receptors are extremely expressed in mesenteric arteries and can mediate strong vasoconstriction effects (8).…”

Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis

“…Nonselective betablockers, represented by propranolol, are the only drugs recommended for prophylaxis against variceal bleeding in cirrhotic patients . However, less than a half of patients accepting NSBBs treatment can achieve the therapeutic goal of reducing portal pressure to below 12 mmHg or at least 20% of baseline . As we know, the pathological process of PHT refers to several pathophysiologic mechanisms including hemodynamic alterations, inflammatory pathways activation, and neoangiogenetic induction .…”

“…9 However, less than a half of patients accepting NSBBs treatment can achieve the therapeutic goal of reducing portal pressure to below 12 mmHg or at least 20% of baseline. 10,11 As we know, the pathological process of PHT refers to several pathophysiologic mechanisms including hemodynamic alterations, inflammatory pathways activation, and neoangiogenetic induction. [12][13][14] Our previous work demonstrated AG490, the specific inhibitor of JAK2/STAT3 signaling, could significantly reduce portal pressure and ameliorate organic fibrogenesis and neoangiogenesis.…”

Alkaloids inErythrinaby UPLC-ESI-MS andIn VivoHypotensive Potential of Extractive Preparations

“…In order to investigate some possible mechanisms involved in the hypotensive response of the extracts, some drugs were tested after 30 minutes of stabilization: L-NAME, an NO synthesis inhibitor (30 mg/kg, n = 8); losartan, AT1 receptor antagonist of angiotensin II (10 mg/kg, n = 8); hexamethonium, ganglionic blocker (20 mg/kg, n = 8); and propranolol, β -adrenergic blocker (5 mg/kg, n = 8) [ 24 – 27 ]. After drug administration, a new stabilization period was done and then the extract was administrated (25 mg/kg and 50 mg/kg).…”