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.
Highlights
Portal hypertension is the main complication of liver cirrhosis
We found that zolmitriptan caused a slight and transient decrease in ARF (Figure 1B) which was significantly less intense than that produced by doses of terlipressin that induced similar effects on portal venous pressure (PVP) (Figure 1C and D)
In rats subjected to four weekCBDL, we found that terlipressin (50 mg/kg) provoked a substantial increase of MAP (14% with respect baseline) together with a significant decrease of Cardiac output (CO) and a marked elevation of Systemic vascular resistance (SVR) while zolmitriptan caused no significant changes in CO and SVR and only a mild elevation of MAP (1% with respect baseline) (Figure 2A, B and C)
Summary
Portal hypertension is the main complication of liver cirrhosis. It develops in the majority of patients and is responsible for massive gastrointestinal bleeding from ruptured gastro-esophageal varices. Portal hypertension is associated with the development of hyperdynamic circulation as result of intense splanchnic vasodilation and increased splanchnic blood flow [2] Pharmacological therapy of this condition is basically aimed at correcting the increased portal blood inflow using splanchnic vasoconstrictors. Propranolol seems to act by limiting the splanchnic vasodilating effects resulting from the enhanced b2-adrenoceptor drive present in cirrhotic patients owing to increased sympathetic tone [3]. Others vasoconstrictors, such as somatostatin or terlipressin, require parenteral administration and are only used for short-term administration, as in the treatment of acute variceal hemorrhage [1]. Only 37% of patients are hemodynamic responders to propranolol [4]
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