Dataset Information

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

ABSTRACT:

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 ?2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by ?2-agonists.

Conclusion

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.

SUBMITTER: Reboredo M

PROVIDER: S-EPMC3547109 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

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

Reboredo Mercedes M Chang Haisul C Y HC Barbero Roberto R Rodríguez-Ortigosa Carlos M CM Pérez-Vizcaíno Francisco F Morán Asunción A García Mónica M Banales Jesús M JM Carreño Norberto N Alegre Félix F Herrero Ignacio I Quiroga Jorge J Prieto Jesús J Sangro Bruno B

PloS one 20130116 1

<h4>Objective</h4>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.<h4>Methods</h4>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 includin ...[more]

PMID: 23341903

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Project description:Background The current standard for assessing the severity of portal hypertension is the invasive acquisition of hepatic venous pressure gradient (HVPG). A noninvasive US-based technique called subharmonic-aided pressure estimation (SHAPE) could reduce risk and enable routine acquisition of these pressure estimates. Purpose To compare quantitative SHAPE to HVPG measurements to diagnose portal hypertension in participants undergoing a transjugular liver biopsy. Materials and Methods This was a prospective cross-sectional trial conducted at two hospitals between April 2015 and March 2019 (ClinicalTrials.gov identifier, NCT02489045). This trial enrolled participants who were scheduled for transjugular liver biopsy. After standard-of-care transjugular liver biopsy and HVPG pressure measurements, participants received an infusion of a US contrast agent and saline. During infusion, SHAPE data were collected from a portal vein and a hepatic vein, and the difference was compared with HVPG measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity of SHAPE. Results A total of 125 participants (mean age ± standard deviation, 59 years ± 12; 80 men) with complete data were included. Participants at increased risk for variceal hemorrhage (HVPG ≥12 mm Hg) had a higher mean SHAPE gradient compared with participants with lower HVPGs (0.79 dB ± 2.53 vs -4.95 dB ± 3.44; P < .001), which is equivalent to a sensitivity of 90% (13 of 14; 95% CI: 88, 94) and a specificity of 80% (79 of 99; 95% CI: 76, 84). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the HVPG measurements (r = 0.68). Conclusion Subharmonic-aided pressure estimation is an accurate noninvasive technique for detecting clinically significant portal hypertension. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.

Project description:OBJECTIVEVon Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.METHODSPatient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL-/- RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.RESULTSPropranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).CONCLUSIONSPropranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

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