Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bi-potential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. While Notch2 has a dominant role in IHBD formation there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Since changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. Conclusion There is a threshold requirement for Notch signaling at multiple steps, IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture.

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9, 46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

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