Ambrisentan: A New Drug For Pulmonary Arterial Hypertension

Questions Yet To Be Answered

PAH is a vasculopathy; the vascular abnormalities (e.g., sustained vasoconstriction and excessive vascular remodeling and intimal lesions) occur primarily in the medium-sized and small pulmonary arteries (or distal arteries). Although the potential beneficial effect of ETA-selective blockade appears obvious, more studies need to be done using human pulmonary arteries to confirm that: a ) the ETA receptor on pulmonary artery smooth muscle cells is the predominant receptor that mediates vasoconstriction; b ) the ETB receptor on pulmonary artery endothelial cells is the predominant receptor responsible for production and release of NO, prostacyclin, and EDHF; c ) the ETB receptor on pulmonary artery smooth muscle cells and pulmonary artery endothelial cells is involved in ET endocytosis; d) that blockade of ETA receptors can significantly inhibit agonist-induced pulmonary vasoconstriction and mitogen-mediated proliferation and migration in tissues and cells isolated from PAH patients.

Based on kinetic studies, binding of ET-1 to ETA receptor is largely irreversible,[52] so an ETA receptor antagonist (e.g., ambrisentan) should affect only receptors that were not previously bound to ET-1. In other words, it should be very difficult for the blocker (e.g., ambrisentan) to bind to the ET-1-bound form of the ETA receptor. Because ambrisentan is effective in treating patients with PAH, it suggests that the turnover time of ETA receptors is rapid and there are more “unoccupied' receptors than ET-1-bound receptors on the cell membrane. To prove this, it is critical to know the half-life of ETA mRNA and protein in vascular tissue isolated from the lungs of patients with PAH. If ETA receptors in cells from PAH patients are mostly occupied or bound to ET-1 (especially in patients with high levels of ET-1 in the plasma), it may indicate ambrisentan works through mechanisms other than by antagonizing the binding of ET-1 to ETA receptors.  Printer- Friendly Email This

AccessMedicine from McGraw-Hill.  2008; ©2008 The McGraw-Hill Companies
All rights reserved. From Tintinalli's Emergency Medicine
This is a part of article Ambrisentan: A New Drug For Pulmonary Arterial Hypertension Taken from "Sildenafil Citrate Tablet" Information Blog