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In 2011, Lowe appeared on The Oprah Winfrey Show and stated that he left the show because he did not feel he was being respected, when the other lead characters received a raise and he did not. In 2005, he starred as Lieutenant Daniel Kaffee in a London West End production of Sorkin's play A Few Good Men, the first time the two had worked together since The West Wing.
After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
He recalled meeting Paul Newman there, and that the older actor encouraged him to work in the theatre in 1993 when filming a British TV production of the Tennessee Williams play Suddenly, Last Summer with (the now) Dame Maggie Smith and Natasha Richardson.
In addition to his 2001 Emmy nomination for The West Wing, He is of German, English, Irish, Scottish, and Welsh ancestry. , Lowe found out that one of his ancestors, Christopher East, was a Hessian soldier.In June 2006, he was the guest host for an episode in the third series of The Friday Night Project for the United Kingdom's Channel 4.Lowe has also appeared in a televised advertisement for 'Visit California', along with other celebrities including Governor Arnold Schwarzenegger.But the acclaimed cast of the show—including Allison Janney, Richard Schiff, Dulé Hill, John Spencer, Bradley Whitford, Martin Sheen (whose President Bartlet was initially scripted as a small role) and Stockard Channing (whose First Lady was initially scripted as a guest role)— were all strong actors and eventually Lowe's character was no longer the lead.Lowe and series creator Aaron Sorkin soon found themselves at odds over the network's meddling with the show, most notably the network demanding changes in the Sam Seaborn character.