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Former top-10 star James Blake's singles career came to an end on a rainy Wednesday at the U.S. Open.

Ivo Karlovic of Croatia fired 38 aces past Blake to claim a 6-7 (2-7), 3-6, 6-4, 7-6 (7-2), 7-6 (7-2) victory in a match that lasted over three hours.

Blake's only other first-round loss here came in 1999.

"I don't know when its going to hit me. I don't think I'll be sleeping a lot tonight," Blake said.

Blake announced Monday that this would be his last tournament. The 33-year-old American ended his career with 10 singles titles. He reached the quarterfinals at the U.S. Open in 2005 and 2006 and Australian Open in 2008, and also landed in the final at the Tennis Masters Cup in 2006.

"It's hitting me now I'm never going to have this again in my life, a teary- eyed Blake said. "That ovation makes me realize every bit of hard work is worth it."

In 2004, while practicing with fellow American Robby Ginepri in Rome, Blake broke his neck when he slipped on a clay court and collided with the net post. In July of that year, his father died of stomach cancer. At the same time, Blake developed shingles, which temporarily paralyzed half his face and blurred his sight.

Blake was the ATP's Comeback Player of the Year in 2005 and was named the Arthur Ashe Humanitarian of the Year in 2008.

Meanwhile, defending champion Andy Murray and former title winner Juan Martin del Potro posted first-round wins on Wednesday.

The third-seeded Murray cruised past French left-hander Michael Llodra 6-2, 6-4, 6-3. The reigning Wimbledon and U.S. Open titlist beat Novak Djokovic in last year's final in Flushing and was a runner-up here in 2008.

Murray will next do battle with Leonardo Mayer, who took down Victor Hanescu 7-6 (7-4), 6-4, 3-6, 7-6 (7-4).

The sixth-seeded 2009 champion del Potro snuck past Guillermo Garcia-Lopez by a 6-3, 6-7 (5-7), 6-4, 7-6 (9-7) margin in a match that lasted over four hours on a rainy Wednesday.

Garcia-Lopez saved three match points in the final tiebreaker before del Potro put him away.

The last time del Potro came into the U.S. Open seeded No. 6 was four years ago and he went on to capture the title.

Next up for del Potro is former world No. 1 Lleyton Hewitt, who defeated American Brian Baker by a 6-3, 4-6, 6-3, 6-4 score.

Hewitt, who captured the U.S. Open in 2001 and was the 2004 runner-up to Roger Federer, improved his impressive record at Flushing Meadows to 44-11.

Stanislas Wawrinka, the No. 9 seed, discarded Czech Radek Stepanek 7-6 (7-2), 6-3, 6-2. The 28-year-old Wawrinka will take on Karlovic in the second round.

American Rajeev Ram upset 16th-seeded Italian Fabio Fognini 6-1, 6-2, 6-2. He will play Marcel Granollers in the second round. Granollers outlasted Jurgen Zopp 6-1, 3-6, 1-6, 6-3, 6-4.

No. 17 seed Kevin Anderson, No. 20 seed Andreas Seppi and No. 21 seed Mikhail Youzhny avoided the upset bug. Anderson took down Daniel Brands 7-5, 4-6, 6-2, 6-3, Seppi beat Xavier Malisse 6-3, 3-6, 7-5, 7-5 and Youzhny got past Nicolas Mahut 6-4, 6-4, 7-6 (7-4).

Evgeny Donskoy cruised past 29th-seeded Austrian Jurgen Melzer 7-5, 6-3, 7-6 (7-3), while Russian Alex Bogomolov Jr. outlasted 24th-seeded Frenchman Benoit Paire 7-5, 2-6, 6-4, 5-7, 7-6 (7-5).

Other first-round wins came from former Australian Open runner-up and former top-10 star Marcos Baghdatis, Peter Gojowczyk, Tim Smyczek, Alexandr Dolgopolov, Somdev Devvarman.