A day after snapping a career-high 16-game hitting streak with an 0-for-4 night, Pence had three hits, including a shot to the first row in right field in the fourth inning. It landed near a neon orange sign that read "Hunter Pence Rocks" in bold block letters.
Pence also had a single and a double and has 18 RBIs in the last 18 games.
Miguel Tejada doubled in the fourth inning for his 1,800th hit. He is the 44th shortstop in major league history to reach the milestone and has the most RBIs (34) and hits (64) of any player at his position this season.
Lance Berkman walked before Carlos Lee popped out. Geoff Blum then walked to load the bases before Pence's second career grand slam.
Astros closer Jose Valverde pitched a scoreless ninth for his 13th save in 16 opportunities.
Aramis Ramirez's two-run homer to left-center field put Chicago up 2-0 in the fourth inning. It was his second consecutive game with a home run after going 20 games without one. Derrek Lee doubled before the homer by Ramirez.
Astros starter Chris Sampson (3-3) continued his success against the Cubs, allowing seven hits and two runs in 6 2-3 innings. Sampson is 3-0 in four career starts against Chicago with four earned runs allowed.
Sampson gave up a pair of singles with two outs in the first before retiring the next seven batters. After the home run by Ramirez in the fourth, he retired nine of the next 10.
He was replaced in the seventh inning by Doug Brocail after giving up a pair of singles and a walk.
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Ryan Dempster (5-2) allowed six hits and four runs with five strikeouts in six innings. Jose Ascanio, called up from Triple-A Iowa after Monday night's game, allowed two hits and walked two in two scoreless innings.
Kosuke Fukudome saved the Cubs from another homer with an impressive leaping catch at the right-field wall on a ball hit by Geoff Blum in the eighth inning.
Notes: Cubs 2B Mark DeRosa extended his hitting streak to a career-high 11 games with two hits. ... Berkman was 1-for-3 with a walk and a pair of strikeouts after snapping his 17-game hitting streak on Monday night. On his second strikeout, he lost the bat, sending it flying toward Carlos Lee who had to duck to avoid it.
[Associated Press; By KRISTIE RIEKEN]
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