Tom Jensen on the Republican primary threat:

The fact that someone like Hutchison who has generally been among the more popular Senators in the country and has always won by wide margins has been at least partially pushed out by the Tea Party is indicative of a new reality for Republican Senators- pretty much no incumbent is safe if these folks decide to target them. Among GOP Senators up for reelection next year we've found a 71% approval rating for Arizona's Jon Kyl with Republicans, a 53% approval rating for Maine's Olympia Snowe with them, a 74% approval rating for Massachusetts' Scott Brown with them, a 59% approval rating for Nevada's John Ensign with them, and an 84% approval rating for Wyoming's John Barrasso with them. 

With the exception of Barrasso every single one of those folks has worse numbers with Republicans than Murkowski did just seven months prior to losing the primary, and most of them have numbers pretty comparable to where Castle's were as well. Now obviously not every single one of these folks is going to draw a viable, well funded Tea Party opponent. But if they do any of them could be in a lot of trouble- there is pretty much no Republican incumbent immune to a challenge from the right these days and Hutchison evidently saw the writing on the wall and got out. Not saying that's the only reason she retired but I'm sure it's a piece of it or else she would have made this decision a long time ago.

Incumbents tend to be terrified of primary challenges. It has become a very powerful tool of partisan discipline in the Republican Party. Even very slight gestures of bipartisanship can be career ending.