Cramer's expected bid led election ratings site Sabato's Crystal Ball to change the North Dakota race from "leans" Democratic to a "toss-up." The third-term congressman has proven a reliable Trump ally in the House and helped to craft his energy policy during the 2016 election.

Cramer's entry helps the GOP's chances of either holding on to or expanding its 51-seat majority in the Senate. Heitkamp, currently serving her first term, is one of several Senate Democrats defending seats later this year in states Trump carried.

The state's lone congressman, Rep. Kevin Cramer, a favorite of Republican leaders, is set to announce his bid for Heitkamp's seat in November's midterm elections. Cramer initially declined to run, and his expected campaign bolsters Republican hopes of taking the seat in a state President Donald Trump won easily in 2016.

Democratic Sen. Heidi Heitkamp 's path to re-election in North Dakota will get tougher on Friday evening.

"The entrance of Rep. Cramer in the North Dakota Senate race immediately puts that contest in play," said Ryan Williams, managing director of public affairs at FP1 Strategies and a GOP campaign veteran. He notes that it will further cause Democrats to "stretch their resources" as they face several difficult races.

Heitkamp always thought her re-election would prove difficult in a state Trump carried with 63 percent of the vote, compared with about 27 percent for Democrat Hillary Clinton.

"It doesn't change anything. This was always going to be a tough race," Heitkamp told CNN on Thursday. "I don't think there's any doubt about it. ... It's a state the president won by 36 percent."

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Democrats hope opposition to Trump can help them win back the House and survive a daunting Senate map in 2018. They have recently ramped up economic messaging as the response to the Republican tax law has appeared to bolster public opinion of the GOP.

Heitkamp has walked a tightrope in the Senate ahead of her election. As Democrats have mounted nearly unified opposition to many Trump policies or nominees, Heitkamp has tried to show some sense of bipartisanship.

For instance, she broke with her party in January in a doomed vote to avoid a government shutdown. When Trump went to North Dakota to make a tax reform speech in September, in part to push Heitkamp to support the GOP tax plan, she rode with him on Air Force One. She ended up voting against the tax proposal — a policy Republicans are trying to leverage into midterm support.

The president called Heitkamp a "good woman" during that appearance.

— CNBC's Elizabeth Gurdus contributed to this report.