After 18 months of holding together on issues big and small, Senate Republican leaders last week found the first major crack in their foundation as some of their most loyal colleagues defected in the face of political headwinds.

It came down to a critical test vote on a bill that delays a physician pay cut under Medicare. The measure failed to move forward last month, but on the second attempt Wednesday, Democrats brought back an ailing Sen. Edward Kennedy (Mass.) to get them to the 60 ayes they needed to overcome GOP objections and pass it. Kennedy’s return — and subsequent vote — also pushed nine of the previously opposed Republicans to buck their top leaders and side with the Democrats.

Afterward, many Senators were left wondering whether the Republicans’ difficult odds this fall, and the challenges for GOP incumbents in 2010, had taken over. And some Senators questioned whether the 18 turncoats represent a weakening of influence of Minority Leader Mitch McConnell (R-Ky.) and his No. 2, Whip Jon Kyl (Ariz.).

“The plates have shifted under the earth politically,” Sen. Byron Dorgan (D-N.D.) said. “There was clear pain on their side during the vote. … You could almost feel the air being sucked out of the chamber as they were trying to keep their guys together.”

Dorgan’s partisanship notwithstanding, he said he believed many Republican Senators are realizing they can no longer stick to the same strategy with just four months to go until Election Day. In some politically charged cases, Dorgan predicted, GOP incumbents are going to bail on their leadership to ensure their own survival.

Twenty-three Republican-held seats are up for grabs this cycle, compared with just a dozen Democratic slots. Of the 18 Republicans who supported the Medicare bill, nine are up for re-election this fall, and another five are running in 2010. Many of them are moderates, but others — such as GOP Conference Vice Chairman John Cornyn (Texas) — are conservative.

Cornyn was among the Republicans who came under intense pressure from the American Medical Association and others in his home state for his earlier vote on the Medicare measure. What’s more, his Texas colleague, Sen. Kay Bailey Hutchison, was also among the group of GOP Senators who switched sides.

Sen. Judd Gregg (R-N.H.), who sided with the GOP majority and his top leaders in voting no, said his colleagues who bucked the party made a tactical blunder that already has damaged the minority’s strength. Gregg called it “a dangerous time” for the Senate Republican Conference.

“The minority can only function if it hangs together,” Gregg said. “We can hang together or hang separately. Some of my colleagues don’t appreciate the importance of coalescing.”

Gregg pointed to the fierce lobbying campaign by the physicians groups against worried Senators as the culprit for the mass defections, and he said it could undermine what has been an effective minority led by McConnell. Asked whether the leadership is weaker for it, Gregg was unequivocal: “Absolutely. But if [the defectors] don’t understand the obvious, there’s not much we can do about it.”

For his part, McConnell’s aides sought to downplay the significance of the Medicare vote on his influence over the caucus. McConnell Communications Director Don Stewart, while arguing that the issue will have little resonance with voters in November, said any broader concerns with leadership’s strategy over the vote are misplaced.

Rather, Stewart shifted the attack on the Democrats, saying that Majority Leader Harry Reid’s (D-Nev.) unwillingness to allow Republican amendments to legislation has made compromise with the majority almost impossible. Reid’s gambit forced the GOP into an all-too-familiar spot, he said.

“It’s incredibly difficult to work out a bipartisan bill when you don’t have a chance to make amendments. When the majority is unyielding … it is just incredibly difficult to make changes” Stewart said.

But Stewart also warned that given the lack of amendment chances, the only other option open to leadership was to capitulate to Democratic demands — a course of action McConnell believes is unwise. “It’s not a good idea to accept their only offer when their only offer is to raise taxes or hurt our national security,” Stewart argued.

Kyl’s office declined to comment.

While GOP Senators uniformly agree that simply giving up isn’t the appropriate course, that sentiment isn’t stopping private conversations among Senators over what happened. Several Republicans confessed that emotions are raw and questioned whether the Conference should continue its strategy of employing their 49 votes to prevent Democrats from racking up accomplishments.

Asked whether the Conference will frankly discuss the Medicare vote in the coming days, one GOP Senator, speaking on the condition of anonymity, said “we already have.”

Cornyn, the No. 5 leader, said his vote change occurred only after Kennedy gave Democrats the 60 votes to thwart the GOP filibuster. At that point, Cornyn said, his individual objections couldn’t stop the bill from proceeding, and he didn’t want to stand in the way of helping doctors avoid a painful cut in Medicare payments.

Cornyn said he still has problems with the Democratic measure and preferred his version of the “doctors’ fix.” But Wednesday’s vote proved to be the only choice he had once Democrats had secured the votes, and one that should in no way reflect poorly on his leaders’ ability to unify the rank and file.

“Medicare is an exception,” Cornyn argued. “Like I said, we’ve been successful at sticking to 41 to protect minority rights. The alternative is to give up and have a miserable experience the rest of the year and beyond.”

Sen. John Thune (R-S.D.), the Chief Deputy Minority Whip under Kyl, agreed that the stars aligned against the GOP on the Medicare bill. Kennedy’s surprise return, coupled with an earlier decision by most House Republicans to support the bill, stacked the decks against the Conference, he said.

Still, Thune acknowledged that the Medicare vote painted a stark reality for Republicans: “It’s obvious there’s a message in this for us. If we want influence, we have to stick together — if we want to be an effective minority and keep bad things from happening. This should be a lesson to all of us.”

Sen. Bob Bennett (R-Utah), McConnell’s closest ally, said the Medicare vote was a rare event for a GOP Conference that has consistently found strength in stopping the Democratic agenda. With 49 Members, Republicans need only 41 to stop Democrats from overcoming a filibuster and passing legislation.

Bennett argued that “nobody jumped ship” until Democrats reached 60, and at that point, he said, it didn’t matter if Republicans voted on “what was best for them in their states.” He flatly dismissed the idea that the vote represented a shift in attitudes in the GOP ranks, or that McConnell and the other leaders have since lost influence.

“I don’t think it’s the beginning of a trend,” he said. “It was a one-of-a-kind situation. There were so many good things in the bill that many people wanted to be on record being for it.”

Still, some Senate Republicans believe the Medicare bill should serve as wake-up call. Blocking Democratic bills often makes sense, they said, but shouldn’t be done at all costs.

“There could have been a lot better-thought-out plan. I think a lot of undue pain was inflicted on a bunch of Members,” one Republican Senate aide said.

Sen. Bob Corker (R-Tenn.), who sided with his leadership on the Medicare bill in June but like Cornyn changed his vote on the second round, said he believed Republicans need to be choosier in picking their battles. In this case, he said, “I felt we had taken a position as a caucus that wasn’t necessarily fully hashed out.”

“Everyone needs to be a little more thoughtful when deciding to block something procedurally or not,” Corker said. “Certainly that’s not why I came to Washington. I came here to put in place some good policy.”