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Email to Some Domains Stuck in Queue (Exchange 2010)

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I'm losing my mind...

A couple weeks ago we switched ISPs and with that came a whole slew of problems with getting my Exchange server exchanging mail again. 

Two days ago everything was working fine. Inbound and outbound email was moving along nicely. No bouncebacks, no blacklists, and I even cured the bogus spam messages stuck in the queue. 

Something has gone horribly wrong since them. Although much email is clearing the queue a growing number of messages are getting stuck with 451 4.4.0 Primary target IP address responded with: "421 4.2.1 Unable to connect." Attempted to failover to alternate host, but that did not succeed...etc.

I have no idea what's wrong and I'm about to throw in the towel and find a new job. LoL... well not really, but this is very frustrating. 

Help?


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