I wasted so much time on this problem I felt compelled to post of info regarding it.
New install of Groupwise 7 sp2 on 2003, new system, domain, everything. Can receive incoming mail no problem, but can’t send….. get the dreaded 450 host down in most instances. This indicates a DNS problem, or a connectivity issue. DNS is right, I’m sitting on load-balanced gig copper, so that rules that out. As it turns out, it IS a DNS issue…. I can add a manual entry to my resolv.conf and then I can send to that domain. Double-checked my DNS servers, they are right, I swear it! Ah, but alas, Novell decided to stick the DNS entries in a registry entry! Lame.
http://support.novell.com/cgi-bin/search/searchtid.cgi?10053688
Gotta give props to the folks at NDSengineers.com for help with this one, albeit a bit late (moved everything back to Netware, works great) 
