I just spent several hours attempting to set my outbound SMTP traffic from Exchange 2007 to use a specific IP on my ISA Server 2006 external NIC of the 5 available. I wanted to isolate mail traffic to a specific IP address. However, it turns out that you cannot send traffic over a specific IP in ISA 2006 for any protocol, unless you install another NIC with the IP address that you want to send on. Here is a blurb that was posted by someone on Experts-Exchange after they spoke with Microsoft support on this issue (Not linking since you won’t be able to see the link):
'No version of ISA can, to date, select the IP address that will be used for outbound NAT addressing - only inbound as I have mentioned before. This facility WILL be introduced in ISA 2008 either in the beta release or in the full version. Yes, you can use an additional NIC with a public IP and route mail through that connector but long term, this is not a scaleable option'.