VS installs your add-on as a normal Excel add-on when you start a debug session. It then launches Excel, and attaches itself as a debugger to Excel.exe. The VS debugger is quite capable of differentiating native code from .NET code.
It's been quite a while ago since I last wrote an Office add-on, but if memory serves, VS 2010 does not clean up after itself. It does not remove the add-on from Excel when the debug session terminates. You may have to do that manually. There may or may not be a context-menu item at the project node in in the solution explorer pane in VS that might uninstall it.
Just to be clear: Excel doesn't know about your debug session. Debugging is solely the purview of the VS debugger and the Win32 debugger APIs.
Debugging your add-in should be very straight-forward and should not contravene the established VS debugging experience. If you have some specific question regarding the process I would recommend asking that.