Inside the kidney, there are lots of AT1 receptors on the vasa recta. ATII can alter glomerular filtration rate by constricting the afferent arteriole, by contracting the mesangial cells or by constricting the efferent arteriole. In normal animals, the end result of ATII on GFR is not much change, but in hypotension the effects on the efferent arterioles are thought to predominate. (This is inferred from two experiments using small numbers of dogs which were also sodium depleted, either by dietary restriction or frusemide administration and dietary restriction. They were also anaesthetised, heparinised and subject to very invasive surgery and extracorporeal circulation.) An alternative theory is that the afferent arterioles constrict in direct response to being stretched by increased blood pressure, resulting in constant glomerular flow rates and GFR.
Acute renal failure has been reported after ACE inhibitors in man, but usually in cases of renal artery stenosis, which lowers the pressure in the afferent arteriole. Only two cases have been reported in dogs, both of which also had frusemide (one had digoxin (at toxic levels) as well). It seems likely that the frusemide was at least as much to blame as the ACE inhibitor in these cases. Both had low plasma sodium concentrations (132 & 137mM) which were probably caused by the frusemide. Since ATII helps maintain blood pressure in low sodium states, they were probably hypotensive as well (not measured). Since GFR will depend on the pressure in the afferent arteriole, in the absence of a downstream constriction, that will depend on arterial blood pressure. Thus reduced GFR will result in a reduced amount of urea filtered. However, there is some evidence that in sodium depletion active uptake of urea occurrs to try to maintain the hyperosmolarity in the medulla (normally 66% due to sodium, 33% urea). The dehydration caused by overdosing with frusemide will also cause uraemia (nb. dogs are usually given 4 - 20 times the human maintenance dose of frusemide). If the uraemia causes nausea and vomiting and stops the animal drinking, then a vicious circle will have been set up.
