Effect of PD 123319, an AT-2 antagonist, on renal function of the anesthetized dog: comparison with EXP 3174, an AT-1 blocker.
In anaesthetized dogs fed a diet delivering 3.5 mmol NaCl/kg/day, PD 123319 - an angiotensin (AT) II (Ang II) antagonist preferentially bound to AT-2 receptors - was infused into the renal artery for 20 min at 10 microg/kg/min, the lowest effective dose (group 1 dogs). In group 2 dogs, EXP 3174 (30 microg/kg/min) - an AT-1 blocker - was coinfused while, in group 3, EXP 3174 was infused alone. In all groups, during and immediately after infusion, increased sodium, water, and urea excretions from the infused but not from the contralateral kidney were seen. This increase was the same in all groups throughout the infusion; however, in groups infused with EXP 3174, it persisted even after the infusion had been discontinued. Thus, the total amounts of sodium and water excreted during the whole experiment were higher when EXP 3174 was present in the infusion solution than after PD 123319 alone. Moreover, an increase in glomerular filtration rate (creatinine clearance) and renal blood flow (electromagnetic flowmeter) was seen during the infusion period in groups receiving EXP 3174, but not PD 123319. Although it is possible to assume that blockade of AT-1 receptors only is responsible for the changes in excretion rates as PD 123319 is known to interact with these receptors at high concentrations, it is difficult to explain why it does not react with the same receptors responsible for changes in glomerular filtration rate and renal blood flow. An alternative explanation assumes that the excretory changes are due to blockade of both AT-1 and AT-2 receptors; the identity in effect and the absence of additivity of both antagonists could be explained by the existence of a final common pathway leading to the inhibition of the Ang II effect. This pathway could be reached either from AT-1 or AT-2 receptors.
Heller
J
J
Department of Experimental Medicine, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
Horácek
V
V
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D004338:Drug Combinations; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007269:Injections, Intra-Arterial; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D019808:Losartan; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D012079:Renal Circulation / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D004338:Drug Combinations; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; C073402:PD 123319; C066026:losartan carboxylic acid; D019808:Losartan