Effect of angiotensin II type 1 receptor blockade on conduit artery tone in subtotally nephrectomized rats.
BACKGROUND
Angiotensin II type 1 (AT1) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT1 blockade on conduit artery function in renal failure is unknown.


METHODS
The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT1 receptors quantified using autoradiography.


RESULTS
NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [125I]-Sar1,Ile8-angiotensin II binding to renal AT1 receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca2+-activated K+ channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K+ channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K+ channel agonist, was impaired in untreated but not in losartan-treated NX rats.


CONCLUSIONS
Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K+ channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT1 blockade confers functional benefits to large arteries in renal failure.
Kööbi
Peeter
P
Department of Pharmacological Sciences, Medical School, University of Tamperel, Tampere, Finland. peeter.koobi@uta.fi
Jolma
Pasi
P
Kalliovalkama
Jarkko
J
Tikkanen
Ilkka
I
Fan
Meng
M
Kähönen
Mika
M
Moilanen
Eeva
E
Pörsti
Ilkka
I
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000503:physiopathology; D007668:Kidney / Q000737:chemistry; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan