AT1 Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 41; no. 6; pp. 1364 - 1371
• Main Authors: Kööbi, Peeter, Kalliovalkama, Jarkko, Jolma, Pasi, Rysä, Jaana, Ruskoaho, Heikki, Vuolteenaho, Olli, Kähönen, Mika, Tikkanen, Ilkka, Fan, Meng, Ylitalo, Pauli, Pörsti, Ilkka
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.06.2003; Hagerstown, MD Lippincott
• Subjects: Angiotensin Receptor Antagonists; Animals; Aorta - chemistry; Atrial Natriuretic Factor - biosynthesis; Atrial Natriuretic Factor - blood; Atrial Natriuretic Factor - genetics; Biological and medical sciences; Blood Pressure; Cardiovascular system; Endothelium, Vascular - physiology; Heart Ventricles - metabolism; In Vitro Techniques; Losartan - therapeutic use; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - pathology; Mesenteric Arteries - physiopathology; Natriuretic Peptide, Brain - biosynthesis; Natriuretic Peptide, Brain - genetics; Nephrectomy; Peptidyl-Dipeptidase A - analysis; Pharmacology. Drug treatments; Potassium Channel Blockers - pharmacology; Potassium Channels, Calcium-Activated - antagonists & inhibitors; Protein Precursors - blood; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renal Insufficiency - drug therapy; Renal Insufficiency - pathology; Renal Insufficiency - physiopathology; RNA, Messenger - biosynthesis; Vasoconstriction; Vasodilation - drug effects; Vasodilator agents. Cerebral vasodilators; Kidney disease; Adenosine; Urinary system disease; Small dimension; Vasodilator agent; Rat; Rodentia; kidney failure; Non peptide compound; Biological activity; Artery; arteries ·receptors, angiotensin II; endothelium-derived factors; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Losartan; angiotensin II; potassium channels; Renal failure; Aorta; Arterial pressure; Angiotensin antagonist
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000073782.30879.16

ABSTRACT—It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8-week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6-fold after nephrectomy, and ventricular synthesis of atrial and B-type natriuretic peptides was increased 2.2-fold and 1.7-fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium-mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium-activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham-operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate-sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodelingWall-to-lumen ratio was increased without change in wall cross-sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin-angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.