Renal responses of the nonclipped kidney of two-kidney/one-clip Goldblatt hypertensive rats to type 1 angiotensin II receptor blockade with candesartan.
Recent studies with normal rats indicated that systemic administration of the angiotensin II (AngII) type 1 (AT1) receptor blocker candesartan elicited divergent renal hemodynamic and excretory responses depending on the magnitude of associated decreases in mean arterial pressure. To evaluate the responses to candesartan in hypertensive rats, experiments were performed 25 d after unilateral renal arterial constriction with a 0.25-mm clip. The rats were anesthetized and prepared for acute clearance experiments. Control arterial pressure responses to a bolus AngII dose (50 ng) averaged 35+/-7 mmHg; the control decreases in cortical renal blood flow (RBF), measured with laser Doppler flowmetry, were 58+/-9%. The vasoconstrictor responses to AngII were abolished by candesartan doses of 1 and 0.1 mg/kg. Treatment with 0.01 mg/kg candesartan attenuated the arterial pressure responses but did not prevent the cortical RBF decreases. The highest dose of candesartan (1 mg/kg) elicited rapid reductions in arterial pressure (from 154+/-5 to 122+/-9 mmHg), leading to associated decreases in RBF (from 5.5+/-0.2 to 4.6+/-0.4 ml/min x g) and sodium excretion (from 0.4+/-0.1 to 0.2+/-0.1 microEq/min x g). The 0.1 mg/kg dose of candesartan led to gradual reductions in arterial pressure (from 155+/-5 to 140+/-5 mmHg), and there were significant increases in RBF (from 5.4+/-0.2 to 6.8+/-0.4 ml/min x g) and decreases in renal vascular resistance. However, this dose still decreased urine flow and sodium excretion. In contrast, when candesartan was administered at 0.01 mg/kg, a dose that did not significantly decrease arterial pressure, there were significant increases in RBF (26+/-11%) and urine flow (43+/-19%) and proportionately greater increases in sodium excretion (284+/-89%) and fractional sodium excretion (351+/-99%). These data demonstrate the divergent renal hemodynamic and sodium excretory responses to AT1 receptor blockade in hypertensive rats, depending on the magnitude of decreases in arterial pressure. The lower candesartan dose, which did not cause hypotension, elicited substantial increases in RBF and proportionally much greater increases in sodium excretion, revealing the direct renal vasodilation and natriuretic effects of AT1 receptor blockade.
Cervenka
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Tulane University School of Medicine, Department of Physiology, New Orleans, Louisiana 70112, USA.
Navar
L G
LG
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000652:urine; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012039:Regional Blood Flow / Q000187:drug effects; D012964:Sodium / Q000652:urine; D013777:Tetrazoles / Q000627:therapeutic use*; D013997:Time Factors; D014664:Vasodilation
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; D012964:Sodium; C081643:candesartan