Vol. 299, Issue 3, 978-987, December 2001

A₁ Receptor Blockade Induces Natriuresis with a Favorable Renal Hemodynamic Profile in SHHF/Mcc-fa^cp Rats Chronically Treated with Salt and Furosemide

Edwin K. Jackson , Curtis K. Kost, Jr. , William A. Herzer, Glenn J. Smits and Stevan P. Tofovic

Center for Clinical Pharmacology (E.K.J., C.K.K., W.A.H., S.P.T.), Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., C.K.K., S.P.T.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and Biogen, Inc., Cambridge, Massachusetts (G.J.S.)

Our goal was to test the hypothesis that A₁ receptor blockade induces diuresis/natriuresis with a favorable renal hemodynamic/cardiac profile in aged, lean SHHF/Mcc-fa^cp rats, a rodent model of hypertensive dilated cardiomyopathy. Thirteen-month-old SHHF/Mcc-fa^cp rats were pretreated for 72 h before experiments with furosemide (100 mg/kg by gavage 72, 48, and 24 h before experiments) to mimic the clinical setting of chronic diuretic therapy and were given 1% NaCl as drinking water to reduce dehydration/sodium depletion. Animals were instrumented for measurement of systemic and renal hemodynamics, renal excretory function, and cardiac performance, and baseline values were obtained during a 30-min clearance period. Animals then received either vehicle (n = 9), BG9719 [the S-enantiomer of 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)] xanthine (also called CVT-124)] (highly selective A₁ receptor antagonist; 0.1 mg/kg bolus + 10 µg/kg/min; n = 9) or furosemide (loop diuretic; 30 mg/kg; n = 8) and measurements were repeated during four subsequent clearance periods. Both BG9719 and furosemide increased urine volume and absolute and fractional sodium excretion. BG9719 increased renal blood flow and glomerular filtration rate, but did not affect fractional potassium excretion. Furosemide decreased renal blood flow and glomerular filtration rate and increased fractional potassium excretion. Neither drug altered afterload; however, furosemide, but not BG9719, decreased preload (central venous pressure and ventricular end diastolic pressure). Neither drug altered systolic function (+dP/dt_max); however, furosemide, but not BG9719, attenuated diastolic function (decreased dP/dt_max, increased tau). In the setting of left ventricular dysfunction, chronic salt loading and prior loop diuretic treatment, selective A₁ receptor antagonists are effective diuretic/natriuretic agents with a favorable renal hemodynamic/cardiac performance profile.