A(1) receptor blockade induces natriuresis with a favorable renal hemodynamic profile in SHHF/Mcc-fa(cp) rats chronically treated with salt and furosemide

Our goal was to test the hypothesis that A(1) receptor blockade induces diu resis/natriuresis with a favorable renal hemodynamic/cardiac profile in age d, lean SHHF/Mcc-fa(cp) rats, a rodent model of hypertensive dilated cardio myopathy. 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 be fore experiments) to mimic the clinical setting of chronic diuretic therapy and were given 1% NaCl as drinking water to reduce dehydration/sodium depl etion. Animals were instrumented for measurement of systemic and renal hemo dynamics, renal excretory function, and cardiac performance, and baseline v alues 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 A(1) re ceptor antagonist; 0.1 mg/kg bolus + 10 mug/kg/min; n = 9) or furosemide (l oop diuretic; 30 mg/kg; n = 8) and measurements were repeated during four s ubsequent clearance periods. Both BG9719 and furosemide increased urine vol ume and absolute and fractional sodium excretion. BG9719 increased renal bl ood flow and glomerular filtration rate, but did not affect fractional pota ssium excretion. Furosemide decreased renal blood flow and glomerular filtr ation rate and increased fractional potassium excretion. Neither drug alter ed afterload; however, furosemide, but not BG9719, decreased preload (centr al venous pressure and ventricular end diastolic pressure). Neither drug al tered systolic function (+dP/dt(max)), however, furosemide, but not BG9719, attenuated diastolic function (decreased -dP/dt(max), increased tau). In t he setting of left ventricular dysfunction, chronic salt loading and prior loop diuretic treatment, selective A(1) receptor antagonists are effective diuretic/natriuretic agents with a favorable renal hemodynamic/cardiac perf ormance profile.