Plasma nitrate accumulation during the development of pacing-induced dilated cardiac myopathy in conscious dogs is due to renal impairment

Heart failure is associated with an increase in plasma nitrate and nitrite (NOx). To date there is still some controversy regarding the causes of nitr ate accumulation during the development of heart failure. The goal of this study was to analyze the underlying mechanisms that cause accumulation of p lasma nitrates during the development of heart failure in dogs. Dogs were c hronically instrumented for measurement of hemodynamics and renal function. Hearts were paced initially at 210 bpm for 3 weeks and then at 240 until t he development of heart failure. Hemodynamics, renal function, renal blood flow, arterial blood gases, hemoglobin, plasma and urine NOx levels, and cr eatinine levels were measured weekly. Heart failure was assessed by hemodyn amic alterations, physical signs such as lethargy, ascites, cachexia, and p ostmortem evidence of cardiac hypertrophy. LVSP (from 127 +/- 3 to 106 +/- 3 mmHg), LV dP/dt (from 2658 +/- 173 to 1439 +/- 217 mmHg/s), MAP (from 101 +/- 1.9 to 83 +/- 1.8 mmHg) fell, whereas LVEDP tripled (from 6.4 +/- 0.9 to 20 +/- 2.6 mmHg), and heart rate rose (from 101 +/- 4.2 to 117 +/- 6.3 b pm), all changes P < 0.05. RBF (from 146 +/- 10 to 96 +/- 9.9 ml/min), urin e output (V) (from 0.26 +/- 0.02 to 0.16 +/- 0.02 ml/min), GFR (from 63 +/- 1.8 to 49 +/- 2 ml/min), and Na excretion (from 45 +/- 4.5 to 14 +/- 4.6 < mu>Eq/min) all decreased (P < 0.05), whereas RVR increased (from 0.68 +/- 0 .05 to 0.94 +/- 0.1 mmHg/ml/min). These changes took place during a rise in plasma NOx (from 3.7 +/- 0.5 to 16+/-3.3 <mu>M), a decrease in urine NOx ( from 33 +/- 9.9 to 8.1 +/- 4.9 muM), and a concurrent increase in NOx reabs orption (from 221 +/- 31 to 818 +/- 166 nmol/min). There was a direct corre lation between the increase in plasma NOx levels and an increase in filtere d load (r(2) = 0.97, P = 0.02), a negative correlation between NOx levels a nd NOx excretion (r(2) = 0.65 P < 0.09), and a direct correlation between p lasma NOx levels and NOx reabsorption (r(2) = 0.97, P = 0.02). These result s indicate that elevated plasma NOx during heart failure are most likely th e result of an impairment of the renal function and not increased NOx produ ction. Furthermore, without knowing changes in renal function the measureme nt of plasma NOx in and of itself is a meaningless index of NO formation. ( C) 2001 Academic Press.