Mechanisms of Nitrate Accumulation in Plasma during Pacing-Induced Heart Failure in Conscious Dogs

Abstract The goal of this study was to understand the mechanisms behind the changes in plasma NO x during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks ( n = 14) and then 240 bpm for 1 week ( n = 7). Hemodynamics, arterial blood gases, plasma NO x , and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 ± 6 to 135 ± 9 bpm), and LV dP / dt fell (2810 ± 82 to 1471 ± 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 ± 0.7 to 25 ± 0.8 mm Hg), and diastolic wall stress quadrupled (11 ± 1.3 to 43 ± 6.0 g/cm 2 , all P x (5.5 ± 1.5 to 10 ± 1.6 μM, P x through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 ± 0.32 to 1.21 ± 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NO x did not correlate with LV dP / dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NO x rose in direct relation to plasma creatinine levels ( Y = 4.8 X + 2.8, r 2 = 0.84), suggesting that the rise in plasma NO x during heart failure is due to decreased renal function not increased NO production.