Left Ventricular Contractile Effects of Inducible Nitric Oxide Synthase in the Human Allograft

Abstract

Background Myocardial expression of inducible (i) nitric oxide (NO) synthase (iNOS) gene has been reported in transplant recipients and in dilated cardiomyopathy. NO derived from NO donor or from coronary endothelium has previously been shown in the human heart to reduce end-systolic left ventricular (LV) pressure, especially during β-adrenoreceptor stimulation, because of earlier onset of LV relaxation. The present study investigated in transplant recipients whether a similar cardiodepressant effect could be attributed to NO derived from iNOS. Methods and Results In 16 transplant recipients who were free of rejection or graft vasculopathy, microtip LV pressure recordings, LV angiograms, and endomyocardial biopsies were obtained at annual coronary angiography. In 8 transplant recipients, microtip LV pressure recordings were obtained during intravenous dobutamine(5 μg · kg −1 · min −1 ). Competitive reverse transcription–polymerase chain reaction of iNOS mRNA was performed on the endomyocardial biopsies, and the intensity of iNOS mRNA expression was quantified on a scale ranging from 0 to 5+. All measures of baseline LV function were comparable in transplant recipients with low (≤2+) or high myocardial iNOS mRNA. During intravenous dobutamine infusion, there was a significant correlation between the abbreviation of LV electromechanical systole time (LVEST is the time from onset of QRS to dP/dt min ) and the rise of LV dP/dt max ( r =.79; P <.02). By use of a multiple regression analysis, addition of the intensity of iNOS mRNA expression as an independent variable significantly ( P <.005) improved the correlation between ΔLVEST and ΔLV dP/dt max ( P <.001; r =.97), implying a larger abbreviation of LV contraction for a similar rise in LV dP/dt max , when myocardial iNOS mRNA was higher. The larger abbreviation of LV contraction in-patients with high iNOS mRNA was associated with a decrease in LV end-systolic pressure (−31±16 mm Hg). Conclusions Myocardial iNOS gene expression in the human allograft influences the LV contractile response to β-adrenergic stimulation through earlier onset of LV relaxation and reduction of LV end-systolic pressure. These effects are similar to the LV contractile effects of NO derived from NO donor or from coronary endothelium.