LEFT-VENTRICULAR CONTRACTILE EFFECTS OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN THE HUMAN ALLOGRAFT

Background Myocardial expression of inducible (i) nitric oxide (NO) sy nthase (iNOS) gene has been reported in transplant recipients and in d ilated cardiomyopathy. NO derived from NO donor or from coronary endot helium has previously been shown in the human heart to reduce end-syst olic left ventricular (LV) pressure, especially during beta-adrenorece ptor stimulation, because of earlier onset of LV relaxation. The prese nt study investigated in transplant recipients whether a similar cardi odepressant effect could be attributed to NO derived from iNOS. Method s and Results In 16 transplant recipients who were free of rejection o r graft vasculopathy, microtip LV pressure recordings, LV angiograms, and endomyocardial biopsies were obtained at annual coronary angiograp hy. In 8 transplant recipients, microtip LV pressure recordings were o btained during intravenous dobutamine (5 mu g.kg(-1).min(-1)). Competi tive reverse transcription-polymerase chain reaction of iNOS mRNA was performed on the endomyocardial biopsies, and the intensity of iNOS mR NA expression was quantified on a scale ranging from 0 to 5+. All meas ures of baseline LV function were comparable in transplant recipients with low (less than or equal to 2+) or high myocardial iNOS mRNA. Duri ng intravenous dobutamine Infusion, there was a significant correlatio n 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, ad dition of the intensity of iNOS mRNA expression as an independent vari able significantly (P < .005) improved the correlation between Delta L VEST and Delta LV dP/dt(max)) (P < .001 r = .97), implying a larger ab breviation of LV contraction for a similar rise in LV dP/dt(max), when myocardial iNOS mRNA was higher. The larger abbreviation of LV contra ction in-patients with high iNOS mRNA was associated with a decrease I n LV end-systolic pressure (-31 +/- 16 mm Hg). Conclusions Myocardial iNOS gene expression in the human allograft influences the LV contract ile response to beta-adrenergic stimulation through earlier onset of L V 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.