Nitric oxide synthase inhibition and elevated endothelin increase oxygen consumption but do not affect glucose and...

Evidence indicates that nitric oxide (NO) suppresses myocardial oxygen consumption (MVO(2)) and regulates myocardial substrate oxidation, however data from in vivo and isolated heart preparations are conflicting. In addition, cardiac endothelin (ET-1) release has been shown to increase with inhibition of NO synthase (NOS), however the effects of ET-1 on myocardial energetics is not clear. We employed the isolated rat heart model to assess the role of NO and ET-1 on myocardial function and metabolism. Oxidation of glucose and FFA was measured using [U-(14)C]glucose and [9,10-(3)H]palmitate. NOS inhibition with N(G)-methyl-L-arginine acetate salt (L-NMMA, 50 microM), resulted in an increase in MVO(2) at a given rate of myocardial external workload, and no change in myocardial glucose or FFA oxidation. ET-1 (25 pM), which caused coronary vasoconstriction similar to that produced by L-NMMA, also increased MVO(2) without an effect on cardiac workload, or substrate oxidation, suggesting a role for ET-I in the regulation of myocardial energetics. We assessed also the effect of ET(A)/ET(B) receptor blockade (tezosentan; 5 nM) on MVO(2) and glucose and FFA oxidation and observed no effect, suggesting that basal ET-1 production does not play a role in regulating MVO2 or substrate selection. In conclusion, inhibition of NOS or the addition of ET-1 resulted in an increase in MVO2, but did not affect glucose or FFA oxidation.