Effects of chronic heart failure on neuronal nitric oxide synthase-mediated control of microvascular O2 pressure in contracting rat skeletal muscle

Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of the skeletal muscle microvascular O2 delivery/ ratio (which sets the microvascular O2 pressure, ). Given the pervasiveness of endothelial dysfunction in CHF, this NO-mediated dysregulation is attributed generally to eNOS. It is unknown whether nNOS-mediated regulation is altered in CHF. We tested the hypothesis that CHF impairs nNOS-mediated control. In healthy and CHF (left ventricular end diastolic pressure (LVEDP): 6 +/- 1 versus 14 +/- 1 mmHg, respectively, P < 0.05) rats spinotrapezius muscle blood flow (radiolabelled microspheres), (phosphorescence quenching), and (Fick calculation) were measured before and after 0.56 mg kg-1 i.a. of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC). In healthy rats, SMTC increased baseline (Control: 29.7 +/- 1.4, SMTC: 34.4 +/- 1.9 mmHg, P < 0.05) by reducing (?20%) without any effect on blood flow and speeded the mean response time (MRT, time to reach 63% of the overall kinetics response, Control: 24.2 +/- 2.0, SMTC: 18.5 +/- 1.3 s, P < 0.05). In CHF rats, SMTC did not alter baseline (Control: 25.7 +/- 1.6, SMTC: 28.6 +/- 2.1 mmHg, P > 0.05), at rest, or the MRT (Control: 22.8 +/- 2.6, SMTC: 21.3 +/- 3.0 s, P > 0.05). During the contracting steady-state, SMTC reduced blood flow (?15%) and (?15%) in healthy rats such that was unaltered (Control: 19.8 +/- 1.7, SMTC: 20.7 +/- 1.8 mmHg, P > 0.05). In marked contrast, in CHF rats SMTC did not change contracting steady-state blood flow, , or (Control: 17.0 +/- 1.4, SMTC: 17.7 +/- 1.8 mmHg, P > 0.05). nNOS-mediated control of skeletal muscle microvascular function is compromised in CHF versus healthy rats. Treatments designed to ameliorate microvascular dysfunction in CHF may benefit by targeting improvements in nNOS function.