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

UNLABELLED: Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of the skeletal muscle microvascular O(2) delivery/V(O(2)) ratio (which sets the microvascular O(2) pressure, PO(2)mv). Given the pervasiveness of endothelial dysfunction in CHF, this NO-mediated dysregulation is attributed generally to eNOS. It is unknown whether nNOS-mediated PO(2)mv regulation is altered in CHF. We tested the hypothesis that CHF impairs nNOS-mediated PO(2)mv 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), PO(2)mv (phosphorescence quenching), and V(O(2)) (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 PO(2)mv ( CONTROL: 29.7 ± 1.4, SMTC: 34.4 ± 1.9 mmHg, P < 0.05) by reducing V(O(2)) (↓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 PO(2)mv ( CONTROL: 25.7 ± 1.6, SMTC: 28.6 ± 2.1 mmHg, P > 0.05), V(O(2)) 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 V(O(2)) (↓15%) in healthy rats such that PO(2)mv 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, V(O(2)), or PO(2)mv ( 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.