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

Abstract

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.

Figure 1. Effects of SMTC and l-NAME on the 50% recovery time from the hypotensive effects of rapid ACH infusions

Data are means ± SEM. *P < 0.05 versus control and SMTC for healthy (n = 7) and CHF (n = 6) rats.

Figure 2. Average raw profiles for healthy (left panel, n = 14) and CHF (right panel, n = 12) rats during control and SMTC conditions

Uni-directional SEM bars are shown for clarity. Time ‘0’ represents the onset of contractions.

Figure 3. Effects of nNOS inhibition with SMTC on resting and contracting steady-state spinotrapezius muscle in healthy (n = 14) and CHF (n = 12) rats

Data are means ± SEM. *P < 0.05 versus control.

Figure 4. Effects of nNOS inhibition with SMTC on resting and contracting steady-state spinotrapezius muscle blood flow in healthy (n = 14) and CHF (n = 12) rats

Data are means ± SEM. *P < 0.05 versus control, †P < 0.05 versus healthy.

Figure 5. Effects of nNOS inhibition with SMTC on contracting steady-state spinotrapezius muscle blood flow (Δ blood flow), () and the blood flow/ relationship (Δ blood flow/, which dictates the steady-state )

Note how nNOS inhibition did not alter contracting Δ blood flow/ in healthy (n = 14) or CHF (n = 12) rats; but these values were achieved very differently (i.e. blood flow and reductions in healthy rats compared to no changes in CHF rats). Data are means ± SEM. #P < 0.05 versus zero.