Exogenous nitric oxide induces protection during hemorrhagic shock

Abstract

Introduction: This study analyzed the systemic and microvascular hemodynamic changes related to increased nitric oxide (NO) availability during the early phase of hemorrhagic shock. Hemodynamic responses to hemorrhagic shock were studied in the hamster window chamber.

Materials and methods: Exogenous NO was administered in the form of nitrosothiols (nitrosylated glutathione, GSNO) and was given prior the onset of hemorrhage. Moderate hemorrhage was induced by arterial controlled bleeding of 50% of the blood volume, and the hypovolemic shock was followed over 90 min.

Results: Animals pre-treated with GSNO maintained systemic and microvascular conditions during hypovolemic hemorrhagic shock, when compared to animal treated with glutathione (GSH) or the Sham group. Low concentrations of NO released during the early phase of hypovolemic shock from GSNO mitigated arteriolar vasoconstriction, increased capillary perfusion and venous return, and improved cardiac function (recovered of blood pressure and stabilized heart rate). GSNO's effect on resistance vessels influenced intravascular pressure redistribution and blood flow, preventing tissue ischemia.

Discussion: Increases in NO availability during the early phase of hypovolemic shock could preserve cardiac function and microvascular perfusion, sustaining organ function. Direct translation into a clinical scenario may be limited, although the pathophysiological importance of NO in the early phase of hypovolemia is clearly highlighted here.

Figure 1

Relative changes in mean arterial pressure (MAP) and heart rate (HR) after pretreatment for all groups prior hemorrhage. Broken line represents baseline level. MAP (mmHg, mean ± SD) for each animal group were as follows: Baseline: SHAM, 112 ± 7, n = 6; GSH, 118 ± 6 n = 6; GSNO, 114 ± 8, n = 6. n = number of animals. HR (bpm, mean ± SD) for each animal group were as follows: Baseline: SHAM, 432 ± 34; GSH, 428 ± 36; GSNO, 434 ± 32.

Figure 2

Relative changes in arteriolar and venular diameter and blood flow after pretreatment for all groups, prior hemorrhage. Broken line represents baseline level. Diameters (μm, mean ± SD) for each animal group were as follows: Baseline: SHAM (arterioles (A): 59.1 ± 9.4, n = 42; venules (V): 59.9 ± 8.0, n = 44); GSH (A: 58.1 ± 9.4, n = 44; V: 56.8 ± 9.6, n = 47); GSNO (A: 57.9 ± 8.6, n = 43, V: 58.6 ± 8.9, n = 44). n = number of vessels studied. RBC velocities (mm/s, mean ± SD for each animal group were as follows: Baseline: SHAM (A: 4.4 ± 1.1, V: 2.4 ± 0.8); GSH (A: 4.4 ± 0.9; V: 2.4 ± 0.8); GSNO (A: 4.5 ± 0.8; V: 2.6 ± 0.6). Calculated flows (nl/s, mean ± SD) in Figures 2E (arteriolar) and 2F (venular) for each animal group were as follows: Baseline: SHAM (A: 11.5 ± 3.6; V: 6.7 ± 2.3); GSH (A: 11.5 ± 3.1; V: 6.6 ± 2.0); GSNO (A: 11.0 ± 2.5; V: 6.5 ± 2.1).

Figure 3

Relative changes in mean arterial pressure (MAP) and heart rate (HR) after hemorrhage for all groups. Broken line represents baseline level. †, P<0.05 compared to baseline; ‡, P<0.05 compared to Sham; §, P<0.05. Baseline MAP and HR are presented in the legend for Figure 1.

Figure 4

Relative changes in arteriolar and venular diameter and blood flow after pretreatment for all groups, prior hemorrhage. Broken line represents baseline level. †, P<0.05 compared to baseline; ‡, P<0.05 compared to Sham; ¥, P<0.05 compared to GSH; §, P<0.05. Baseline diameter, RBC velocity and blood flow are presented in the legend for Figure 2.

Figure 5

Changes in Functional capillary density (FCD) during hypovolemic shock post hemorrhage for all groups. †, P<0.05 compared to baseline; ‡, P<0.05 compared to Sham; ¥, P<0.05 compared to GSH; §, P<0.05.