Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Abstract

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Trial registration: ClinicalTrials.gov NCT01000649.

Figures

Fig. 1.

Systemic vascular resistance (A) and left ventricular contractility, demonstrating the left ventricular stroke work index (LVSWI) values in relation to the individual left atrial pressure (LAP) values at this time for each group (B). *P < 0.05 vs. baseline (BL); †P < 0.05 vs. control; ‡P < 0.05 vs. arginine vasopressin (AVP). Arrow, average time point of treatment initiation in the 3 study groups. Data are represented as means ± SE; n = 6 each. SVRI, systemic vascular resistance index.

Fig. 2.

Bloodless wet-to-dry-weight ratio (A) and arterial partial pressure of oxygen (PaO2)-to-inspiratory fraction of oxygen (FiO2) ratio (B). *P < 0.05 vs. BL; †P < 0.05 vs. control; ‡P < 0.05 vs. AVP; §P < 0.05 vs. sham. Data are represented as means ± SE; n = 6 each. ALI, acute lung injury; ARDS, acute respiratory distress syndrome.

Fig. 3.

Fluid input (A) and hourly calculated net fluid balance (B). *P < 0.05 vs. BL; †P < 0.05 vs. control; ‡P < 0.05 vs. AVP. Arrow, average time point of treatment initiation in the 3 study groups. Data are represented as means ± SE; n = 6 each.

Fig. 4.

Cumulative fluid balance (A) and chest and abdominal fluid volume (B). †P < 0.05 vs. control; ‡P < 0.05 vs. AVP. Data are represented as means ± SE; n = 6 each.

Fig. 5.

Plasma levels of nitrites/nitrates (A) and tissue concentration of angiopoietin-2 (B). *P < 0.05 vs. BL; †P < 0.05 vs. control; ‡P < 0.05 vs. AVP; §P < 0.05 vs. sham. Data are represented as means ± SE; n = 6 each.