Selective V1a agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Sebastian Rehberg, Yusuke Yamamoto, Linda Sousse, Eva Bartha, Collette Jonkam, Anthony K. Hasselbach, Lillian D. Traber, Robert A. Cox, Martin Westphal, Perenlei Enkhbaatar, Daniel L. Traber

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 V2-receptor stimulation induces vasodilation and procoagulant effects, a higher V1a- versus V2-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V1a-agonist Phe2-Orn8-Vasotocin (POV) is more effective than the mixed V1a-/V2-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 <em>n</em> = 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; <em>P</em> < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO2-to-FiO2 ratio) versus control animals. Highly selective V1a-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number10
DOIs
StatePublished - Nov 15 2012

Fingerprint

Vasotocin
Blood Vessels
Sheep
Sepsis
Vasopressins
Vasopressin Receptors
Arterial Pressure
Neutrophils
Hemodynamics
Angiopoietin-2
Staphylococcal Pneumonia
Lung
Water-Electrolyte Balance
Left Ventricular Dysfunction
Methicillin-Resistant Staphylococcus aureus
Septic Shock
Vasodilation
Sodium Chloride
Vascular Endothelial Growth Factor A
Peroxidase

Keywords

  • Angiopoietin-2
  • Arginine vasopressin
  • Vascular endothelial growth factor
  • Vascular leakage

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Selective V1a agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. / Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda; Bartha, Eva; Jonkam, Collette; Hasselbach, Anthony K.; Traber, Lillian D.; Cox, Robert A.; Westphal, Martin; Enkhbaatar, Perenlei; Traber, Daniel L.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 303, No. 10, 15.11.2012.

Research output: Contribution to journalArticle

Rehberg, Sebastian ; Yamamoto, Yusuke ; Sousse, Linda ; Bartha, Eva ; Jonkam, Collette ; Hasselbach, Anthony K. ; Traber, Lillian D. ; Cox, Robert A. ; Westphal, Martin ; Enkhbaatar, Perenlei ; Traber, Daniel L. / Selective V1a agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 303, No. 10.
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AU - Hasselbach, Anthony K.

AU - Traber, Lillian D.

AU - Cox, Robert A.

AU - Westphal, Martin

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N2 - 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 V2-receptor stimulation induces vasodilation and procoagulant effects, a higher V1a- versus V2-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V1a-agonist Phe2-Orn8-Vasotocin (POV) is more effective than the mixed V1a-/V2-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, PaO2-to-FiO2 ratio) versus control animals. Highly selective V1a-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

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