Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor*

Rehberg, Sebastian; Enkhbaatar, Perenlei; Rehberg, Janina; La, Erin; Ferdyan, Nicky; Qi, Steve; Wiśniewski, Kazimierz; Traber, Lillian D.; Schteingart, Claudio D.; Rivière, Pierre; Laporte, Régent; Traber, Daniel L.

doi:10.1097/ccm.0b013e31824e0fe5

Cited by 15 publications

(10 citation statements)

References 9 publications

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“…Notably, in endothelial Weibel-Palade bodies angiopoietin-2 and von Willebrand factor are stored and secreted together (12), and the release of von Willebrand factor is known to be mediated by V 2 -receptor activation (18). Recently, our group was able to demonstrate that the mixed V 1a /V 2 -agonist AVP induces the release of von Willebrand factor in doses used to treat septic shock, whereas a selective V 1a -agonist does not (37).…”

Section: Discussionmentioning

confidence: 94%

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Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Rehberg

Yamamoto

Sousse

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Section: Discussionmentioning

confidence: 94%

“…Whereas vasoconstriction is mediated by vascular V 1a -receptors (1,34), stimulation of endothelial V 2 -receptors causes vasodilation (1,17), leukocyte rolling (16), and secretion of procoagulant factors like von Willebrand factor (37). Therefore, a higher selectivity for the V 1a -versus the V 2 -receptor could be advantageous in sepsis.…”

mentioning

confidence: 98%

Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Rehberg

Yamamoto

Sousse

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…In this study, the cardiovascular safety of the selective V 1A receptor agonist selepressin [12–14] and AVP was investigated in comparison with that of the septic shock standard of care NE in a well-established rabbit model of early-stage atherosclerosis. The key observations are that the hemodynamic effects of these three vasopressors, as well as the serum concentrations obtained by incremental infusion rates, did not differ between A and NA animals, suggesting that early-stage atherosclerosis did not influence the pharmacokinetics or cardiovascular pharmacodynamics of these vasopressors.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated in this model, the cardiovascular safety of the V 1A receptor agonist selepressin (FE 202158) and AVP in comparison with NE. Selepressin is a nonameric peptide analog of AVP highly selective for the V 1A receptor in contrast with the mixed agonism of AVP at the V 1A , V 2 , and OT receptors [12–14]. While V 1A receptor activation induces vasoconstriction, maintaining AP in septic shock [15], V 2 receptor activation may have deleterious effects in such a setting, including vasodilation and release of the pro-coagulant factor VIII and von Willebrand factor [16,17].…”

Section: Introductionmentioning

confidence: 99%

Selepressin and Arginine Vasopressin Do Not Display Cardiovascular Risk in Atherosclerotic Rabbit

Boucheix¹,

Blakytny²,

Haroutunian

et al. 2016

PLoS ONE

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BackgroundSeptic shock remains associated with significant mortality rates. Arginine vasopressin (AVP) and analogs with V1A receptor agonist activity are increasingly used to treat fluid-resistant vasodilatory hypotension, including catecholamine-refractory septic shock. Clinical studies have been restricted to healthy volunteers and catecholamine-refractory septic shock patients excluding subjects with cardiac co-morbidities because of presumed safety issues. The novel selective V1A receptor agonist selepressin, with short half-life, has been designed to avoid V2 receptor-related complications and long-term V1A receptor activation. Cardiovascular safety of selepressin, AVP, and the septic shock standard of care norepinephrine was investigated in a rabbit model of early-stage atherosclerosis.MethodsAtherosclerosis was established in New Zealand White rabbits using a 1% cholesterol-containing diet. Selepressin, AVP, or norepinephrine was administered as cumulative intravenous infusion rates to atherosclerotic and non-atherosclerotic animals.ResultsSelepressin and AVP induced a slight dose-dependent increase in arterial pressure (AP) associated with a moderate decrease in heart rate, no change in stroke volume, and a moderate decrease in aortic blood flow (ABF). In contrast, norepinephrine induced a marked dose-dependent increase in AP associated with a lesser decrease in the heart rate, an increase in stroke volume, and a moderate increase in ABF. For all three vasopressors, there was no difference in responses between atherosclerotic and non-atherosclerotic animals.ConclusionFurther studies should be considered using more advanced atherosclerosis models, including with septic shock, before considering septic shock clinical trials of patients with comorbidities. Here, selepressin and AVP treatments did not display relevant cardiovascular risk in early-stage rabbit atherosclerosis.

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“…Selepressin (formerly labeled FE201258), a short-acting, selective V1a receptor agonist (12,13), may overcome these drawbacks (14). Selepressin does not stimulate release of the procoagulant van Willebrand factor (15) and reduced extravascular fluid accumulation in ovine sepsis resulting from combined lung burn injury and Pseudomonas aeruginosa pneumonia (16). Fluid extravasation is determined by Starling law, and selepressin could alter the permeability and/or could decrease the vascular surface area, which could decrease extravascular fluid loss.…”

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confidence: 97%

Selepressin in Septic Shock

Asfar

Russell

Tuckermann

et al. 2016

Critical Care Medicine

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Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor*

Cited by 15 publications

References 9 publications

Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Selepressin and Arginine Vasopressin Do Not Display Cardiovascular Risk in Atherosclerotic Rabbit

Selepressin in Septic Shock

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Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor*

Cited by 15 publications

References 9 publications

Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Selepressin and Arginine Vasopressin Do Not Display Cardiovascular Risk in Atherosclerotic Rabbit

Selepressin in Septic Shock

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Product

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Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis