Selepressin, a novel selective V1A receptor agonist: Effect on mesenteric flow and gastric mucosa perfusion in the endotoxemic rabbit.

Intestinal or mesenteric ischemia generally leads to inflammation and injury, potentially developing hypoxia, causing cell death and tissue necrosis. This in turn can lead to sepsis and shock. Conversely, following shock, the intestinal tract is a main organ to experience ischemic/reperfusion injury. Increased intestinal cell-membrane permeability through mesenteric ischemia provoking bacterial translocation and gut-barrier injury can lead to sepsis and multi-organ failure. Hypotension induced by systemic vasodilation and vascular leak in systemic inflammatory response syndrome and sepsis is countered by immediate fluid resuscitation and vasopressor administration, primarily norepinephrine (NE), with possible arginine vasopressin (AVP) supplementation, an agonist of vasopressin V1A and V2 receptors. Selepressin is a selective V1A-receptor agonist, avoiding potential V2 receptor-associated adverse effects. Selepressin, non-selective AVP, and NE effects on mesenteric blood flow (MBF) and gastric mucosa perfusion (GMP) were compared in control rabbits and a lipopolysaccharide-induced, fluid-resuscitated rabbit endotoxemia model. AVP induced a pronounced decrease in MBF and GMP in non-endotoxemic and endotoxemic rabbits, whereas the reduction after selepressin treatment was significantly less for both indicators in the endotoxemic animals. By contrast, NE increased the MBF and did not affect GMP in both groups. Selepressin and AVP induced a pronounced dose-dependent increase in mesenteric vascular resistance in non-endotoxemic and endotoxemic rabbits, tending to be less in endotoxemic animals, whereas a minor increase in both groups was observed with NE. Therefore, in this safety study, the risk for mesenteric ischemia on selepressin treatment was not inferior to AVP, being less in endotoxemic than in non-endotoxemic animals.

Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs.

Selepressin is a new selective vasopressin V1a agonist for treatment of vasodilatory hypotension in shock. Its effect on coronary and aortic blood flow, hemodynamics, and electrocardiogram as an indication of drug safety in healthy dogs was compared with arginine vasopressin (AVP). Eight dogs were fasted, anesthetized, intubated, and ventilated. Following thoracotomy, coronary and aortic blood flows were monitored, left ventricular and peripheral arterial blood pressures were measured, and electrocardiogram was recorded. Selepressin or AVP was administered by dose-escalating infusions (1-300, 0.3-100 ng · kg(-1) · min(-1), respectively). Drug formulation analysis and plasma bioanalysis confirmed exposure. For each dose level, hemodynamic parameters, drug potency, and efficacy were determined. Selepressin and AVP induced a similar increase in mean blood pressure (+13% to 18%), a moderate decrease in aortic blood flow (-40% to 45%), and a slight decrease in coronary blood flow (-16% to 22%). These vasopressors displayed similar hemodynamic characteristics, with peripheral vasoconstriction and decreased aortic blood flow being more pronounced than the increase in coronary resistance and decrease in coronary blood flow. Importantly, selepressin bore no relevant coronary ischemic liability, suggesting that V1a receptor agonists are a potential pharmacological target for treatment of vasodilatory hypotension in shock.