Selective V1a Receptor Agonist Research Articles

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

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.

Effects of Selective Agonists of V1a, V2, and V1b Receptors on Sodium Transport in Rat Kidney.

The role of subtypes of vasopressin receptors in modulation of renal sodium reabsorption was studied in in vivo experiments on Wistar rats. Selective V1a receptor agonist reduced sodium reabsorption in the kidneys and expression of these receptors increased by practically 100 times. This effect was similar to the effect of furosemide. Selective V2 receptor agonist enhanced sodium reabsorption in the kidney and simultaneously increased reabsorption of solute-free water. Stimulation of V1b receptors did not affect sodium transport. Our findings attest to the key role of V1a receptors in the regulation of renal excretion of sodium ions.

Pharmacological characterization of FE 201874, the first selective high affinity rat V1Avasopressin receptor agonist

Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V1A receptors. We modified an available human selective V1A receptor agonist (F180) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation). FE 201874 exhibited nanomolar affinity for the rat V1A receptor; it was highly selective towards the rat V1B and V2 vasopressin receptors and behaved as a full V1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo. On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator-induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin.

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

To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock. Prospective, randomized, controlled laboratory experiment. University animal research facility. Twenty-four chronically instrumented sheep. After a 5-day recovery from instrumentation, sheep were randomly assigned to receive a single intravenous bolus of the selective vasopressin type 2 receptor agonist desmopressin (1 nmol·kg(-1)) or continuous intravenous infusions of arginine vasopressin (3 pmol·kg(-1)·min(-1)), the selective vasopressin type 1a receptor agonist FE 202158 (10 pmol·kg(-1)·min(-1)), or vehicle (0.9% NaCl) (n = 6 each). The von Willebrand factor antigen activity relative to hemoglobin concentration (vWF:Ag/Hb ratio) was measured at different time points during the 120-min study period. Maximal vWF:Ag/Hb ratio expressed as percentage of baseline level was significantly increased compared to vehicle-infused animals (3 ± 2%) in the desmopressin (40 ± 6%, p < .001) and arginine vasopressin groups (25 ± 4%, p < .001). The ratio for the FE 202158 group was not statistically different from the sham group (9 ± 2%, p = .208). Notably, maximal vWF:Ag/Hb ratio was lower in the FE 202158 than the arginine vasopressin group (p < .005). Unlike the mixed vasopressin type 1a receptor/vasopressin type 2 receptor agonist arginine vasopressin, the selective vasopressin type 1a receptor agonist FE 202158 does not release von Willebrand factor. Because von Willebrand factor is involved in coagulatory and inflammatory pathways during septic shock, future studies should clarify the role of the vasopressin type 2 receptor-mediated von Willebrand factor increase by arginine vasopressin and the potential benefit of selective vasopressin type 1a receptor-agonists like FE 202158.

Selective V1a agonism reduces vascular leakage and cardiopulmonary dysfunction in methicillin-resistant Staphylococcus aureus sepsis

This randomized, controlled experimental trial was performed to compare the effects of the selective V1a-receptor agonist (Phe2Orn8) vasotocin (POV) and the mixed V1a/V2-receptor agonist (Arg8) vasopressin (AVP) on vascular leakage and cardiopulmonary dysfunction associated with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced septic shock using an established ovine model.

The selective V1a receptor agonist FE 202158 does not cause von Willebrand factor release in sheep unlike arginine vasopressin

The mixed V1a/V2 receptor agonist arginine vasopressin (AVP) is recommended by the guidelines of the Surviving Sepsis Campaign as an adjunct vasopressor in norepinephrine-resistant septic shock. However, AVP may be procoagulant through V2 receptor-mediated effects (for example, von Willebrand factor (vWF) release).

Selective V1a receptor agonist FE 202158 reverses platelet-activating factor-induced hypotension, vascular leak, impaired tissue perfusion, and mortality in rats

Platelet-activating factor (PAF) is a phospholipid autacoid inducing peripheral vasodilation and vascular leak, both pathophysiological hallmarks of sepsis-induced cardiovascular dysfunction resulting in hypotension [1]. Indeed, PAF has been implicated in various animal models of sepsis and in septic humans [2]. A deficiency in the vasopressor hormone arginine vasopressin (AVP), a mixed V1a/V2 receptor agonist, also contributes to the cardiovascular dysfunction of septic shock, leading to clinical use of AVP for this condition [3,4]. These various findings led us to hypothesize that the selective V1a receptor agonist FE 202158 would be effective in a rat model of PAF-induced hypotension.

Vasopressin increases GABAergic inhibition of rat hypothalamic paraventricular nucleus neurons in vitro.

This investigation used an in vitro hypothalamic brain slice preparation and whole cell and perforated-patch recording to examine the response of magnocellular neurons in hypothalamic paraventricular nucleus (PVN) to bath applications of vasopressin (VP; 100-500 nM). In 22/38 cells, responses were characterized by an increase in the frequency of bicuculline-sensitive inhibitory postsynaptic potentials or currents with no detectable influence on excitatory postsynaptic events. Perforated-patch recordings confirmed that VP did not have an effect on intrinsic membrane properties of magnocellular PVN neurons (n = 17). Analysis of intrinsic membrane properties obtained with perforated-patch recording (n = 23) demonstrated that all of nine VP-sensitive neurons showed a rebound depolarization after transient membrane hyperpolarization from rest. By contrast, 12/14 nonresponding neurons displayed a delayed return to resting membrane potentials. Recordings of reversed inhibitory postsynaptic currents with chloride-loaded electrodes showed that responses to VP persisted in media containing glutamate receptor antagonists but were abolished in the presence of tetrodotoxin. In addition, responses were mimicked by vasotocin [Phe(2), Orn(8)], a selective V(1a) receptor agonist, and blocked by [beta-Mercapto-beta, beta-cyclopentamethylenepropionyl(1),O-Me-Tyr(2), Arg(8)]-VP (Manning compound), a V(1a)/OT receptor antagonist. Neither [deamino-Cys(1),Val(4),D-Arg(8)]-VP, a selective V(2) receptor agonist, nor oxytocin were effective. Collectively, the results imply that VP acts at V(1a) receptors to excite GABAergic neurons that are presynaptic to a population of magnocellular PVN neurons the identity of which features a unique rebound depolarization. Endogenous sources of VP may be VP-synthesizing neurons in suprachiasmatic nucleus, known to project toward the perinuclear regions of PVN, and/or the magnocellular neurons within PVN.

Vasopressin constricts outer medullary descending vasa recta isolated from rat kidneys.

Arginine vasopressin (AVP) can selectively decrease blood flow in the renal medulla, but the sites of vasoconstriction are uncertain. We have examined the effects of vasopressin-receptor agonists and antagonists on the diameters of outer medullary descending vasa recta (OMDVR), isolated and perfused in vitro. AVP can constrict OMDVR, apparently via V1a-receptors. Ablumenal AVP (10(-10)-10(-6)M) or the selective V1a-receptor agonist [Phe2, Ile3, Orn8]-vasopressin (PO-VT, 10(-8) M) constricted OMDVR focally and (at higher AVP concentrations) transiently. The V1b agonist ideamino-Cys1,D-3-(pyridyl)Ala2,Arg8)vasopressin (DP-VP; 10(-8) M) and the V2 agonist [deamino-Cys1, D-Arg8]vasopressin (DDAVP; 10(-8) M) did not constrict OMDVR. The V1a antagonist [d(CH2)5(1), O-Me-Tyr2,Arg8]vasopressin (CTM-VP, 10(-10) 10(-8) M) inhibited vasoconstriction by AVP 10(-9 M), whereas the V2 antagonist [d(CH2)5(1), D-Ile2,Ile4 Arg8]vasopressin (II-VP) at low concentration (10(-10) M) did not. V2 stimulation seems to inhibit V1a constriction of OMDVR. DDAVP prevented constriction by PO-VT (10(-8) M) applied at the same time and dilated OMDVR preconstricted with PO-VT.