Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension

Abstract

The present study is aimed at characterizing the portal, splanchnic, and systemic circulatory effects of F-180, a new long-acting analog of vasopressin (VP) with selective effect on the vascular (V 1 ) receptor, both in normal rats and in portal-hypertensive animals. In preliminary vasopressor tests, F-180 was 18 times more potent than terlipressin (TP) (164 ؎ 10 IU ؋ mmol ؊1 vs. 9.2 ؎ 1.2 IU ؋ mmol ؊1 ) and four times less potent than arginine VP (614 ؎ 25 IU ؋ mmol ؊1 ). F-180 had negligible antidiuretic potency, resulting in vascular selectivity (V 1 /V 2 ) of 858 compared with 1.0 for VP and 2.2 for TP. In portal-hypertensive rats with partial portal vein ligation (PPVL), the vasopressor effect of F-180 was 19 times that of TP on a molar basis (ED 50 F-180: 0.54 vs. TP: 10.02 nmol ؋ kg ؊1 ). At low doses (0.405 nmol ؋ kg ؊1 ), F-180 significantly reduced portal pressure (PP) (؊13.8% ؎ 6.7%) and superior mesenteric artery blood flow (SMABF) (؊25.6% ؎ 4.5%), whereas TP at 8.10 nmol ؋ kg ؊1 was required to achieve comparable splanchnic effects; however, this dose caused a significantly greater increase in mean arterial pressure (MAP) than F-180 at 0.405 nmol ؋ kg ؊1 (28.2% ؎ 2.7% vs. 8.9% ؎ 2.7% at 20 minutes; P F .05). F-180 at 0.405 nmol ؋ kg ؊1 had effects on PP and SMABF similar to a 30-minute intravenous infusion of VP at 10 mU ؋ kg ؊1 in PPVL rats, but VP caused a significantly greater elevation in systemic vascular resistance (SVR) and MAP, and more pronounced reduction in cardiac index (P F .05). (HEPATOLOGY 1998;27:351-356.)

Pharmacological Characterization of FE 202158, a Novel, Potent, Selective, and Short-Acting Peptidic Vasopressin V1aReceptor Full Agonist for the Treatment of Vasodilatory Hypotension

“…Pretreatment with the irreversible ␣-adrenergic receptor antagonist Dibenamine eliminates the sympathetic influence on arterial pressure, thereby enhancing the vasopressive effect of intravenous boluses of V 1a R agonists, thus making the vasopressive effect a sensitive and specific surrogate marker of the vasoconstrictive effect (Dekanski, 1952). In this assay, FE 202158 was as short-acting as the endogenous hormone AVP unlike the previously disclosed potent and selective V 1a R peptidic agonist F-180 (Aurell et al, 1991;Bernadich et al, 1998;Andrés et al, 2002), which exhibited a much longer duration of action. The duration of action of FE 202158 in this model is consistent with the expected plasma concentrations for a compound with low nanomolar potency in vivo.…”

“…We further hypothesized that this agonist would need to remain as short-acting a vasopressor as AVP to permit dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety. Thus, a long-acting selective V 1a R agonist such as F-180 [Hmp 1 ,Phe 2 ,Hgn 4 ,Dbu(Abu) 8 ]vasotocin, where Hmp is 2-hydroxy-3-mercaptopropionic acid and Hgn is homoglutamine] (Aurell et al, 1991;Bernadich et al, 1998;Andrés et al, 2002) would not be suitable.…”

Effects of two different dosing regimens of terlipressin on organ functions in ovine endotoxemia

“…The vasoconstrictive effects of AVP during sepsis are basically related to its agonistic effects on vascular V1 receptors [18]. Because TP has a higher selectivity for the V1 receptor than AVP (V1/V2 ratio 2.2) [19], TP may be more potent in restoring catecholamine refractory septic shock. In addition, the prolonged effective half-life of TP as compared to AVP (50 vs. 6 min) [19,20] may help in avoiding rebound arterial hypotension after discontinuation of the drug [21].…”

Effects of Blood Volume Restitution Following A Portal Hypertensive-Related Bleeding in Anesthetized Cirrhotic Rats

“…The techniques used for the hemodynamic measurements have been previously described. 9,10,14 All catheters were connected to highly sensitive pressure transducers, calibrated before each study, and hemodynamic parameters were inscribed on a multichannel recorder (MT6-PX; Lectromed, St. Peters, Jersey Channel Islands, UK). The external zero reference point was placed at the midpoint of the animal, 1 cm above the operating table.…”