Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure

Abstract

Aims: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models.

Methods and results: In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing-induced HF, and (ii) conscious telemetric dogs with a non-invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP-induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m² , P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (-5348.6 ± 3601.3 dyn × s/cm⁵ , P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect.

Conclusions: Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP-mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

Keywords: Animal model; Heart failure; Pecavaptan; V1a receptor; V2 receptor; Vasopressin antagonist.

Figure 1

Study design using a canine tachypacing model of heart failure. AVP, arginine vasopressin.

Figure 2

Study design for cardiac output monitoring in conscious telemetric dogs. AVP, arginine vasopressin.

Figure 3

Diuretic (A) and haemodynamic (B, C) effects of pecavaptan and tolvaptan during continuous arginine vasopressin (AVP) infusion in anaesthetised heart failure dogs. All data are mean of n = 3 ± standard error of the mean. CO, cardiac output; i.v., intravenous; TPR, total peripheral resistance. *P < 0.05.

Figure 4

Diuretic (A) and haemodynamic (B–D) effects of oral treatment with pecavaptan or tolvaptan during infusion of increasing dosages of arginine vasopressin (AVP). All data are mean of n = 9 ± standard error of the mean. CI, cardiac index; CO, cardiac output; Pl, placebo; TPR, total peripheral resistance; UV, urine volume. *P < 0.05; **P < 0.01; ***P < 0.001.