Hyperammonaemia in V1a vasopressin receptor knockout mice caused by the promoted proteolysis and reduced intrahepatic blood volume

Abstract

An analysis of arginine-vasopressin (AVP) V1a receptor-deficient (V1aR−/−) mice revealed that glucose homeostasis and lipid metabolism were altered in the mutant mice. Here, we used V1aR−/− mice to investigate whether the deficiency of the V1a receptor, which led to altered insulin sensitivity, affected protein metabolism. The serum 3-methylhistidine levels were increased in V1aR−/− mice under feeding conditions, indicating that proteolysis was enhanced in muscle tissue from V1aR−/− mice. Furthermore, serum amino acid profiling revealed that the amino acid levels, including glycogenic and branched-chain amino acids, were reduced in V1aR−/− mice. In addition, an alanine-loading test showed that gluconeogenesis was enhanced in V1aR−/− mice. Blood ammonia, which is a by-product of amino acid catabolism, was two times higher in V1aR−/− mice without hepatopathy under the feeding and fasting conditions than in wild-type mice. Amino acid profiling also revealed that the amino acid pattern was not typical of a urea-cycle enzymatic disorder. An ammonia tolerance test and an indocyanine green elimination test showed that V1aR−/− mice had lower ammonia clearance due to a decreased intrahepatic circulating blood volume. Metabolic acidosis, including lactic-and keto-acidosis, was not observed in V1aR−/− mice. These results provide evidence that proteolysis promotes the production of glucose in the muscles of V1aR−/− mice and that hyperammonaemia is caused by promoted protein catabolism and reduced intrahepatic blood volume. Thus, our study with V1aR−/− mice indicates that AVP plays a physiological role via the V1a receptor in regulating both protein catabolism and glucose homeostasis.

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…In agreement with this finding on the role of AVP in bile salt release, V1a receptor deficiency in mice resulted in an increase in the total bile acid level in blood, and an enlargement of the cholecyst (219). No apparent sign of liver dysfunction was evident in the blood chemistry test of V1aR-KO mice, and no obstruction of extrahepatic biliary ducts was observed.…”

“…Among the biochemical markers studied in mice, blood ammonia levels were significantly higher in V1aR-KO mice than those in WT controls, but most other parameters, including AST and ALT, in V1aR-KO mice were indistinguishable from WT mice (219). The higher blood ammonia levels in V1aR-KO mice accompanied higher serum 3-methylhistidine levels, a marker of muscle protein breakdown (546), under a feeding, but not fasting, condition (219). The total amount of amino acids in serum was decreased in V1aR-KO mice under a feeding, but not fasting, condition.…”

“…Although the mechanisms for the reduced ammonia tolerance and reduced ICG clearance in V1aR-KO mice remain to be fully clarified, these may be due to decreased hepatic perfusion pressure and reduced intrahepatic circulation, secondary to the lowered systemic BP and reduced systemic circulating blood volume in V1aR-KO mice. The increases in myofibrillar protein degradation and accompanying ammonia production may contribute at least in part to the development of hyperammonemia (219). Taken together, it appears that AVP not only helps promote protein synthesis but also regulates levels of by-products of protein degradation, and blockade of the V1a receptor leads to altered protein metabolism, seen in such conditions as hyperammonemia.…”

“…In addition, V1aR-KO mice had lower levels of blood HCO 3 Ϫ concentration and carbon dioxide partial pressure (PCO 2 ), indicating that they undergo metabolic acidosis with respiratory compensation (219,246). Plasma K ϩ concentration was higher in V1aR-KO mice, whereas the urinary pH under basal conditions was lower in V1aR-KO mice than in WT mice (246).…”

New Topics in Vasopressin Receptors and Approach to Novel Drugs: Effects of Vasopressin Receptor on Regulations of Hormone Secretion and Metabolisms of Glucose, Fat, and Protein

“…These results provide evidence that proteolysis promotes the production of glucose in the muscles of V1aR-KO mice and that hyperammonemia is caused by promoted protein catabolism and reduced intrahepatic blood volume. Thus, these findings with V1aR-KO mice indicate that AVP plays a physiological role via the V1a receptor in regulating both protein catabolism and glucose homeostasis (14).…”