The α(1D)-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

To investigate the physiological role of the α(1D)-adrenergic receptor (α(1D)-AR) subtype, we created mice lacking the α(1D)-AR (α(1D)(–/–)) by gene targeting and characterized their cardiovascular function. In α(1D)(–/–) mice, the RT-PCR did not detect any transcript of the α(1D)-AR in any tissue examined, and there was no apparent upregulation of other α(1)-AR subtypes. Radioligand binding studies showed that α(1)-AR binding capacity in the aorta was lost, while that in the heart was unaltered in α(1D)(–/–) mice. Non-anesthetized α(1D)(–/–) mice maintained significantly lower basal systolic and mean arterial blood pressure conditions, relative to wild-type mice, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30–40% in α(1D)(–/–) mice. Furthermore, the contractile response of the aorta and the pressor response of isolated perfused mesenteric arterial beds to α(1)-AR stimulation were markedly reduced in α(1D)(–/–) mice. We conclude that the α(1D)-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction

The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions

The neurohypophyseal peptide [Arg(8)]-vasopressin (AVP) exerts major physiological actions through three distinct receptor isoforms designated V1a, V1b, and V2. Among these three subtypes, the vasopressin V1b receptor is specifically expressed in pituitary corticotrophs and mediates the stimulatory effect of vasopressin on ACTH release. To investigate the functional roles of V1b receptor subtypes in vivo, gene targeting was used to create a mouse model lacking the V1b receptor gene (V1bR–/–). Under resting conditions, circulating concentrations of ACTH and corticosterone were lower in V1bR–/– mice compared with WT mice (V1bR+/+). The normal increase in circulating ACTH levels in response to exogenous administration of AVP was impaired in V1bR–/– mice, while corticotropin-releasing hormone–stimulated ACTH release in the V1bR–/– mice was not significantly different from that in the V1bR+/+ mice. AVP-induced ACTH release from primary cultured pituitary cells in V1bR–/– mice was also blunted. Furthermore, the increase in ACTH after a forced swim stress was significantly suppressed in V1bR–/– mice. Our results clearly demonstrate that the V1b receptor plays a crucial role in regulating hypothalamic-pituitary-adrenal axis activity. It does this by maintaining ACTH and corticosterone levels, not only under stress but also under basal conditions

Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats

1. The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. 2. Cerebral ischaemia was induced by administration of 900 microspheres (48 μm) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30 mg kg(−1) nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. 3. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. 4. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. 5. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain

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

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